Advances and development of prostate cancer, treatment, and strategies: A systemic review.

The most common type of cancer in the present-day world affecting modern-day men after lung cancer is prostate cancer. Prostate cancer remains on the list of top three cancer types claiming the highest number of male lives. An estimated 1.4 million new cases were reported worldwide in 2020. The incidence of prostate cancer is found predominantly in the regions having a high human development index. Despite the fact that considerable success has been achieved in the treatment and management of prostate cancer, it remains a challenge for scientists and clinicians to curve the speedy advancement of the said cancer type. The most common risk factor of prostate cancer is age; men tend to become more vulnerable to prostate cancer as they grow older. Commonly men in the age group of 66 years and above are the most vulnerable population to develop prostate cancer. The gulf countries are not far behind when it came to accounting for the number of individuals falling prey to the deadly cancer type in recent times. There has been a consistent increase in the incidence of prostate cancer in the gulf countries in the past decade. The present review aims at discussing the development, diagnostics via machine learning, and implementation of treatment of prostate cancer with a special focus on nanotherapeutics, in the gulf countries.

A Review on Nanocarrier Mediated Treatment and Management of Triple Negative Breast Cancer: A Saudi Arabian Scenario.

People have continued to be petrified by the devastating effects of cancer for decades and thus a pursuit for developing anticancer agents have seen an ever-increasing trend in the past few decades. Globally, breast cancer is the most common malignancy in women and the second most common cause of cancer-related deaths. In Saudi Arabia, breast cancer is the most common type of cancer among women, constituting almost 14.2% of the total cancer burden. Triple-negative breast cancer (TNBC) is a subtype of breast cancer, which is a pathologically diverse disease of higher grade characterized by the absence of the estrogen receptor (ER), the progesterone receptor (PR), and the human epidermal growth factor receptor 2 (HER2) expressions. Despite the considerable advancements achieved in the therapeutic management of cancer, TNBC remains an unbeatable challenge, which requires immediate attention as it lacks conventional targets for treatment, leading to a poor clinical prognosis. The present research goals are directed toward the development and implementation of treatment regimens with enhanced bioavailability, targetability, minimized systemic toxicity, and improved outcomes of treatment options. The present treatment and management scenario of TNBC continues to provoke oncologists as well as nanomedical scientists to develop novel and efficient nanotherapies. Lately, scientific endeavors have addressed the importance of enhanced availability and targeted cellular uptake with minimal toxicity, which are achieved by the application of nano drug-carriers. This review intends to summarize the incidence rates of TNBC patients, the importance of nanotherapeutic options for patients suffering from TNBC, the identification of promising molecular targets, and challenges associated with the development of targeted nanotherapeutics with special reference to the Saudi Arabian context.

The metabolism of cells regulates their sensitivity to NK cells depending on p53 status.

Leukemic cells proliferate faster than non-transformed counterparts. This requires them to change their metabolism to adapt to their high growth. This change can stress cells and facilitate recognition by immune cells such as cytotoxic lymphocytes, which express the activating receptor Natural Killer G2-D (NKG2D). The tumor suppressor gene p53 regulates cell metabolism, but its role in the expression of metabolism-induced ligands, and subsequent recognition by cytotoxic lymphocytes, is unknown. We show here that dichloroacetate (DCA), which induces oxidative phosphorylation (OXPHOS) in tumor cells, induces the expression of such ligands, e.g. MICA/B, ULBP1 and ICAM-I, by a wtp53-dependent mechanism. Mutant or null p53 have the opposite effect. Conversely, DCA sensitizes only wtp53-expressing cells to cytotoxic lymphocytes, i.e. cytotoxic T lymphocytes and NK cells. In xenograft in vivo models, DCA slows down the growth of tumors with low proliferation. Treatment with DCA, monoclonal antibodies and NK cells also decreased tumors with high proliferation. Treatment of patients with DCA, or a biosimilar drug, could be a clinical option to increase the effectiveness of CAR T cell or allogeneic NK cell therapies.

Study of HLA-G gene 14-bp ins/del and codon 93 (CAC/CAT) polymorphisms association with spontaneous abortion in a Tunisian population.

In the recent years, spontaneous abortion (SA) frequency increased awareness about medical and social-economic related problems. Human leukocyte antigen-G (HLA-G) is a non-classic HLA I molecule initially described in trophoblastic tissue in foeto-maternal interface. HLA-G polymorphism association with SA has been extensively studied. One amongst the foremost studied variants was HLA-G 14-bp Insertion (Ins)/Deletion (Del) polymorphism. Nevertheless, such a study was not performed in Tunisian population yet. We aim to investigate two HLA-G polymorphisms, 14-bp Ins/Del 3'UTR, and for the first time, codon 93 (CAC/CAT) polymorphisms association with SA risk in the Tunisian population. The results revealed HLA-G 14-bp Ins/Del polymorphism and CIns haplotype association with SA. No association of the HLA-G codon 93 (CAC/CAT) polymorphism to SA was observed. Considering both polymorphism together, female's homozygosity for 14-bp Ins/Del and for codon 93 (CAC/CAT) polymorphism may increase the risk of SA susceptibility.

