Breast cancer is the most common cancer diagnosed among females worldwide. Although breast cancer survival has largely improved in the past 30 years, it remains highly heterogeneous in its response to treatment. Triple-negative breast cancer (TNBC) is a subtype of breast cancer that lacks the expression of the estrogen receptor (ER), progesterone receptor (PR) and epidermal growth factor receptor-2 (Her2). While TNBC may initially be responsive to chemotherapy, recurrence and subsequent high mortality rates are frequently reported. Studies have shown curcumin and its derivatives to be effective against TNBC cell lines in vitro. To improve its anti-cancer effects, we have synthesized Fe³⁺–curcumin (Fe–Cur₃) and Cu²⁺–curcumin (CD) complexes and investigated them experimentally. Further, CD was encapsulated into a poly(styrene)-co-maleic acid (SMA) micelle to enhance its stability. We assessed the cytotoxicity of these formulations both in vitro and in vivo. SMA–CD demonstrated dose-dependent cytotoxicity and abolished TNBC tumor growth in vivo. The encapsulation of the curcumin–copper complex improved its anti-cancer activity without overt adverse effects in a murine model of TNBC. These results provide evidence and insights into the value of nanoformulations in enhancing drug-delivery and increasing the potential therapeutic efficacy of curcumin derivatives.

Common variants of Apolipoprotein A5 (APOA5) gene have been associated with lipid levels yet very few studies have reported full sequence data in differentfrom various ethnic groups. The purpose of this study was to re-sequenceanalyse the full APOA5 gene sequence to identify variants in 100 healthy Kuwaitis of Arab ethnicities and assess their association with variation in lipid levels in a cohort of 733 samples. Sanger method was used in the direct sequencing of the full 3.7Kb APOA5 and multiple sequence alignment was used to identify variants. The complete APOA5 sequence in Kuwaiti Arabs has been deposited in GenBank ( KJ401315). A total of twenty reported single nucleotide polymorphisms (SNPs) were identified. Two novel SNPs were also identified: a synonymous 2197G>A polymorphism at genomic position 116661525 and a 3’ UTR 3222 C>T polymorphism at genomic position 16660500 based on human genome assembly GRCh37/hg:19. Analysis of genotype and allele frequency revealed nine variants as common with a minor allele frequency (MAF) above 5%. Five SNPs along with the two novel SNPs were selected for validation in a the cohort. Association of those SNPs with lipid levels was tested and minor alleles of three SNPs (rs2072560 , rs2266788 and rs662799) were found significantly associated with TG and VLDL levels. Linkage analysis was also examined and revealed five major haplotype groups that did not have effect on TG levels. This is the first study to report the full APOA5 sequence and SNPs in an Arab ethnic group. Analysis of the variants identified and comparison to other populations suggests a distinctive genetic component in Arabs. The positive association observed for rs2072560 and rs2266788 with TG and VLDL levels confirms their role in lipid metabolism.

Background: Inflammatory bowel disease (IBD) comprises a group of disorders that manifest through chronic inflammation of the colon and small intestine. Although the exact cause of IBD is still unclear, dysfunctional immunoregulation involving overproduction of inflammatory cytokines such as TNF‐α, and IL‐6 have been implicated in pathogenesis. Current therapy relies on immunosuppression, cytotoxic drugs, and monoclonal antibodies against TNF‐α. These classes of drugs have severe side‐effects, especially when used for long duration. Our previous work with raloxifene, a selective estrogen receptor modulator, has shown that the drug, and to a greater extent its micellar formulation, has a significant suppressive effect on NF‐κB, an essential immune‐regulator. This finding directed the current work towards testing the anti‐inflammatory and immunomodulatory effects of raloxifene using cell lines, as well as testing the potential use of the styrene maleic acid (SMA) micelles loaded with raloxifene (SMA‐Ral) against dextran sulfate sodium (DSS) induced colitis in an in vivo model of IBD.Results: Treatment of MCF‐7 cells with TNF‐α was shown to protect the cells from the cytotoxic effect of raloxifene (42 vs. 10% cell death, with TNF‐α. Treating CaCo‐2 cells with both free and SMA‐Ral improved cell survival after exposure to 2% DDS with significantly higher protection with SMA‐Ral. Treatment of U‐937 with SMA‐Ral and free‐Ral resulted in down‐regulation of TNF‐α, IL‐1β, IL‐6, and MIP1α, with greater inhibition of the SMA‐Ral, compared to free Ral. Balb/c mice treated with raloxifene and SMA‐Ral showed weight gain at 14 days, compared to the control group (122, and 115% respectively). Treatment with raloxifene prevented DSS‐induced diarrhea in 6/6 of free raloxifene treated mice and in 5/6 mice treated with SMA‐Ral. Control group of DSS‐treated mice showed average colon length of 7.4 cm compared to 13 cm in the control group. The average colon length was 12.3 and 11.5 cm for raloxifene and SMA‐Ral treated groups, respectively. Furthermore, inflammatory cytokines such as IL‐6 and TNF‐α were reduced in serum of animals treated with free‐Ral and SMA‐Ral.Conclusions: Raloxifene and its micellar formulation warrants further studies to understand their effect on the treatment of colitis.

