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The advancement of HIV treatment has led to increased life expectancy. However, people living with HIV (PLWH) are at a higher risk of developing colorectal cancers. Chronic inflammation has a key role in oncogenesis, affecting the initiation, promotion, transformation, and advancement of the disease. PLWH are prone to opportunistic infections that trigger inflammation. It has been documented that 15-20% of cancers are triggered by infections, and this percentage is expected to be increased in HIV co-infections. The incidence of parasitic infections such as helminths, with Ascariasis being the most common, is higher in HIV-infected individuals. Cancer cells and opportunistic infections drive a cascade of inflammatory responses which assist in evading immune surveillance, making them survive longer in the affected individuals. Their survival leads to a chronic inflammatory state which further increases the probability of oncogenesis. This review discusses the key inflammatory signaling pathways involved in disease pathogenesis in HIV-positive patients with colorectal cancers. The possibility of the involvement of co-infections in the advancement of the disease, along with highlights on signaling mechanisms that can potentially be utilized as therapeutic strategies to prevent oncogenesis or halt cancer progression, are addressed.

Background: Breast cancer is the most common type of cancer in women, and vast research is being conducted throughout the world for the treatment of this malignancy by natural products using various computational approaches. Xanthohumol, a prenylated flavonoid, is known for its anticancer activity; however, the mechanism behind its action is still in the preliminary stage., Methods: The current study aimed to analyze the efficacy of xanthohumol compared to the currently available anticancer drugs targeting phosphoinositide-3-kinase (PI3K), serine/threonine kinase (AKT) receptors, and human epidermal growth factor receptor 2 (HER2) for breast cancer treatment through in silico analysis., Results: The result revealed that the target compound showed significant binding affinity to targets within the PI3K, AKT, and HER2 signaling pathways with a binding energy of -7.5, -7.9, and -7.9 kcal/mol, respectively. Further prediction studies were then made concerning this compound's absorption, distribution, metabolism, and excretion (ADME) as well as drug-likeness properties, resulting in its oral bioavailability with only a single violation of Lipinski's rule of five., Conclusions: The finding revealed the ability of xanthohumol to bind with multiple cancer cell signaling molecules including PI3K, AKT kinase, and HER2. The current novel study opened the door to advancing research into the management and treatment of breast cancer., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Gupta, Sharma, Chandra, Panwar, Bhardwaj, Altwaijry, Alsfouk, Dlamini, Afzal, Altamimi, Khan and Mishra.)

Gastric cancer (GC) is one of the major causes of cancer deaths worldwide. The disease is seldomly detected early and this limits treatment options. Because of its heterogeneous and complex nature, the disease remains poorly understood. The literature supports the contribution of the gut microbiome in the carcinogenesis and chemoresistance of GC. Drug resistance is the major challenge in GC therapy, occurring as a result of rewired metabolism. Metabolic rewiring stems from recurring genetic and epigenetic factors affecting cell development. The gut microbiome consists of pathogens such as H. pylori, which can foster both epigenetic alterations and mutagenesis on the host genome. Most of the bacteria implicated in GC development are Gram-negative, which makes it challenging to eradicate the disease. Gram-negative bacterium co-infections with viruses such as EBV are known as risk factors for GC. In this review, we discuss the role of microbiome-induced GC carcinogenesis. The disease risk factors associated with the presence of microorganisms and microbial dysbiosis are also discussed. In doing so, we aim to emphasize the critical role of the microbiome on cancer pathological phenotypes, and how microbiomics could serve as a potential breakthrough in determining effective GC therapeutic targets. Additionally, consideration of microbial dysbiosis in the GC classification system might aid in diagnosis and treatment decision-making, taking the specific pathogen/s involved into account.

Worldwide, oesophageal cancer is the sixth leading cause of deaths related to cancer and represents a major health concern. Sub-Saharan Africa is one of the regions of the world with the highest incidence and mortality rates for oesophageal cancer and most of the cases of oesophageal cancer in this region are oesophageal squamous cell carcinoma (OSCC). The development and progression of OSCC is characterized by genomic changes which can be utilized as diagnostic or prognostic markers. These include changes in the expression of various genes involved in signaling pathways that regulate pathways that regulate processes that are related to the hallmarks of cancer, changes in the tumor mutational burden, changes in alternate splicing and changes in the expression of non-coding RNAs such as miRNA. These genomic changes give rise to characteristic profiles of altered proteins, transcriptomes, spliceosomes and genomes which can be used in clinical applications to monitor specific disease related parameters. Some of these profiles are characteristic of more aggressive forms of cancer or are indicative of treatment resistance or tumors that will be difficult to treat or require more specialized specific treatments. In Sub-Saharan region of Africa there is a high incidence of viral infections such as HPV and HIV, which are both risk factors for OSCC. The genomic changes that occur due to these infections can serve as diagnostic markers for OSCC related to viral infection. Clinically this is an important distinction as it influences treatment as well as disease progression and treatment monitoring practices. This underlines the importance of the characterization of the molecular landscape of OSCC in order to provide the best treatment, care, diagnosis and screening options for the management of OSCC.

Cervical cancer (CC) is the primary cause of female cancer fatalities in low-middle-income countries (LMICs). Persistent infections from the human papillomavirus (HPV) can result in cervical cancer. However, numerous different factors influence the development and progression of cervical cancer. Transcriptomic knowledge of the mechanisms with which HPV causes cervical cancer pathogenesis is growing. Nonetheless, there is an existing gap hindering the development of therapeutic approaches and the improvement of patient outcomes. Alternative splicing allows for the production of numerous RNA transcripts and protein isoforms from a single gene, increasing the transcriptome and protein diversity in eukaryotes. Cancer cells exhibit astounding transcriptome modifications by expressing cancer-specific splicing isoforms. High-risk HPV uses cellular alternative splicing events to produce viral and host splice variants and proteins that drive cancer progression or contribute to distinct cancer hallmarks. Understanding how viruses utilize alternative splicing to drive pathogenesis and tumorigenesis is essential. Although research into the role of miRNAs in tumorigenesis is advancing, the function of other non-coding RNAs, including lncRNA and circRNA, has been understudied. Through their interaction with mRNA, non-coding RNAs form a network of competing endogenous RNAs (ceRNAs), which regulate gene expression and promote cervical cancer development and advancement. The dysregulated expression of non-coding RNAs is an understudied and tangled process that promotes cervical cancer development. This review will present the role of aberrant alternative splicing and immunosuppression events in HPV-mediated cervical tumorigenesis, and ceRNA network regulation in cervical cancer pathogenesis will also be discussed. Furthermore, the therapeutic potential of splicing disruptor drugs in cervical cancer will be deliberated.

