Smart biomaterials for enhancing cancer therapy by overcoming tumor hypoxia: a review.

Hypoxia is a distinctive feature of most solid tumors due to insufficient oxygen supply of the abnormal vasculature, which cannot work with the demands of the fast proliferation of cancer cells. One of the main obstacles to limiting the efficacy of cancer medicines is tumor hypoxia. Thus, oxygen is a vital parameter for controlling the efficacy of different types of cancer therapy, such as chemotherapy (CT), photodynamic therapy (PDT), photothermal therapy (PTT), immunotherapy (IT), and radiotherapy (RT). Numerous technologies have attracted much attention for enhancing oxygen distribution in humans and improving the efficacy of cancer treatment. Such technologies include treatment with hyperbaric oxygen therapy (HBO), delivering oxygen by polysaccharides (e.g., cellulose, gelatin, alginate, and silk) and other biocompatible synthetic polymers (e.g., PMMA, PLA, PVA, PVP and PCL), decreasing oxygen consumption, producing oxygen in situ in tumors, and using polymeric systems as oxygen carriers. Herein, this review provides an overview of the relationship between hypoxia in tumor cells and its role in the limitation of different cancer therapies alongside the numerous strategies for oxygen delivery using polysaccharides and other biomaterials as carriers and for oxygen generation.

Evaluation of molecular signatures in the urinary bladder and upper tract urothelial carcinomas: a prospective controlled clinical study.

BACKGROUND: Urothelial carcinomas (UC) can be either in the upper or in the lower urinary tract or both. Urothelial bladder cancer (UBC) is more common than upper tract urothelial carcinoma (UTUC). This research was designed to study the difference between UBC and UTUC using the molecular pathways including (MAPK/ERK) pathway, cell cycle regulating genes, and oncogenic genes. METHODS: To study the discrepancy between UBC and UTUC, a prospective trial was carried out for 31 radical cystectomy and 19 nephrouretrectomy fresh-frozen specimens of UBC and UTUC patients, respectively. The expression level of mRNA of eight genes namely EGFR, ELK1, c-fos, survivin, TP53, RB1, FGFR3, and hTERT was assessed in normal adjacent tissues, UTUC, and UBC by RT-PCR. RESULTS: Comparison between UTUC and UBC regarding the expression level of mRNA of the EGFR, ELK1, c-fos, survivin, TP53, and FGFR3 had significant difference (p-value < 0.001), while the expression level of RB1 and hTERT level had no significance. Sensitivity/specificity of EGFR, Elk1, c-fos, survivin, TP53, and FGFR3 was 0.78/0.90, 0.84/0.90, 0.84/0.80, 0.84/0.96, 0.94/0.93, and 0.89/0.93, respectively, to differentiate between UTUC and UBC. CONCLUSIONS: Despite the fact that UTUC and UBC share the same origin, there is a clear evidence that there is a molecular difference between them. This molecular difference could be the reason that UTUC is more aggressive than UBC.

Prediction of recurrence of non-muscle invasive bladder cancer: The role of androgen receptor and miRNA-2909.

