MicroRNA and alternative mRNA splicing events in cancer drug response/resistance : potent therapeutic targets

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 30UTR 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 30UTR 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.This research was funded by the South African Medical Research Council (SAMRC).The South African Medical Research Council (SAMRC)https://www.mdpi.com/journal/biomedicinesam2022Maxillo-Facial and Oral SurgeryMedical OncologySurger

Microbiomics in collusion with the nervous system in carcinogenesis : diagnosis, pathogenesis and treatment

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.The South African Medical Research Council (SAMRC).https://www.mdpi.com/journal/microorganismsam2022Surger

Do perforated gastric ulcers require routine intra-operative biopsy?

A research report submitted to the Faculty of Health Sciences, University of the Witwatersrand, in fulfillment of the requirements for the degree of Master of Medicine (General Surgery). Johannesburg, 2018.Background. It is recommended that perforated peptic ulcers undergo intraoperative biopsy to rule out an occult malignancy. Furthermore, there is a recommendation for routine postoperative outpatient follow-up gastroscopy to examine and biopsy residual ulcers. In view of the low incidence of malignancy (<1%) and the changing epidemiology of perforated gastric ulcers, evidenced by an increased incidence of patients younger than the typical gastric cancer age group (60-79 years), presenting with this condition, the question is raised: is it necessary to biopsy all perforated gastric ulcers at the time of surgical repair? Objectives To determine the demographics and potential risk factors for perforated peptic ulcers as well as the incidence of occult malignancy in these ulcers. Methods A retrospective study was carried out from 1 January 2010 to 31 December 2011 in three public university affiliated hospitals in Johannesburg. Data analysis was conducted using Microsoft ExcelTM spreadsheet tools. The descriptive analysis was carried out as follows. First, categorical variables were summarized by frequency and percentage tabulations and illustrated by means of bar charts. Second, continuous variables were summarized by mean, standard deviation, median, and interquartile range and their distribution illustrated by histograms. The X2 test was used to assess the association between age category, gender, and ulcer location. Fischer’s exact test was used for 2x2 tables and where the requirements for the X2 test could not be met. Finally, the Phi coefficient and Cramer’s V were used to measure the strength of association. Results During the study period 171 patients underwent operative management of perforated ulcers. Most were young (20 – 39 years) with a median age of 42 years, 54.4% of the ulcers were gastric ulcers and intra-operative biopsy was performed in 72% of cases. Of these 25 (26.88 %) were adequate biopsies. Of the inadequate biopsies 97.62% had no mucosa in the biopsy specimen. 90.2% of the biopsies were benign and 2.4% malignant. One case of H. pylori infection was noted. There was a nonattendance rate of 72% for follow-up gastroscopy. For the perforated gastric ulcers, the most prevalent risks factors include smoking (55.9%), NSAIDS (40.0%), and alcohol (34.4%). Conclusion A South African protocol for the management of perforated peptic ulcers, recognizing that most patients do not return for follow-up gastroscopy, should be developed. Intra-operatively biopsy should be performed in view of the low patient follow-up rate, however the biopsy specimen must include mucosa to improve the diagnostic rate of malignancy and H. pylori.LG201

Colorectal cancer genetics, incidence and risk factors : in search for targeted therapies

Each year, colorectal cancers (CRCs) affect over a quarter of a million people. The risk of developing CRC in industrialized nations is approximately 5%. When the disease is localised, treatment success rates range from 70–90%; however, advanced CRC has a high mortality rate, consistently ranking in the top three causes of cancer-related deaths. There is a large geographic difference in global distribution, and CRC is predominantly associated with developed countries and a Western lifestyle and diet. As such, the developed world accounts for more than 63% of all cases of CRC. Geographic variations also predict cancer outcomes, which differ between racial and ethnic groups. This variation is due to inequalities in wealth, differences in the exposure to risk factors and barriers to high-quality cancer prevention, early detection and treatment. The aim of this paper was to review CRC in lowand middle-income countries such as South Africa, India, Brazil and China, and compare them with high-income countries such as the United States of America and the United Kingdom. It is important to note that these economically less developed countries, with historically low CRC rates, are experiencing an increased frequency of CRC. The review also discusses biological markers and genetic pathways involved in the development of colorectal cancer. Genes known to be responsible for the most common forms of inherited CRCs have also been identified but more remain to be identified. This would provide more candidate genes to be added to known biomarkers. CRC burden can be controlled through the widespread application of existing knowledge, such as reduced smoking habits, vaccination, early detection and promoting physical activity, accompanied by a healthy diet. An increased understanding of the molecular mechanisms and events underlying colorectal carcinogenesis will enable the development of new targets and therapeutic drugs.South African Medical Research Councilhttp://www.dovepress.com/cancer-management-and-research-journalpm2020Surger

Microbiomics in Collusion with the Nervous System in Carcinogenesis : Diagnosis, Pathogenesis and Treatment

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.Funding Agencies|South African Medical Research Council (SAMRC)UK Research &amp; Innovation (UKRI)Medical Research Council UK (MRC)</p