Malignant mesotheliomas (MM) are hard to treat malignancies with poor prognosis and high mortality rates. This cancer is highly misdiagnosed in Sub-Saharan African countries. According to literature, the incidence of MM is likely to increase particularly in low-middle-income countries (LMICs). The burden of asbestos-induced diseases was estimated to be about 231,000 per annum. Lack of awareness and implementation of regulatory frameworks to control exposure to asbestos fibers contributes to the expected increase. Exposure to asbestos fibers can lead to cancer initiation by several mechanisms. Asbestos-induced epigenetic modifications of gene expression machinery and non-coding RNAs promote cancer initiation and progression. Furthermore, microbiome-epigenetic interactions control the innate and adaptive immunity causing exacerbation of cancer progression and therapeutic resistance. This review discusses epigenetic mechanisms with more focus on miRNAs and their interaction with the microbiome. The potential use of epigenetic alterations and microbiota as specific biomarkers to aid in the early detection and/or development of therapeutic targets is explored. The advancement of combinatorial therapies to prolong overall patient survival or possible eradication of MM especially if it is detected early is discussed.

About 15% of all human cancers have a viral etiology. Although progress has been made, understanding the viral oncogenesis and associated molecular mechanisms remain complex. The discovery of cellular miRNAs has led to major breakthroughs. Interestingly, viruses have also been discovered to encode their own miRNAs. These viral, small, non-coding miRNAs are also known as viral-miRNAs (v-miRNAs). Although the function of v-miRNAs largely remains to be elucidated, their role in tumorigenesis cannot be ignored. V-miRNAs have also been shown to exploit the cellular machinery to benefit viral replication and survival. Although the discovery of Hepatitis C virus (HCV), and its viral miRNAs, is a work in progress, the existence of HPV-, EBV-, HBV-, MCPyV- and KSHV-encoded miRNA has been documented. V-miRNAs have been shown to target host factors to advance tumorigenesis, evade and suppress the immune system, and deregulate both the cell cycle and the apoptotic machinery. Although the exact mechanisms of v-miRNAs-induced tumorigenesis are still unclear, v-miRNAs are active role-players in tumorigenesis, viral latency and cell transformation. Furthermore, v-miRNAs can function as posttranscriptional gene regulators of both viral and host genes. Thus, it has been proposed that v-miRNAs may serve as diagnostic biomarkers and therapeutic targets for cancers with a viral etiology. Although significant challenges exist in their clinical application, emerging reports demonstrate their potent role in precision medicine. This review will focus on the roles of HPV-, HCV-, EBV-, HBV-, MCPyV-, and KSHV-produced v-miRNAs in tumorigenesis, as effectors in immune evasion, as diagnostic biomarkers and as novel anti-cancer therapeutic targets. Finally, it will discuss the challenges and opportunities associated with v-miRNAs theranostics in precision oncology.

Immune response has been shown to play an important role in defining patient prognosis and response to cancer treatment. Tumor-induced immunosuppression encouraged the recent development of new chemotherapeutic agents that assists in the augmentation of immune responses. Molecular mechanisms that tumors use to evade immunosurveillance are attributed to their ability to alter antigen processing/presentation pathways and the tumor microenvironment. Cancer cells take advantage of normal molecular and immunoregulatory machinery to survive and thrive. Cancer cells constantly adjust their genetic makeup using several mechanisms such as nucleotide excision repair as well as microsatellite and chromosomal instability, thus giving rise to new variants with reduced immunogenicity and the ability to continue to grow without restrictions. This review will focus on the central molecular signaling pathways involved in immunosuppressive cells and briefly discuss how cancer cells evade immunosurveillance by manipulating antigen processing cells and related proteins. Secondly, the review will discuss how these pathways can be utilized for the implementation of precision medicine and deciphering drug resistance.

Background: Urinary tract infection (UTI) in pregnancy is associated with significant morbidity for both the mother and the foetus. The aim of this study was to determine the prevalence of UTI, urinary bacterial susceptibility, and resistance patterns among pregnant women with a possible UTI at Rahima Moosa Mother and Child Hospital (RMMCH) in Johannesburg., Methods: In this retrospective study, we analysed mid-stream urine culture and antibiotic susceptibility data from both inpatients and outpatients of pregnant women who attended RMMCH from January 2017 to December 2017. Data were collected from patients' files and then matched with urine microscopy, sensitivity and culture (MC&S) results from the National Health Laboratory Services (NHLS) data., Results: Urine microscopy, cultures and sensitivities were performed on 1984 specimens belonging to pregnant women who presented with symptoms and/or signs of a UTI. A total of 333 patients (16.8%) had positive bacterial cultures. Escherichia coli (E. coli) was the commonest bacterial isolate (49.9%). Other microorganisms isolated included Klebsiella species (14.4%), Enterococcus faecalis (12.9%) and coagulase-negative staphylococci (CoNS); (8.9%). Approximately 98% of organisms were sensitive to cephalexin. Cefuroxime (95.2%), ceftriaxone/cefotaxime (94.4%) and nitrofurantoin (81.9%) demonstrated antimicrobial effectiveness as indicated. Most isolates were resistant to ampicillin/amoxicillin (84.4%), Trimethoprim/Sulfamethoxazole (55.6%) and amoxicillin-clavulanic acid (50.2%)., Conclusion: E. coli was the commonest pathogen causing UTIs in pregnancy with Enterococcus faecalis increasing in prevalence. The choice of antimicrobial therapy in pregnancy should be determined according to sensitivity and resistance and foeto-maternal safety., Competing Interests: The authors declare that they have no financial or personal relationships that may have inappropriately influenced them in writing this article., (© 2022. The Authors.)

MicroRNAs (miRNA) are small non-coding RNAs that are 20-23 nucleotides in length, functioning as regulators of oncogenes or tumor suppressor genes. They are molecular modulators that regulate gene expression by suppressing gene translation through gene silencing/degradation, or by promoting translation of messenger RNA (mRNA) into proteins. Circulating miRNAs have attracted attention as possible prognostic markers of cancer, which could aid in the early detection of the disease. Epithelial to mesenchymal transition (EMT) has been implicated in tumorigenic processes, primarily by promoting tumor invasiveness and metastatic activity; this is a process that could be manipulated to halt or prevent brain metastasis. Studies show that miRNAs influence the function of EMT in glioblastomas. Thus, miRNA-related EMT can be exploited as a potential therapeutic target in glioblastomas. This review points out the interrelation between miRNA and EMT signatures, and how they can be used as reliable molecular signatures for diagnostic purposes or targeted therapy in glioblastomas.