AIM: The exact role of androgen receptor (AR) and miR-2909 in non-muscle invasive bladder cancer (NMIBC) remains controversial. Our aim is to assess the relationship between NMIBC recurrences with AR expression and miRNA-2909. PATIENTS AND METHODS: This prospective controlled cohort study included 99 male patients with NMIBC (Ta-T1) who were treated by transurethral resection and 50 male patients as healthy control. We quantified blood AR messenger RNA variants 1 and 2 (AR1, AR2) and plasma miRNA-2909 with real-time quantitative polymerase chain reaction and the full length AR (AR-FL) using enzyme-linked immunosorbent assay in serum samples. In addition, AR1 and AR2 expression in tumor as well as normal tissues were analyzed. Kaplan-Meier survival curves and multivariate Cox analysis were used to identify independent predictors of recurrence-free survival. RESULTS: In comparison to control group, blood AR1, AR2, and serum AR-FL expression were significantly lower in the NMIBC group compared to plasma miRNA-2909 expression that was significantly higher in the control group. Blood AR1, AR2, and serum AR-FL were significantly correlated with higher tumor stage (pT1) while plasma miRNA-2909 was not. The median survival time (months) was significantly better for higher blood AR1 (34 vs. 21; P = 0.03), lower plasma miRNA-2909 (29 vs. 8; P <0.001), lower AR2 in normal tissues (32 vs. 22; P = 0.007). On multivariate analysis, serum free testosterone (hazards ratio [HR]: 8.9; 95% CI: 1.8-45.1; P = 0.008), serum AR1 (HR: 0.5; 95% CI: 0.3-0.9; P = 0.02), and plasma miRNA-2909 (HR: 5.8; 95% CI: 2.3-14.7; P = 0.0002), and tissue AR2 (HR: 2.6; 95% CI: 1.4-4.7; P = 0.002) were independent predictor for NMIBC recurrence. CONCLUSIONS: Blood and tissue levels of AR expression have a potential significant effect on NMIBC recurrence. Further studies are recommended to establish its exact role.

Gene expression and oxidative stress markers profile associated with toxic metals in patients with renal cell carcinoma.

BACKGROUND: Toxic metals are associated with cancer progression. Studies have reported the relation between some toxic metals and renal cell carcinoma (RCC). METHODS AND RESULTS: Blood levels of Cd and Pb were determined in 94 RCC patients (RCC group) and 91 matched controls as well as blood level of malondialdehyde (MDA) and catalase (CAT) activity as markers of oxidative stress and antioxidant, respectively. Gene expression of MAP kinase pathway (P38 and JNK), hypoxia-inducible factor 1-alpha (HIF1α), vascular endothelial growth factor (VEGF), cytochrome C oxidase subunit 6 (COX6), metallothionein (MT2A), and heat shock protein (HSP90AA1) were evaluated in the obtained tissue specimens. Blood Cd and Pb levels were significantly higher in RCC group comparing to control group with preferential significant increase of Cd in chromophobe RCC (chRCC) sub-type. MDA level was significantly higher and CAT activity was lower in the RCC compared to controls. The difference was evident only in chRCC. The expressions of genes were significantly increased in the cancer tissues than in non-cancerous tissues in RCC sub-types and there was a significant correlation between Cd levels and expression of genes VEGF, MT2A, P38 and JNK in chRCC group. Immunohistochemical staining of clear cell RCC tissues shows a marked expression of VEGF and HIF-1α.While COX6 staining show marked expression in chRCC. CONCLUSIONS: There is a positive correlation between Cd toxicity and the development of RCC, especially chRCC sub-type. Cd is strongly incriminated in the pathogenesis of chRCC through the effort on some genes and oxidative stress markers.

Mercaptopurine-Loaded Sandwiched Tri-Layered Composed of Electrospun Polycaprolactone/Poly(Methyl Methacrylate) Nanofibrous Scaffolds as Anticancer Carrier with Antimicrobial and Antibiotic Features: Sandwich Configuration Nanofibers, Release Study and in vitro Bioevaluation Tests.

