PEGylated Pemetrexed and PolyNIPAM Decorated Gold Nanoparticles: A Biocompatible and Highly Stable CT Contrast Agent for Cancer Imaging.

This study describes a multifunctional nanoparticle platform for targeted CT imaging and therapy of cancers. Pemetrexed (conjugated with polyethylene glycol, MW 2000 Da) and polyNIPAM (PEGylated) were designed for targeted delivery to folate receptors and thermally ablated tumors, respectively. These moieties were coated on gold nanoparticles (7 and 30 nm), and the prepared compounds were characterized using 1H NMR, FT-IR, CHNS, DLS, TEM, TGA, and UV-vis. The resulting agents exhibited 2-4 times higher X-ray attenuation compared to Visipaque and demonstrated specific accumulation in tumor tissue (4T1 xenograft model) 90 min after injection in mice. The nanoparticles displayed anticancer activity against 4T1 and MDA-MB-231 breast cancer cells (IC50: 182.87 and 206.18 µg/mL) and good biocompatibility. Importantly, the platform showed excellent stability over a year and at pH 2-12 and temperature range of -78 to 40 °C, and a water-dichloromethane extraction method was optimized for efficient purification, facilitating large-scale production.

The role of glycans in the mechanobiology of cancer.

Although cancer is a genetic disease, physical changes such as stiffening of the extracellular matrix also commonly occur in cancer. Cancer cells sense and respond to extracellular matrix stiffening through the process of mechanotransduction. Cancer cell mechanotransduction can enhance cancer-promoting cell behaviors such as survival signaling, proliferation, and migration. Glycans, carbohydrate-based polymers, have recently emerged as important mediators and/or modulators of cancer cell mechanotransduction. Stiffer tumors are characterized by increased glycan content on cancer cells and their associated extracellular matrix. Here we review the role of cancer-associated glycans in coupled mechanical and biochemical alterations during cancer progression. We discuss the recent evidence on how increased expression of different glycans, in the form of glycoproteins and proteoglycans, contributes to both mechanical changes in tumors and corresponding cancer cell responses. We conclude with a summary of emerging tools that can be used to modify glycans for future studies in cancer mechanobiology.

Cell encapsulation in alginate-based microgels using droplet microfluidics; a review on gelation methods and applications.

Cell encapsulation within the microspheres using a semi-permeable polymer allows the two-way transfer of molecules such as oxygen, nutrients, and growth factors. The main advantages of cell encapsulation technology include controlling the problems involved in transplanting rejection in tissue engineering applications and reducing the long-term need for immunosuppressive drugs following organ transplantation to eliminate the side effects. Cell-laden microgels can also be used in 3D cell cultures, wound healing, and cancerous clusters for drug testing. Since cell encapsulation is used for different purposes, several techniques have been developed to encapsulate cells. Droplet-based microfluidics is one of the most valuable techniques in cell encapsulating. This study aimed to review the geometries and the mechanisms proposed in microfluidic systems to precisely control cell-laden microgels production with different biopolymers. We also focused on alginate gelation techniques due to their essential role in cell encapsulation applications. Finally, some applications of these microgels and researches will be explored.

The Diagnosis and Treatment of a Rare Maxillary Plasmacytoma: a Case Report.

The jaw plasmacytoma is a very rare condition, which its diagnosis is difficult in clinical routine. Up to now, less than 60 cases of jaw plasmacytoma have been reported in the literature. In the present case report, we reported a rare case of jaw plasmacytoma in a 42-year-old female, which was misdiagnosed with dental granuloma and abscess. The diagnosis of plasmacytoma was done by immunohistochemistry (IHC) evaluation following a cone beam computed tomography (CBCT) assessment. The patient was treated with radiotherapy and is disease free after 2 years.

Sol-Gel Synthesis, Physico-Chemical and Biological Characterization of Cerium Oxide/Polyallylamine Nanoparticles.