Angiogenesis is one of the hallmarks of cancer, and the establishment of new blood vessels is vital to allow for a tumour to grow beyond 1-2 mm in size. The angiogenic switch is the term given to the point where the number or activity of the pro-angiogenic factors exceeds that of the anti-angiogenic factors, resulting in the angiogenic process proceeding, giving rise to new blood vessels accompanied by increased tumour growth, metastasis, and potential drug resistance. Long noncoding ribonucleic acids (lncRNAs) have been found to play a role in the angiogenic switch by regulating gene expression, transcription, translation, and post translation modification. In this regard they play both anti-angiogenic and pro-angiogenic roles. The expression levels of the pro-angiogenic lncRNAs have been found to correlate with patient survival. These lncRNAs are also potential drug targets for the development of therapies that will inhibit or modify tumour angiogenesis. Here we review the roles of lncRNAs in regulating the angiogenic switch. We cover specific examples of both pro and anti-angiogenic lncRNAs and discuss their potential use as both prognostic biomarkers and targets for the development of future therapies.

Precision oncology can be defined as molecular profiling of tumors to identify targetable alterations. Emerging research reports the high mortality rates associated with type II endometrial cancer in black women and with prostate cancer in men of African ancestry. The lack of adequate genetic reference information from the African genome is one of the major obstacles in exploring the benefits of precision oncology in the African context. Whilst external factors such as the geography, environment, health-care access and socio-economic status may contribute greatly towards the disparities observed in type II endometrial and prostate cancers in black populations compared to Caucasians, the contribution of African ancestry to the contribution of genetics to the etiology of these cancers cannot be ignored. Non-coding RNAs (ncRNAs) continue to emerge as important regulators of gene expression and the key molecular pathways involved in tumorigenesis. Particular attention is focused on activated/repressed genes and associated pathways, while the redundant pathways (pathways that have the same outcome or activate the same downstream effectors) are often ignored. However, comprehensive evidence to understand the relationship between type II endometrial cancer, prostate cancer and African ancestry remains poorly understood. The sub-Saharan African (SSA) region has both the highest incidence and mortality of both type II endometrial and prostate cancers. Understanding how the entire transcriptomic landscape of these two reproductive cancers is regulated by ncRNAs in an African cohort may help elucidate the relationship between race and pathological disparities of these two diseases. This review focuses on global disparities in medicine, PCa and ECa. The role of precision oncology in PCa and ECa in the African population will also be discussed.

Cancer is a multifaceted disease that involves several molecular mechanisms including changes in gene expression. Two important processes altered in cancer that lead to changes in gene expression include altered microRNA (miRNA) expression and aberrant splicing events. MiRNAs are short non-coding RNAs that play a central role in regulating RNA silencing and gene expression. Alternative splicing increases the diversity of the proteome by producing several different spliced mRNAs from a single gene for translation. MiRNA expression and alternative splicing events are rigorously regulated processes. Dysregulation of miRNA and splicing events promote carcinogenesis and drug resistance in cancers including breast, cervical, prostate, colorectal, ovarian and leukemia. Alternative splicing may change the target mRNA 3'UTR binding site. This alteration can affect the produced protein and may ultimately affect the drug affinity of target proteins, eventually leading to drug resistance. Drug resistance can be caused by intrinsic and extrinsic factors. The interplay between miRNA and alternative splicing is largely due to splicing resulting in altered 3'UTR targeted binding of miRNAs. This can result in the altered targeting of these isoforms and altered drug targets and drug resistance. Furthermore, the increasing prevalence of cancer drug resistance poses a substantial challenge in the management of the disease. Henceforth, molecular alterations have become highly attractive drug targets to reverse the aberrant effects of miRNAs and splicing events that promote malignancy and drug resistance. While the miRNA-mRNA splicing interplay in cancer drug resistance remains largely to be elucidated, this review focuses on miRNA and alternative mRNA splicing (AS) events in breast, cervical, prostate, colorectal and ovarian cancer, as well as leukemia, and the role these events play in drug resistance. MiRNA induced cancer drug resistance; alternative mRNA splicing (AS) in cancer drug resistance; the interplay between AS and miRNA in chemoresistance will be discussed. Despite this great potential, the interplay between aberrant splicing events and miRNA is understudied but holds great potential in deciphering miRNA-mediated drug resistance.

The use of nanocarriers for biomedical applications has been gaining interests from researchers worldwide for the delivery of therapeutics in a controlled manner. These "smart" vehicles enhance the dissolution and the bioavailability of drugs and enable their delivery to the target site. Taking the potential toxicity into consideration, the incorporation of natural "green" materials, derived from plants or microbial sources, in the nanocarriers fabrication, improve their safety and biocompatibility. These green components can be used as a mechanical platform or as targeting ligand for the payload or can play a role in the synthesis of nanoparticles. Several studies reported the use of green based nanocarriers for the treatment of diseases such as cancer. This review article provides a critical analysis of the different types of green nanocarriers and their synthesis mechanisms, characterization, and their role in improving drug delivery of anticancer drugs to achieve precision cancer treatment. Current evidence suggests that green-based nanocarriers can constitute an effective treatment against cancer.

The influence of the naturally occurring population of microbes on various human diseases has been a topic of much recent interest. Not surprisingly, continuously growing attention is devoted to the existence of a gut brain axis, where the microbiota present in the gut can affect the nervous system through the release of metabolites, stimulation of the immune system, changing the permeability of the blood-brain barrier or activating the vagus nerves. Many of the methods that stimulate the nervous system can also lead to the development of cancer by manipulating pathways associated with the hallmarks of cancer. Moreover, neurogenesis or the creation of new nervous tissue, is associated with the development and progression of cancer in a similar manner as the blood and lymphatic systems. Finally, microbes can secrete neurotransmitters, which can stimulate cancer growth and development. In this review we discuss the latest evidence that support the importance of microbiota and peripheral nerves in cancer development and dissemination.

Cervical cancer is a public health problem and has devastating effects in low-to-middle-income countries (LTMICs) such as the sub-Saharan African (SSA) countries. Infection by the human papillomavirus (HPV) is the main cause of cervical cancer. HIV positive women have higher HPV prevalence and cervical cancer incidence than their HIV negative counterparts do. Concurrent HPV/HIV infection is catastrophic, particularly to African women due to the high prevalence of HIV infections. Although various studies show a relationship between HPV, HIV and cervical cancer, there is still a gap in the knowledge concerning the precise nature of this tripartite association. Firstly, most studies show the relationship between HPV and cervical cancer at genomic and epigenetic levels, while the transcriptomic landscape of this relationship remains to be elucidated. Even though many studies have shown HPV/HIV dual viral pathogenesis, the dual molecular oncoviral effects on the development of cervical cancer remains largely uncertain. Furthermore, the effect of highly active antiretroviral therapy (HAART) on the cellular splicing machinery is unclear. Emerging evidence indicates the vital role played by host splicing events in both HPV and HIV infection in the development and progression to cervical cancer. Therefore, decoding the transcriptome landscape of this tripartite relationship holds promising therapeutic potential. This review will focus on the link between cellular splicing machinery, HPV, HIV infection and the aberrant alternative splicing events that take place in HIV/HPV-associated cervical cancer. Finally, we will investigate how these aberrant splicing events can be targeted for the development of new therapeutic strategies against HPV/HIV-associated cervical cancer.