BACKGROUND: 6-Mercaptopurine (6-MP) is a potential anti-cancer agent which its therapeutic and limitation applicability due to its high toxicity. OBJECTIVE: Herein, 6-MP was loaded into tri-layered sandwich nanofibrous scaffold (the top layer composed of poly methyl methacrylate/polycaprolactone (PMMA/PCL), the middle layer was PCL/PMMA/6-MP, and the bottom layer was PCL/PMMA to improve its bioactivity, adjusting the release-sustainability and reduce its toxicity. METHODS: Electrospun tri-layered nanofibers composed of PCL/PMMA were utilized as nano-mats for controlling sustained drug release. Four groups of sandwich scaffold configurations were investigated with alteration of (PMMA: PCL) composition. RESULTS: The sandwich scaffold composed of 2%PCL/4%PMMA/1%6-MP showed the best miscibility, good homogeneity and produced the smoothest nanofibers and low crystallinity. All fabricated 6-MP-loaded-PCL/PMMA scaffolds exhibited antimicrobial properties on the bacterial and fungal organisms, where the cytotoxicity evaluation proved the safety of scaffolds on normal cells, even at high concentration. Scaffolds provided a sustained-drug release profile that was strongly dependent on (PCL: PMMA). As (PCL: PMMA) decreased, the sustained 6-MP release from PCL/PMMA scaffolds increased. Results established that ~18% and 20% of 6-MP were released after 23h from (4%PCL/4%PMMA/1%6-MP) and (2%PCL/4%PMMA/1%6-MP), respectively, where this release was maintained for more than 20 days. The anti-cancer activity of all fabricated scaffolds was also investigated using different cancerous cell lines (e.g., Caco-2, MDA, and HepG-2) results showed that 6-MP-loaded-nanofibrous mats have an anti-cancer effect, with a high selective index for breast cancer. We observed that viability of a cancer cell was dropped to about 10%, using nanofibers containing 2%PCL/4%PMMA/1%6-MP. CONCLUSION: Overall, the PCL: PMMA ratio and sandwich configuration imparts a tight control on long-term release profile and initial burst of 6-MP for anticancer treatment purposes.

Novel oxygen-generation from electrospun nanofibrous scaffolds with anticancer properties: synthesis of PMMA-conjugate PVP-H2O2 nanofibers, characterization, and in vitro bio-evaluation tests.

Released oxygen plays a critical role in reducing destructive tumor behavior. This study aims to utilize decomposed hydrogen peroxide as an oxygen source by conjugating it with polyvinylpyrrolidone (PVP). PVP-hydrogen peroxide complex (PHP) composed of different ratios of (PVP : H2O2) (0.5 : 1, 1 : 1, 1 : 1.5, 1 : 5, and 1 : 10) were successfully synthesized. PHP complex with a ratio of 1 : 1.5 was chosen as the optimized ratio, and it was incorporated into the polymethyl methacrylate (PMMA) nanofibrous scaffold via the electrospinning technique. Results have revealed that the PMMA-10% PHP complex provided a significant morphological structure of nanofibrous scaffolds. The mechanical properties of PMMA-10% PHP nanofibers showed the most suitable mechanical features such as Young's modulus, elongation-at-break (%), and maximum strength, in addition to the highest degree of swelling. All PHP complex scaffolds released oxygen in a sustained manner. However, the PMMA-10% PHP complex gave the highest concentration of released-oxygen with (∼8.9 mg L-1, after 2.5 h). PMMA-10% PHP nanofibers provided an ideal model for released-oxygen scaffold with anti-cancer effect and high selectivity for cancer cells, especially for breast cancer cells. Nanofibrous scaffolds with different composition revealed high cell viability for normal cells. Such outcomes support the suitability of using synthesized nanofibrous scaffolds as released-oxygen biomaterials to enhance cancer cells' sensitivity and maximize the treatment effect.

Evaluation of serum fatty acid binding protein-4 (FABP-4) as a novel biomarker to predict biopsy outcomes in prostate biopsy naïve patients.