Changes in metabolism affect expression of ABC transporters through ERK5 and depending on p53 status.

Changes in metabolism require the efflux and influx of a diverse variety of metabolites. The ABC superfamily of transporters regulates the exchange of hundreds of substrates through the impermeable cell membrane. We show here that a metabolic switch to oxidative phosphorylation (OXPHOS), either by treating cells with dichloroacetate (DCA) or by changing the available substrates, reduced expression of ABCB1, ABCC1, ABCC5 and ABCG2 in wild-type p53-expressing cells. This metabolic change reduced histone changes associated to active promoters. Notably, DCA also inhibited expression of these genes in two animal models in vivo. In contrast, OXPHOS increased the expression of the same transporters in mutated (mut) or null p53-expressing cells. ABC transporters control the export of drugs from cancer cells and render tumors resistant to chemotherapy, playing an important role in multiple drug resistance (MDR). Wtp53 cells forced to perform OXPHOS showed impaired drug clearance. In contrast mutp53 cells increased drug clearance when performing OXPHOS. ABC transporter promoters contain binding sites for the transcription factors MEF2, NRF1 and NRF2 that are targets of the MAPK ERK5. OXPHOS induced expression of the MAPK ERK5. Decreasing ERK5 levels in wtp53 cells increased ABC expression whereas it inhibited expression in mutp53 cells. Our results showed that the ERK5/MEF2 pathway controlled ABC expression depending on p53 status.

The PDK1 Inhibitor Dichloroacetate Controls Cholesterol Homeostasis Through the ERK5/MEF2 Pathway.

Controlling cholesterol levels is a major challenge in human health, since hypercholesterolemia can lead to serious cardiovascular disease. Drugs that target carbohydrate metabolism can also modify lipid metabolism and hence cholesterol plasma levels. In this sense, dichloroacetate (DCA), a pyruvate dehydrogenase kinase (PDK) inhibitor, augments usage of the glycolysis-produced pyruvate in the mitochondria increasing oxidative phosphorylation (OXPHOS). In several animal models, DCA decreases plasma cholesterol and triglycerides. Thus, DCA was used in the 70 s to treat diabetes mellitus, hyperlipoproteinemia and hypercholesterolemia with satisfactory results. However, the mechanism of action remained unknown and we describe it here. DCA increases LDLR mRNA and protein levels as well as LDL intake in several cell lines, primary human hepatocytes and two different mouse models. This effect is mediated by transcriptional activation as evidenced by H3 acetylation on lysine 27 on the LDLR promoter. DCA induces expression of the MAPK ERK5 that turns on the transcription factor MEF2. Inhibition of this ERK5/MEF2 pathway by genetic or pharmacological means decreases LDLR expression and LDL intake. In summary, our results indicate that DCA, by inducing OXPHOS, promotes ERK5/MEF2 activation leading to LDLR expression. The ERK5/MEF2 pathway offers an interesting pharmacological target for drug development.

Common polymorphisms of calpain-10 and the risk of polycystic ovary syndrome in Tunisian population: a case-control study.

Recent studies have suggested that calpain-10 (CAPN10) gene polymorphisms play a role in the susceptibility to polycystic ovary syndrome (PCOS). The aim of the present study was to evaluate the possible association between three single nucleotide polymorphisms (SNPs) in CAPN10 gene: UCSNP-43 (rs3792267), UCSNP-19 (rs3842570), and UCSNP-63 (rs5030952) and PCOS in Tunisian cases and control women. Study subjects included 127 women with PCOS (mean age 29.8 ± 4.7 year) and 150 healthy women (mean age 33.5 ± 5.6 year). CAPN10 genotyping was carried-out by direct PCR and PCR-RFLP. Linkage disequilibrium pattern in the genomic region explored was determined by HAPLOVIEW 4.2 while reconstruction of haplotypes was done using PHASE 2.1. The phylogenetic distribution of haplotypes in the population was determined by ARLEQUIN 2.000. Six haplotypes were observed. None of SNPs associated with PCOS or its components while the haplotype H4 associated with the phenotype PCOS-obese (P < 0.025). Moreover the pair of haplotypes H1/H4 strongly associated with high blood-pressure (OR = 14.4, P < 0.012). This work confirms the association of CAPN10 gene with metabolic components in PCOS and highlights the role of haplotypes as strong and efficient genetic markers.