Globally, HIV/AIDS and cancer are increasingly public health problems and continue to exist as comorbidities. The sub-Saharan African region has the largest number of HIV infections. Malignancies previously associated with HIV/AIDS, also known as the AIDS-defining cancers (ADCs) have been documented to decrease, while the non-AIDS defining cancer (NADCs) are on the rise. On the other hand, cancer is a highly heterogeneous disease and precision oncology as the most effective cancer therapy is gaining attraction. Among HIV-infected individuals, the increased risk for developing cancer is due to the immune system of the patient being suppressed, frequent coinfection with oncogenic viruses and an increase in risky behavior such as poor lifestyle. The core of personalised medicine for cancer depends on the discovery and the development of biomarkers. Biomarkers are specific and highly sensitive markers that reveal information that aid in leading to the diagnosis, prognosis and therapy of the disease. This review focuses mainly on the risk assessment, diagnostic, prognostic and therapeutic role of various cancer biomarkers in HIV-positive patients. A careful selection of sensitive and specific HIV-associated cancer biomarkers is required to identify patients at most risk of tumour development, thus improving the diagnosis and prognosis of the disease.

Alternative splicing (AS) is a method of increasing the number of proteins that the genome is capable of coding for, by altering the pre-mRNA during its maturation. This process provides the ability of a broad range of proteins to arise from a single gene. AS events are known to occur in up to 94% of human genes. Cumulative data have shown that aberrant AS functionality is a major factor in human diseases. This review focuses on the contribution made by aberrant AS functionality in the development and progression of esophageal cancer. The changes in the pattern of expression of alternately spliced isoforms in esophageal cancer can be used as diagnostic or prognostic biomarkers. Additionally, these can be used as targets for the development of new treatments for esophageal cancer., Competing Interests: Aristotelis Chatziioannou reports being the CEO of e-NIOS APPLICATIONS PC, during the conduct of the study; and that as CEO and CSO they direct the research activities of e-NIOS APPLICATIONS PC, outside the submitted work. The authors report no other potential conflicts of interest in this work., (© 2021 Dlamini et al.)

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.•RT 2 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., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2021 The Author(s). Published by Elsevier B.V.)

During development, as tissues expand and grow, they require circulatory, lymphatic, and nervous system expansion for proper function and support. Similarly, as tumors arise and develop, they also require the expansion of these systems to support them. While the contribution of blood and lymphatic systems to the development and progression of cancer is well known and is targeted with anticancer drugs, the contribution of the nervous system is less well studied and understood. Recent studies have shown that the interaction between neurons and a tumor are bilateral and promote metastasis on one hand, and the formation of new nerve structures (neoneurogenesis) on the other. Substances such as neurotransmitters and neurotrophins being the main actors in such interplay, it seems reasonable to expect that alternative splicing and the different populations of protein isoforms can affect tumor-derived neurogenesis. Here, we report the different, documented ways in which neurons contribute to the development and progression of cancer and investigate what is currently known regarding cancer-neuronal interaction in several specific cancer types. Furthermore, we discuss the incidence of alternative splicing that have been identified as playing a role in tumor-induced neoneurogenesis, cancer development and progression. Several examples of changes in alternative splicing that give rise to different isoforms in nerve tissue that support cancer progression, growth and development have also been investigated. Finally, we discuss the potential of our knowledge in alternative splicing to improve tumor diagnosis and treatment.

Prostate cancer (PCa) is one of the leading causes of deaths in men globally. This is a heterogeneous and complex disease that urgently warrants further insight into its pathology. Developed countries have thus far the highest PCa incidence rates, with comparatively low mortality rates. Even though PCa in the Asian population seems to have high incidence and mortality rates, the African countries are emerging as the focal center for this disease. It has also been reported that the Sub-Saharan (SSA) countries have both the highest incidence and mortality rates. To date, few studies have reported the link between PCa and African populations. Adequate evidence is still missing to fully comprehend this relationship. While it has been brought to attention that racial, geographical and socioeconomic status are contributing factors, men of African descent across the globe, irrespective of their geographical position have higher PCa incidence and mortality rates compared to their white counterparts. To date, hormone therapy is the mainstay treatment of PCa, while the dysregulation of androgen receptor (AR) signaling is a hallmark of PCa. One of the emerging problems with this therapeutic approach is resistance to antiandrogens, and that AR splice isoforms implicated in the progression of PCa lack the therapeutic ligand-binding domain (LBD) target. AR splice variants targeted therapy is emerging and in clinical trials. Leveraging PCa transcriptomics is key towards PCa precision medicine. The aim of this review is to outline the PCa epidemiology globally and in Africa, PCa associated risk factors, discuss AR signaling and PCa mechanisms, the role of dysregulated splicing in PCa as novel prognostic indicators and therapeutic targets., Competing Interests: None., (AJCR Copyright © 2021.)

Head and neck cancers include cancers that originate from a variety of locations. These include the mouth, nasal cavity, throat, sinuses, and salivary glands. These cancers are the sixth most diagnosed cancers worldwide. Due to the tissues they arise from, they are collectively named head and neck squamous cell carcinomas (HNSCC). The most important risk factors for head and neck cancers are infection with human papillomavirus (HPV), tobacco use and alcohol consumption. The genetic basis behind the development and progression of HNSCC includes aberrant non-coding RNA levels. However, one of the most important differences between healthy tissue and HNSCC tissue is changes in the alternative splicing of genes that play a vital role in processes that can be described as the hallmarks of cancer. These changes in the expression profile of alternately spliced mRNA give rise to various protein isoforms. These protein isoforms, alternate methylation of proteins, and changes in the transcription of non-coding RNAs (ncRNA) can be used as diagnostic or prognostic markers and as targets for the development of new therapeutic agents. This review aims to describe changes in alternative splicing and ncRNA patterns that contribute to the development and progression of HNSCC. It will also review the use of the changes in gene expression as biomarkers or as the basis for the development of new therapies.