OBJECTIVES: To investigate the role of serum fatty acid-binding protein-4 (FABP-4) as a surrogate of obesity and metabolic syndrome in the prediction of the outcome of prostate biopsy. METHODS: A prospective pilot study was conducted for patients undergoing prostate needle biopsy (PNB) for clinically suspected prostate cancer (PCa) between June 2016 and August 2017. Fifty consecutive patients with biopsy-proven PCa were included as study group and 50 consecutive patients with negative biopsy were included as a control group. Receiver Operating Characteristic (ROC) curve was used to calculate the area under the curve (AUC) to compare the accuracy of the different parameters in the diagnosis as well as the presence of high-grade PCa (Gleason score 8-9) at PNB. Predictors of the outcome were analyzed using univariate and multivariate logistic regression analysis. RESULTS: FABP-4 (AUC: 0.75; P < 0.001) and PSA-density (AUC: 0.84; P < 0.001) were the most accurate to detect PCa at PNB. On multivariate analysis, FABP-4 > 22.5 ng/ml (OR: 16.6; 95% CI 2.8-98; P = 0.002) and PSA-density > 0.38 ng/ml/ml OR: 17.7; 95% CI 5.3-59; P < 0.001) were independent predictors of PCa detection. Regarding high-grade PCa at PNB, FABP-4 (AUC: 0.79; P < 0.001) and %Free-PSA (AUC: 0.75; P < 0.001) were the most accurate. Independent predictors of high-grade PCa were FABP-4 > 32.3 ng/ml OR: 9.2; 95% CI 1.8-45; P = 0.006) and %Free-PSA ≤ 21.9 (OR: 5.5; 95% CI 1.1-27; P = 0.03). CONCLUSIONS: FABP-4 is an independent predictor for both the diagnosis and high-grade Gleason score at PNB. This novel biomarker might have a promising role in optimizing PNB outcomes.

Mesenchymal stem cells alleviate hydrochloric acid-induced lung injury through suppression of inflammation, oxidative stress and apoptosis in comparison to moxifloxacin and sildenafil.

INTRODUCTION: Acute lung injury (ALI) is a severe life-threatening disease causing uncontrolled pulmonary inflammation and oxidative damage. There are still no effective therapies for this disease. The aim of this study was to evaluate the protective role of mesenchymal stem cells, moxifloxacin, sildenafil or a combination of moxifloxacin and sildenafil against hydrochloric Acid (HCl) - induced ALI. METHODS: HCl or saline was injected intra-tracheally and after 2 h, moxifloxacin, sildenafil, moxifloxacin + sildenafil or mesenchymal stem cells were injected. After 7 days, rats were sacrificed for evaluation of the blood chemistry and inflammation via determination of the level of oxidative stress markers, apoptosis and the histopathological alterations by H&E. RESULTS: In HCl-injected rats, there were a significant increase in total white blood cells (WBCs), lymphocytes, malondialdehyde (MDA) and caspase-3 gene expression. Also, there were a significant decrease in superoxide dismutase (SOD), catalase (CAT), reduced glutathione (GSH) and Hemeoxygenase-1 (HO-1) gene expression in lung tissue. On the other hand, treatment of lung injured rats with mesenchymal stem cell, moxifloxacin, sildenafil or a combination of moxifloxacin and sildenafil showed a significant decrease in WBCs and lymphocytes and ameliorated the histopathological changes. MDA level in lung tissue was only significantly lowered in rats treated with moxifloxacin alone or in combination with sildenafil or MSCs. GSH was just increased in rats treated with moxifloxacin, sildenafil or with MSCs. Antioxidant parameters and gene expression of HO-1 and caspase-3 were significantly modulated in rats treated with MSCs. CONCLUSION: MSCs ameliorated the toxic effects of HCl through their ability to decrease inflammation, oxidative stress, and apoptosis in acute lung injury.

Serum lipids might improve prostate-specific antigen sensitivity in patients undergoing transrectal ultrasonography-guided biopsy for suspected prostate cancer: A pilot study.