Cytochrome P450 (CYP) enzymes, such as CYP3A4, and CYP3A5, P450 oxidoreductase (POR), peroxisome proliferator activated receptor alpha (PPAR-alpha), and drug transporter (ABCB1) were observed to influence concentrations of immunosuppressants (cyclosporine, everolimus, sirolimus, and tacrolimus) and outcomes in renal transplants. We carried out the present study to evaluate the prevalence and impact of these single nucleotide polymorphisms (SNPs) in adult renal transplants. SNPs were evaluated using commercial TaqMan^® assays. Serum drug concentrations were estimated using immunoassays. One hundred and forty-six patients were recruited. SNPs in CYP3A5*3 were significantly associated with greater dose-adjusted cyclosporine and tacrolimus concentrations. SNPs in POR*28 were observed with significantly lower dose-adjusted concentrations, particularly with cyclosporine and tacrolimus. ABCB1 homozygous polymorphisms were observed with significantly lower time spent in the therapeutic range with cyclosporine and everolimus/sirolimus. Cyclosporine was observed in a significantly greater proportion of patients with elevated GGT, and SNPs in PPAR-alpha were significantly associated with an increased risk of this adverse event. Hypertriglyceridemia with everolimus was significantly associated with POR*28 polymorphisms. There is a need to validate the influence of these SNPs in a prospective study and develop an algorithm predicting the achievement of target concentrations.

Intravenous paracetamol is a commonly administered analgesic and antipyretic in inpatient settings. Paracetamol is metabolized by cytochrome P450 (CYP) enzymes followed by conjugating enzymes to mainly glucuronide but to a lesser extent, sulphate metabolites, and oxidative metabolites. Single nucleotide polymorphisms (SNPs) in the CYP enzymes result in modified enzymatic activity. The present study was carried out to evaluate the prevalence of SNPs related to paracetamol metabolism and principal metabolites in critically ill patients, and those with chronic kidney disease. The present study is a cross-sectional study carried out in adults (>21 years) requiring intravenous paracetamol as part of their standard of care. Details regarding their demographics, and renal and liver function tests were collected. Blood was withdrawn for the analysis of paracetamol and their metabolites, and the SNPs of key CYP enzymes. Paracetamol/paracetamol glucuronide (P/PG), paracetamol/paracetamol sulphate (P/PS) and PG/PS were estimated. Acute liver injury (ALI) and renal dysfunction were defined using standard definitions. We observed a significant prevalence of SNPs in CYP1A2*1C, CYP3A4*3, CYP1A2*1K, CYP1A2*6, CYP2D6*10, and CYP2E1*2 amongst the 150 study participants. Those with CYP1A2*6 (CC genotype) were observed with significantly lower PG and PS concentrations, and a higher P/PS ratio; CYP2D6*10 (1/1 genotype) with a significantly lower PG concentration and a higher P/PG ratio; and CYP1A2*1K (CC genotype) was observed with a significantly higher PG/PS ratio. Good predictive accuracies were observed for determining the SNPs with the cut-off concentration of 0.29 μM for PS in determining CYP1A2*1K, 0.39 μM for PG and 0.32 μM for PS in determining CYP1A2*6 genotype, and 0.29 μM for PG in determining the CYP2D6*10 genotype. Patients with renal dysfunction were observed with significantly greater concentrations of paracetamol, PG and P/PS, and PG/PS ratios, with a lower concentration of PS. No significant differences were observed in any of the metabolites or metabolite ratios in patients with ALI. We have elucidated the prevalence of key CYP enzymes involved in acetaminophen metabolism in our population. Alterations in the metabolite concentrations and metabolic ratios were observed with SNPs, and in patients with renal dysfunction. Population toxicokinetic studies elucidating the dose-response relationship are essential to understand the optimized dose in this sub-population.