It has been estimated that worldwide up to 10% of all human cancers are the result of viral infection, with 7.2% of all cancers in the developed world have a viral aetiology. In contrast, 22.9% of infections in the developing world are the result of viral infections. This number increases to 30% in Sub-Saharan Africa. The ability of viral infections to induce the transformation of normal cells into cancerous cells is well documented. These viruses are mainly Hepatitis B and C viruses, Epstein Barr virus, Human papillomavirus and Human Cytomegalovirus. They can induce the transformation of normal cells into cancer cells and this may be the underlying cause of carcinogenesis in many different types of cancer. These include liver cancer, lymphoma, nasopharyngeal cancer, cervical cancer, gastric cancer and even glioblastoma. Long non-coding RNAs (LncRNAs) can function by regulating the expression of their target genes by controlling the stability of the target mRNAs or by blocking translation of the target mRNA. They can control transcription by regulating the recruitment of transcription factors or chromatin modification complexes. Finally, lncRNAs can control the phosphorylation, acetylation, and ubiquitination of proteins at the post-translation level. Thus, altering protein localisation, function, folding, stability and ultimately expression. In addition to these functions, lncRNA also regulate alternate pre-mRNA splicing in ways that contribute to the formation of tumours. This mainly involves the interaction of lncRNAs with splicing factors, which alters their activity and function. The ability of lncRNAs to regulate the stability, expression and function of tumour suppressor proteins is important in the development and progression of cancers. LncRNAs also regulate viral replication and latency, leading to carcinogenesis. These factors all make lncRNAs ideal targets for the development of biomarker arrays that can be based on secreted lncRNAs leading to the development of affordable non-invasive biomarker tests for the stage specific diagnosis of tumours. These lncRNAs can also serve as targets for the development of new anticancer drug treatments., Competing Interests: None., (AJCR Copyright © 2021.)

Global cancer incidence and mortality are on the rise. Although cancer is fundamentally a non-communicable disease, a large number of cancers are known to have a viral aetiology. A high burden of infectious agents (Human immunodeficiency virus (HIV), human papillomavirus (HPV), hepatitis B virus (HBV)) in certain Sub-Saharan African countries drives the rates of certain cancers. About one-third of all cancers in Africa are attributed to infection. Seven viruses have been identified with carcinogenic characteristics, namely the HPV, HBV, Hepatitis C virus (HCV), Epstein-Barr virus (EBV), Human T cell leukaemia virus 1 (HTLV-1), Kaposi's Sarcoma Herpesvirus (KSHV), and HIV-1. The cellular splicing machinery is compromised upon infection, and the virus generates splicing variants that promote cell proliferation, suppress signalling pathways, inhibition of tumour suppressors, alter gene expression through epigenetic modification, and mechanisms to evade an immune response, promoting carcinogenesis. A number of these splice variants are specific to virally-induced cancers. Elucidating mechanisms underlying how the virus utilises these splice variants to maintain its latent and lytic phase will provide insights into novel targets for drug discovery. This review will focus on the splicing genomics, epigenetic modifications induced by and current therapeutic strategies against HPV, HBV, HCV, EBV, HTLV-1, KSHV and HIV-1.

Gynaecological cancers are attributed to the second most diagnosed cancers in women after breast cancer. On a global scale, cervical cancer is the fourth most common cancer and the most common cancer in developing countries with rapidly increasing mortality rates. Human papillomavirus (HPV) infection is a major contributor to the disease. HPV infections cause prominent cellular changes including alternative splicing to drive malignant transformation. A fundamental characteristic attributed to cancer is the dysregulation of cellular transcription. Alternative splicing is regulated by several splicing factors and molecular changes in these factors lead to cancer mechanisms such as tumour development and progression and drug resistance. The serine/arginine-rich (SR) proteins and heterogeneous ribonucleoproteins (hnRNPs) have prominent roles in modulating alternative splicing. Evidence shows molecular alteration and expression levels in these splicing factors in cervical cancer. Furthermore, aberrant splicing events in cancer-related genes lead to chemo- and radioresistance. Identifying clinically relevant modifications in alternative splicing events and splicing variants, in cervical cancer, as potential biomarkers for their role in cancer progression and therapy resistance is scrutinised. This review will focus on the molecular mechanisms underlying the aberrant splicing events in cervical cancer that may serve as potential biomarkers for diagnosis, prognosis, and novel drug targets.

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., Competing Interests: Declaration of Competing Interest The authors report no declarations of interest., (Copyright © 2021 The Authors. Published by Elsevier B.V. All rights reserved.)

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., (Copyright © 2020 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

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 RT 2 Profiler™ PCR Array. The expression changes of 84 genes key to the cell cycle pathway in humans following EFV treatment was examined. The R 2 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., Competing Interests: CONFLICTS OF INTEREST Authors have no conflicts of interest to declare.

Alternative splicing is deregulated in cancer and alternatively spliced products can be linked to cancer hallmarks. Targeting alternative splicing could offer novel effective cancer treatments. We investigated the effects of the crude extract of a South African medicinal plant, Cotyledon orbiculata , on cell survival of colon (HCT116) and esophageal (OE33 and KYSE70) cancer cell lines. Using RNASeq, we discovered that the extract interfered with mRNA regulatory pathways. The extract caused hnRNPA2B1 to splice from the hnRNPB1 to the hnRNPA2 isoform, resulting in a switch in the BCL2L1 gene from Bcl-xL to Bcl-xS causing activation of caspase-3-cleavage and apoptosis. Similar splicing effects were induced by the known anti-cancer splicing modulator pladienolide B. Knockdown of hnRNPB1 using siRNA resulted in decreased cell viability and increased caspase-3-cleavage, and over-expression of hnRNPB1 prevented the effect of C. orbiculata extract on apoptosis and cell survival. The effect of the hnRNPA2/B1 splicing switch by the C. orbiculata extract increased hnRNPA2B1 binding to Bcl-xl/s, BCL2, MDM2, cMYC, CD44, CDK6, and cJUN mRNA. These findings suggest that apoptosis in HCT116, OE33, and KYSE cancer cells is controlled by switched splicing of hnRNPA2B1 and BCL2L1, providing evidence that hnRNPB1 regulates apoptosis. Inhibiting this splicing could have therapeutic potential for colon and esophageal cancers. Targeting hnRNPA2B1 splicing in colon cancer regulates splicing of BCL2L1 to induce apoptosis. This approach could be a useful therapeutic strategy to induce apoptosis and restrain cancer cell proliferation and tumor progression. Here, we found that the extract of Cotyledon orbiculata , a South African medicinal plant, had an anti-proliferative effect in cancer cells, mediated by apoptosis induced by alternative splicing of hnRNPA2B1 and BCL2L1 ., (Copyright © 2020 Makhafola, Mbele, Yacqub-Usman, Hendren, Haigh, Blackley, Meyer, Mongan, Bates and Dlamini.)