Objectives: To investigate the potential use of body mass index (BMI) and serum lipids in improving prostate-specific antigen (PSA) sensitivity in patients undergoing biopsy for suspicion of prostate cancer, as there is an established relationship between metabolic syndrome, obesity and serum lipids with prostate cancer. Patients and methods: A pilot study was conducted in a tertiary referral centre between June 2016 and August 2017 of patients undergoing transrectal ultrasonography (TRUS)-guided biopsy. After the result of TRUS-biopsy, the first 50 patients diagnosed with prostate cancer (study group) and those with no prostate cancer (control group) were enrolled. BMI, serum PSA level, fasting blood sugar and lipid profile (e.g. cholesterol, triglycerides, low-density lipoprotein [LDL] and high-density lipoprotein [HDL]), were compared between the groups. Results: Higher BMI, cholesterol, LDL and lower HDL together with PSA were significantly associated with a positive biopsy. On multivariate analysis, LDL (odds ratio [OR] 5.3, 95% confidence interval [CI] 1.2-24.9; P = 0.03) and total PSA level (OR 12.9, 95% CI 4.7-35; P < 0.001) were independent predictors of a positive biopsy. A combination of LDL <80 mg/dL and PSA level <26 ng/mL threshold values determined by receiver operating characteristic curve analysis, had a sensitivity and specificity of 94% and 28%, respectively; whilst, the negative (NPV) and positive predictive values were 82.4% and 56.6%, respectively. The sensitivity and NPV of the combination was significantly higher than that of PSA level alone (94% vs 72% and 82.4% vs 75%, respectively; P < 0.001). Conclusions: Serum lipids might have a role in the diagnosis of prostate cancer and could be used as an adjunct to PSA measurement to improve sensitivity and avoid unnecessary biopsies. Abbreviations: AUC: area under the curve; BMI: body mass index; FBS: fasting blood sugar; HDL: high-density lipoprotein; LDL: low-density lipoprotein; LOX-1: lectin-like oxidised LDL receptor-1; OR: odds ratio; ROC: receiver operating characteristic; RP: radical prostatectomy; TG: triglyceride.

Association of polymorphisms G(-174)C in IL-6 gene and G(-1082)A in IL-10 gene with traditional cardiovascular risk factors in patients with coronary artery disease.

Interleukin-6 (IL-6) polymorphism has been associated with the genetic susceptibility to coronary artery disease (CAD) and also with the lipid profile in different populations. The present work aimed at studying the association, if any between the IL-6 (174) G/C and IL-10 (1082) G/A genes with hypertension or hyperlipidimia in Egyptian patients with CAD and the association of the IL-6 -174 G/C polymorphism with serum IL-6 levels. 108 Egyptian patients with CAD and 143 unrelated healthy subjects were included in the study. The different genotypes of IL-6 and IL-10 were detected by polymerase chain reaction. Serum levels of lipoprotein(a) [Lp(a)] and IL-6 were estimated in the patients, as well as in the healthy subjects. Increased frequency of G allele, GG and GC genotypes in IL-6, as well as decreased frequency of C allele and CC genotype were found in CAD patients, compared to healthy subjects [P = < 0.0001, OR = 3.95, 95% CI (2.16-7.22) for GG and GC vs CC genotype], [P = < 0.0001, OR = 3.44, 95% CI (2.26-5.23) for G allele]. There was an increased frequency of G allele vs A allele in IL-10 genotype in CAD patients, compared to healthy subjects [P = 0.005, OR = 1.866, 95% CI (1.2-2.9]. Higher levels of both Lp(a) and IL-6 were observed in CAD patients, compared to control subjects (P = 0.0012, P = 0.0346, respectively). Increased frequency of IL-6 -174 G-allele was implicated in a greater cardiovascular risk and the presence of G allele or homozygosity for G allele of IL-10 G/A (1082) was associated with an increased prevalence of CAD. The GC genotype and G allele in IL-6 had significant correlation with hyperlipidimic CAD patients; however, G allele in IL-6 and IL-10 showed significant association with hypertension. Thus, G allele in IL-6 and IL-10 was considered as an independent risk factor in hypertensive CAD patients.

Evaluation of free radical-scavenging and anti-oxidant properties of black berry against fluoride toxicity in rats.

Oxidative damage to cellular components such as lipids and cell membranes by free radicals and other reactive oxygen species is believed to be associated with the development of degenerative diseases. Fluoride intoxication is associated with oxidative stress and altered anti-oxidant defense mechanism. So the present study was extended to investigate black berry anti-oxidant capacity towards superoxide anion radicals, hydroxyl radicals and nitrite in different organs of fluoride-intoxicated rats. The data indicated that sodium fluoride (10.3mg/kg bw) administration induced oxidative stress as evidenced by elevated levels of lipid peroxidation and nitric oxide in red blood cells, kidney, testis and brain tissues. Moreover, significantly decreased glutathione level, total anti-oxidant capacity and superoxide dismutase activity were observed in the examined tissues. On the other hand, the induced oxidative stress and the alterations in anti-oxidant system were normalized by the oral administration of black berry juice (1.6g/kg bw). Therefore it can be concluded that black berry administration could minimize the toxic effects of fluoride indicating its free radical-scavenging and potent anti-oxidant activities.