Endometrial cancer, also known as uterine cancer, is the most common gynaecological malignancy with burgeoning incidence and mortality rates globally. Racial disparity, socioeconomic and geographical differences are important determinants of endometrial cancer incidence and mortality. Endometrial cancer is mainly categorised as type I and type II. Although less prevalent, type II is the most aggressive form of the disease and typically diagnosed at a late stage, contributing to higher mortality. Black women are at higher risk of developing aggressive, type II disease. Type I tumours are related to higher levels of circulating estrogen with lower-grade tumours that have a good prognosis and frequently related to PTEN mutations. In comparison, type II tumours are estrogen-independent, typically have poor prognosis and associated with the p53, HER2, PPP2R1A, FBXW7 and PIK3R1 mutations. The risk of developing type II malignancy is higher in women with Lynch syndrome as a result of mutations in the MMR gene family. Genetic modifications contribute to aberrant alternative splicing events that are related to tumour development, progression and resistance to therapy. Alternative splicing events are rapidly emerging as potential biomarkers and therapeutic targets. Type II endometrial cancer lacks targeted therapy and biomarkers for novel therapeutic strategies. Recent advances have illustrated a number of molecular targets that are currently explored for the treatment of advanced, late-stage endometrial cancer. The aim of this review is to outline 1) the epidemiology of type II endometrial cancer in black women, 2) discuss the correlated risk factors that contribute to the development of type II endometrial cancer and 3) the associated molecular mechanisms and genetic factors underlying the disease, and 4) aberrant splicing events and biomarkers with therapeutic potential as novel drug targets., Competing Interests: None., (AJCR Copyright © 2020.)

Oesophageal cancer (OC) is an aggressive neoplasm that manifests in the gastrointestinal tract and is the result of numerous factors that can contribute to the development of the disease. These may include old age, nutritional deficiencies, oesophageal obstruction and food ingestion difficulties. Environmental factors serve a large role in increasing the risk of developing OC. Two factors that serve an increasing risk of developing OC are the use of tobacco and the consumption of alcohol. Genetic factors also exhibit a large effect on the risk of developing OC, for example, the causative genes in Black Africans differ from other races. OC is 3-4 times more common among men than women. OC has been previously reported in >450 000 individuals worldwide, and its incidence is increasing. The current review compares OC in low to middle-income countries with developed countries. The incidence of OC, particularly squamous cell carcinoma (SCC) is high in low and middle-income countries. In developed countries, the incidence of SCC is low compared with adenocarcinoma. The majority of OC cases are diagnosed in the late stages of the disease, leading to high mortality rates. The current review aimed to discuss factors that contribute to the development of this disease in different geographical areas and genetic mechanisms governing these findings. The current review also aims to discuss the preventative treatment options for the disease, and also discusses the diagnosis and surveillance in five LMICs, including South Africa, China, Tanzania, India and Brazil., (Copyright: © Hull et al.)

Mycobacterium tuberculosis (Mtb), is one of the foremost organisms causing mortality in humans, and has been for most of human history. When faced with an infection the human immune system is ordinarily very competent in killing both extracellular and intracellular bacilli. However, Mtb is able to evade the host immune system and is even able to establish a persistent infectious reservoir by "hiding" in the immune cells of the host. While the mechanisms by which the bacteria accomplishes this are not fully understood, it is known that the bacterium can subvert cellular processes in cells such as macrophages that prevent the lysis of the bacteria or the cell undergoing apoptosis. They are also able to interfere with immune cell signalling. One of the greatest effects that Mtb has is too alter the transcriptome of the macrophage. An easy way for the bacterium to accomplish this is to alter the alternative splicing patterns of the host. This can lead to a large change in the population of different protein isoforms, some of which have very different functions when compared to the original protein. At the same time the long history of Mtb infecting humans have led to specific immune reactions that occur in the host immune system in order to fight the infection. Many of these specific reactions involve new isoforms of host defence proteins. In this way the human host can use alternate splicing to create new isoforms of immune- related proteins that are more effective in defending against Mtb., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Cervical cancer is a malignant tumour that occurs in the cervix and is classified into two histological types, adenocarcinoma and squamous cell carcinoma (SCC); SCC is more common and accounts for 70% of all cases. In 2018 there were ~569,000 new cases of cervical cancer diagnosed worldwide and ~311,000 deaths were attributed to cervical cancer. Of these, between 84 and 90% occurred in low- and middle-income countries (LMICs) such as South Africa, India, China and Brazil. The most common cause of cervical cancer is persistent infection caused by the sexually transmitted human papilloma virus. Other factors that contribute to the incidence of cervical cancer include geography, traditional practices and beliefs, the screening levels, socioeconomic status, healthcare access, public awareness, use of oral contraceptives, smoking and co-infection with HIV. An estimated 11 million women from LMICs will be diagnosed with cervical cancer in the next 10-20 years. The aim of this review was to explore various types of genetic and epigenetic factors that influence the development, progression or suppression of cervical cancer., (Copyright: © Hull et al.)

Acute myeloid leukemia (AML) is the most common form of acute leukaemia and has the highest mortality rate. Screening for mutations in patients with AML has shown that in many cases genes carrying mutations are involved in the alternate splicing of mRNA. These include members of the Serine Arginine (SR) family of splicing factors, as well as components of the spliceosome. Mutations in associated genes also affect the function of members of the heterogeneous nuclear ribonucleoproteins (hnRNPs). These mutations in splicing factors can lead to changes in the expression of different isoforms whose splicing is controlled by these splicing factors. These different isoforms may have completely different functions, for example, members of the BCl-2 family are alternately spliced to give rise to pro and anti-apoptotic members. Mutations in the splicing factors that control the splicing of these mRNAs can lead to changes in the expression level of these isoforms. In this review we will examine the mechanics of the regulation of the various splice isoforms and how this drives the development of tumors. This information is pertinent for drug discovery, and the splicing factors with the most promise for pharmacological control will be discussed., Competing Interests: None., (AJCR Copyright © 2020.)

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., (Copyright © 2020 Marima, Hull, Dlamini and Penny.)

Artificial intelligence (AI) and machine learning have significantly influenced many facets of the healthcare sector. Advancement in technology has paved the way for analysis of big datasets in a cost- and time-effective manner. Clinical oncology and research are reaping the benefits of AI. The burden of cancer is a global phenomenon. Efforts to reduce mortality rates requires early diagnosis for effective therapeutic interventions. However, metastatic and recurrent cancers evolve and acquire drug resistance. It is imperative to detect novel biomarkers that induce drug resistance and identify therapeutic targets to enhance treatment regimes. The introduction of the next generation sequencing (NGS) platforms address these demands, has revolutionised the future of precision oncology. NGS offers several clinical applications that are important for risk predictor, early detection of disease, diagnosis by sequencing and medical imaging, accurate prognosis, biomarker identification and identification of therapeutic targets for novel drug discovery. NGS generates large datasets that demand specialised bioinformatics resources to analyse the data that is relevant and clinically significant. Through these applications of AI, cancer diagnostics and prognostic prediction are enhanced with NGS and medical imaging that delivers high resolution images. Regardless of the improvements in technology, AI has some challenges and limitations, and the clinical application of NGS remains to be validated. By continuing to enhance the progression of innovation and technology, the future of AI and precision oncology show great promise., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2020 The Author(s).)

Breast cancer is a common malignancy among women worldwide. Regardless of the economic status of a country, breast cancer poses a burden in prevention, diagnosis and treatment. Developed countries such as the U.S. have high incidence and mortality rates of breast cancer. Although low incidence rates are observed in developing countries, the mortality rate is on the rise implying that low- to middle-income countries lack the resources for preventative screening for early detection and adequate treatment resources. The differences in incidence between countries can be attributed to changes in exposure to environmental risk factors, behaviour and lifestyle factors of the different population groups. Genomic modifications are an important factor that significantly alters the risk profile of breast tumourigenesis. The incidence of early-onset breast cancer is increasing and evidence shows that early onset of breast cancer is far more aggressive than late onset of the disease; possibly due to the difference in genetic alterations or tumour biology. Alternative splicing is a pivotal factor in the progressions of breast cancer. It plays a significant role in tumour prognosis, survival and drug resistance; hence, it offers a valuable option as a therapeutic target. In this review, the differences in breast cancer incidence and mortality rates in developed countries will be compared to low- to middle-income countries. The review will also discuss environmental and lifestyle risk factors, and the underlying molecular mechanisms, genetic variations or mutations and alternative splicing that may contribute to the development and novel drug targets for breast cancer., Competing Interests: None., (AJCR Copyright © 2020.)

Retinoblastoma binding protein 6 (RBBP6) is a cancer-related protein that has been implicated in the regulation of cell cycle and apoptosis. RBBP6 isoform 1 has been demonstrated to interact with two tumour suppressors, p53 and pRB. Isoform 1 been shown to regulate p53 through its ubiquitin ligase activity, thus implicating in cell cycle regulation and apoptosis. Isoforms 1 and 2 are multidomain proteins containing a domain with no name (DWNN) domain, a Zinc Finger, a RING Finger, an Rb-binding domain and a p53-binding domain. The RBBP6 isoform 3 comprises the DWNN domain only. Isoform 4 lacks the Rb-binding domain but its role is less understood. RBBP6 isoform 3 has been reported as a cell cycle regulator with anticancer potential. There have been several studies that have clearly demonstrated that RBBP6 may be an important biomarker for cancer diagnosis and a potential drug target for cancer treatment. This work focused on differential expression of RBBP6 transcripts in different cancers, providing detailed analysis of their potential as diagnostic biomarkers for different cancers. These cancers include breast, liver, cervical and colon carcinomas. The expression of RBBP6 transcripts may further provide better understanding of the role of the RBBP6 in carcinogenesis and cell homeostasis.

RBBP6 is a novel gene encoding splicing-associated proteins. There are 3 protein isoforms (isoforms 1-3). RBBP6 isoforms 1 has been shown to interact with both p53 and Rb. It also plays a role in the induction of apoptosis and the regulation of the cell cycle. The expression of RBBP6 has been documented in several cancers but RBBP6 expression in cervical cancer has not been well studied. The aim of this study was to establish expression levels and tissue distribution of the RBBP6 gene products at both protein and messenger RNA (mRNA) levels in cervical cancer by immunocytochemistry and in situ hybridization (ISH). A link between RBBP6 expression, apoptosis, and cervical cancer progression was also investigated. RBBP6 mRNA was expressed in the nuclei and cytoplasm of normal and tumour cervical epithelium. In general, expression was high in the cytoplasm and nuclei of moderately differentiated and invasive carcinoma. Immunolabelling results were confirmed by image analysis and ISH experiments. Apoptosis assays using TUNEL correlated with the expression of the RBBP6 gene in all examined cases. This is the first report on the abundant expression of RBBP6 in cervical cancer and its involvement in the malignant progression of cervical cancer. Because of the high expression and corresponding pro-apoptotic activity observed in cervical cancer cells in this study, we suggest that RBBP6 is involved in the malignant progression of cervical cancer. RBBP6 proteins can therefore be targeted for therapeutic interventions against cervical cancer., Competing Interests: Declaration of conflicting interests:The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

TSPO is a receptor involved in the regulation of cellular proliferation, apoptosis and mitochondrial functions. Previous studies showed that the expression of TSPO protein correlated positively with tumour malignancy and negatively with patient survival. The aim of this study was to determine the transcription of Tspo mRNA in various types of normal and cancer tissues. In situ hybridization was performed to localise the Tspo mRNA in various human normal and cancer tissues. The relative level of Tspo mRNA was quantified using fluorescent intensity and visual estimation of colorimetric staining. RT-PCR was used to confirm these mRNA levels in normal lung, lung cancer, liver cancer, and cervical cancer cell lines. There was a significant increase in the level of transcription in liver, prostate, kidney, and brain cancers while a significant decrease was observed in cancers of the colon and lung. Quantitative RT-PCR confirmed that the mRNA levels of Tspo are higher in a normal lung cell line than in a lung cancer cell line. An increase in the expression levels of Tspo mRNA is not necessarily a good diagnostic biomarker in most cancers with changes not being large enough to be significantly different when detected by in situ hybridisation.