Porphyrin metabolism in rats intaking chemical carcinogens.

This study was performed on rats receiving nitrosamine precursors as potent liver carcinogens in order to investigate and follow up the porphyrin metabolism during the intake of hepatocarcinogens. As clarified from our results, progressive increases in free erythrocyte porphyrins, erythrocyte protoporphyrins, haem content and hepatic total porphyrins were observed after 2 months of intaking these carcinogens and further increases were gradually observed in parallel with the continued intake of these chemicals, which was extended to 7 months. At the same time, such elevations were also observed in the activity of hepatic delta-aminolevulinic acid (ALA)-synthetase and uroporphyrinogen-1-synthetase either in hepatic tissues or erythrocytes of these carcinogen-subjected rats. However, significant inhibition was found in the activity of erythrocyte ALA-dehydratase, which reached 40.5% of the control values after 7 months. Therefore, these observations demonstrated that the intake of hepatocarcinogens may influence the rate of hepatic porphyrin and haem biosynthesis.

Superoxide dismutase activities in serum and white blood cells of patients with some malignancies.

Superoxide dismutase (SOD) activity has been estimated in serum and leukocytes isolated from adults and children with acute lymphoblastic leukemia (ALL), non-Hodgkin lymphoma (NHL), Hodgkin's disease (HD) and neuroblastoma. Superoxide dismutase levels in leukocytes isolated from adult patients with HD, ALL and NHL were significantly higher than the corresponding control values. Serum SOD activity of adult patients with ALL and NHL was significantly decreased compared to the normal value, while its activity was not significantly changed in patients with HD. Marked deficiencies of leukocyte SOD levels in children with ALL, NHL, HD and neuroblastoma were found. There were no apparent differences in serum SOD activity in children suffering from ALL, NHL, HD and neuroblastoma. It is concluded that the assay of leukocyte SOD can be used to differentiate between HD and NHL in both adults and children.

Some urinary enzymes in bilharziasis.

Urinary alkaline phosphatase (ALP), acid phosphatase (ACP), aryl sulphatase (Ar. sulph.), beta-glucuronidase (beta-gluc.) and galactosidase were assayed in a group of Bilharzia haematobium patients and another group of healthy subjects (control group). The results for most of the determined enzymes revealed high activities as compared to the controls. The activity of acid phosphatase in male urine samples increased also, though not significantly. These elevated enzyme activities could be used to establish the diagnosis of schistosomiasis in patients whose urine contains no ova or when it is difficult to detect them. The results are discussed in the light of localization of each enzyme in the urinary tract as well as in other organs like the liver.

Biochemical relationship between urine composition and urinary stone formation in stone forming patients.

The precise relationship between urine composition and stone formation has not yet been completely understood. The object of this work is to study some constituents of the urine in stone formers and normal subjects in a trial to correlate stone formation with urine composition. Urinary levels of oxalic acid, uric acid and phosphate were elevated in oxalate, urate and phosphate stone formers, respectively, while in the urine of mixed stone formers both oxalic and uric acids were increased. Urinary levels of ascorbic acid, citric acid and mucopolysaccharides in all groups of patients were significantly higher than the corresponding control levels. Although oxalic acid, uric acid and phosphate concentrations were high in their respective stones, the concentrations of these constituents were nearly the same in the mixed stones. Also Ca2+ concentration was higher in stones of oxalate and mixed stone formers than in stones of urate and phosphate formers. Exceptionally, magnesium was high in stones of phosphate stone formers. It is recommended that urinary contents of oxalate, urate and phosphate have to be minimized to overcome stone recurrence.