Cancer is a leading cause of mortality and morbidity worldwide and second only to cardiovascular diseases. Cancer is a challenge in African countries because generally there is limited funding available to deal with the cancer epidemic and awareness and this should be prioritised and all possible resources should be utilized to prevent and treat cancer. The current review reports on the role of African medicinal plants in the treatment of cancer, and also outlines methodologies that can also be used to achieve better outcomes for cancer treatment. This review outlines African medicinal plants, isolated compounds and technologies that can be used to advance cancer research. Chemical structures of isolated compounds have an important role in anti-cancer treatments; new technologies and methods may assist to identify more properties of African medicinal plants and the treatment of cancer. In conclusion, African medicinal plants have shown their potential as enormous resources for novel cytotoxicity compounds. Finally it has been noted that the cytotoxicity depends on the chemical structural arrangements of African medicinal plants compounds., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Diabetes mellitus (DM) is a non-communicable, metabolic disorder that affects 416 million individuals worldwide. Type 2 diabetes contributes to a vast 85-90% of the diabetes incidences while 10-15% of patients suffer from type 1 diabetes. These two predominant forms of DM cause a significant loss of functional pancreatic β-cell mass causing different degrees of insulin deficiency, most likely, due to increased β-cell apoptosis. Treatment options involve the use of insulin sensitisers, α-glucosidase inhibitors, and β-cell secretagogues which are often expensive, limited in efficacy and carry detrimental adverse effects. Cost-effective options for treatment exists in the form of herbal drugs, however, scientific validations of these widely used medicinal plants are still underway. Alternative splicing (AS) is a co-ordinated post-transcriptional process in which a single gene generates multiple mRNA transcripts which results in increased amounts of functionally different protein isoforms and in some cases aberrant splicing leads to metabolic disease. In this review, we explore the association of AS with metabolic alterations in DM and the biological significance of the abnormal splicing of some pathogenic diabetes-related genes. An understanding of the molecular mechanism behind abnormally spliced transcripts will aid in the development of new diagnostic, prognostic and therapeutic tools., (© 2017 Society for Endocrinology.)

Oesophageal cancer ranks as the sixth most common malignancy in the world, and recent evidence has shown that its incidence is increasing. ACBPs (Acyl-coA binding proteins) act as intracellular carrier-proteins for medium to long chain acyl-coA, mediating fatty acid transport to the mitochondrion for ß-oxidation. ACBPs are also believed to be putative ligands of PBR (peripheral benzodiazepine receptor), and once they bind to this receptor they facilitate mitochondrial membrane permeabilization, presumably favouring apoptosis. The main aim of the study was to establish the expression patterns of 1- Acyl-coA binding proteins (1-ACBP), B- Acyl-coA binding proteins (B-ACBP), and peripheral bezodiazepine receptor (PBR) in oesophageal cancer, and to link their roles with the disease. In situ hybridization and quantitative real-time PCR methods were performed to determine localization and the expression levels of the three genes in oesophageal cancer. All three genes illustrated substantial up-regulation within the malignant tissue sections as compared to normal oesophageal sections, all three transcripts localized specifically to mast cells, plasma cells and lymphocytes in diseased and normal tissue section. In the diseased tissue B-ACBP and 1-ACBP mRNA localized to endothelial cells of blood vessels in the submucosa. B-ACBP also localized to the nucleus of squamous epithelial cells. PBR localization was indicated in tumour islands of invasive tissue sections. Quantitative RT-PCR also indicated that the expression levels of PBR were higher as compared to the ACBP genes expression in tumours. These results show that 1-ACBP, B-ACBP and PBR play a role in the pathogenesis of oesophageal tumours and possibly in carcinogenic angiogenesis.

High-throughput genotyping has enabled discovery of genetic variants associated with an increased risk of developing prostate cancer using genome-wide association studies (GWAS). The goal of this study was to associate GWAS information of patients with primary organ-confined and metastatic prostate cancer using gene expression data and to identify molecular networks and biological pathways enriched for genetic susceptibility variants involved in the 2 disease states. The analysis revealed gene signatures for the 2 disease states and a gene signature distinguishing the 2 patient groups. In addition, the analysis revealed molecular networks and biological pathways enriched for genetic susceptibility variants. The discovered pathways include the androgen, apoptosis, and insulinlike growth factor signaling pathways. This analysis established putative functional bridges between GWAS discoveries and the biological pathways involved in primary organ-confined and metastatic prostate cancer., Competing Interests: DECLARATION OF CONFLICTING INTERESTS: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Apoptosis is normally kept under strict control by a range of regulators and inhibitors, and loss of this regulation strongly directs tumour progression. The novel RBBP6 gene has been implicated in apoptosis due to its ability to bind both p53 and Rb, as well as its structural and functional affiliation to ubiquitin and E3 ligases. RBBP6 has already been implicated as an important marker for cancer diagnosis and many studies have investigated its suitability as a potential genetic target for cancer treatment. This study endeavoured to assess the transcription and expression patterns and levels of the three isoforms of RBBP6 in colon cancer and to evaluate its potential role in apoptosis. Colorimetric and fluorescent in situ hybridisation was used to localise the mRNA and the different RBBP6 mRNA transcripts in normal and cancerous colon tissue. Immunohistochemistry was used to localise different RBBP6 isoforms in normal and cancerous tissues. All the RBBP6 transcripts were found to be up-regulated in cancerous tissues, and the expression levels of the RBBP6-1 and RBBP6-3 (DWNN) proteins were also found to be increased in cancerous structures. Higher levels of apoptosis were detected in the same regions as those that showed increased expression of RBBP6-3 transcript and protein, whereas Bcl-2 was down-regulated in these areas. In contrast we observed an increase in Bcl-2 levels in areas where RBBP6-3 was down-regulated. These results suggest that the RBBP6-3 isoform may be involved in promoting apoptosis in cancerous cells.

RT-PCR is an invaluable tool for the detection and characterization of mRNA. Cancer cell lines are treated with crude plant extracts and RNA is extracted and purified with DNase prior to RT-PCR. RT-PCR first-strand cDNA synthesis is done using random primers and can be refrigerated at 4 °C. PCR from the stored cDNA is performed using transcript-specific primers and electrophoresed on a molecular grade agarose gel to separate the splice variants.

MicroRNAs (miRNAs) are short noncoding RNAs that regulate pathophysiological processes that suppress gene expression by binding to messenger RNAs. These biomolecules can be used to study gene regulation and protein expression, which will allow better understanding of many biological processes such as cell cycle progression and apoptosis that control the fate of cells. Several pathways have also been implicated to be involved in kidney diseases such as Transforming Growth Factor-β, Mitogen-Activated Protein Kinase signaling, and Wnt signaling pathways. The discovery of miRNAs has provided new insights into kidney pathologies and may provide new innovative and effective therapeutic strategies. Research has demonstrated the role of miRNAs in a variety of kidney diseases including renal cell carcinoma, diabetic nephropathy, nephritic syndrome, renal fibrosis, lupus nephritis and acute pyelonephritis. MiRNAs are implicated as playing a role in these diseases due to their role in apoptosis, cell proliferation, differentiation and development. As miRNAs have been detected in a stable condition in different biological fluids, they have the potential to be tools to study the pathogenesis of human diseases with a great potential to be used in disease prognosis and diagnosis. The purpose of this review is to examine the role of miRNA in kidney disease.