Cerium oxide nanoparticles (CeO2-NPs) have great applications in different industries, including nanomedicine. However, some studies report CeO2-NPs-related toxicity issues that limit their usage and efficiency. In this study, the sol-gel method was applied to the synthesis of CeO2-NPs using poly(allylamine) (PAA) as a capping and/or stabilizing agent. The different molecular weights of PAA (15,000, 17,000, and 65,000 g/mol) were used to investigate the physico-chemical and biological properties of the NPs. In order to understand their performance as an anticancer agent, three cell lines (MCF7, HeLa, and erythrocyte) were analyzed by MTT assay and RBC hemolysis assay. The results showed that the CeO2-NPs had anticancer effects on the viability of MCF7 cells with half-maximal inhibitory concentration (IC50) values of 17.44 ± 7.32, 6.17 ± 1.68, and 0.12 ± 0.03 µg/mL for PAA15000, PAA17000, PAA65000, respectively. As for HeLa cells, IC50 values reduced considerably to 8.09 ± 1.55, 2.11 ± 0.33, and 0.20 ± 0.01 µg/mL, in order. A decrease in the viability of cancer cells was associated with the 50% hemolytic concentration (HC50) of 0.022 ± 0.001 mg/mL for PAA15000, 3.74 ± 0.58 mg/mL for PAA17000, and 7.35 ± 1.32 mg/mL for PAA65000. Ultraviolet-Visible (UV-vis) spectroscopy indicated that an increase in the PAA molecular weight led to a blue shift in the bandgap and high amounts of Ce3+ on the surface of the nanoceria. Thus, PAA65000 could be considered as a biocompatible nanoengineered biomaterial for potential applications in cancer nanomedicine.

Curcumin: a phytochemical modulator of estrogens and androgens in tumors of the reproductive system.

Curcumin (Cur) is an active derivative extracted from turmeric which exerts a wide range of interactions with biomolecules through complex signaling pathways. Cur has been extensively shown to possess potential antitumor properties. In addition, there is growing body of evidence suggesting that Cur may exert potential anti-estrogen and anti-androgen activity. In vitro and in vivo studies suggest that anticancer properties of Cur against tumors affecting the reproductive system in females and males may be underlied by the Cur-mediated inhibition of androgen and estrogen signaling pathways. In this review we examine various studies assessing the crosstalk between Cur and both androgen and estrogen hormonal activity. Also, we discuss the potential chemopreventive and antitumor role of Cur in the most prevalent cancers affecting the reproductive system in females and males.

Clinical and Radiographic Assessments of Tooth Socket Preservation Using Leukocyte Platelet-Rich Fibrin.

Leukocyte platelet-rich fibrin (L-PRF) has the potential to accelerate wound healing. Here, we assess clinical and radiographic outcomes of socket preservation using L-PRF. For this single-blind, randomized, split-mouth clinical trial, we selected 22 patients (15 males and seven females), who required extraction of single-rooted teeth. Subjects were randomly assigned to two groups. We used L-PRF in the extraction socket on one side and no material on the contralateral side. We obtained cone-beam computed tomographic images and diagnostic casts from tooth extraction sockets before surgery and 3 mo after the procedure. Changes in buccolingual diameter and height of bone at 3 mo after tooth extraction (compared to baseline) were determined and digitized data statistically analyzed using Statistical Package for the Social Sciences software, ver. 25.0 (IBM, Armonk, NY) via the paired t-test. In tooth sockets with/without L-PRF application 3 mo after extraction, bone buccolingual diameter significantly decreased at socket center to 0, 1, and 3 mm from the ridge crest, compared to baseline. A significant reduction occurred in sockets with/without L-PRF application in buccal and lingual bone height at the bony socket midbuccal portion of and mesial and distal septa (p < 0.0001). However, the Mann-Whitney U test showed changes to be significantly greater in controls than the case group (p < 0.0001). Taking into account study limitations, application of L-PRF in tooth extraction sockets significantly decreased reductions in bone height and buccolingual diameter compared to control sockets.

Antiproliferative Effects of Free and Encapsulated Hypericum Perforatum L. Extract and Its Potential Interaction with Doxorubicin for Esophageal Squamous Cell Carcinoma.

OBJECTIVES: Esophageal squamous cell carcinoma (ESCC) is considered as a deadly medical condition that affects a growing number of people worldwide. Targeted therapy of ESCC has been suggested recently and required extensive research. With cyclin D1 as a therapeutic target, the present study aimed at evaluating the anticancer effects of doxorubicin (Dox) or Hypericum perforatum L. (HP) extract encapsulated in poly(lactic-co-glycolic acid) (PLGA) nanoparticles on the ESCC cell line KYSE30. METHODS: Nanoparticles were prepared using double emulsion method. Cytotoxicity assay was carried out to measure the anti-proliferation activity of Dox-loaded (Dox NPs) and HP-loaded nanoparticles (HP NPs) against both cancer and normal cell lines. The mRNA gene expression of cyclin D1 was evaluated to validate the cytotoxicity studies at molecular level. RESULTS: Free drugs and nanoparticles significantly inhibited KYSE30 cells by 55-73% and slightly affected normal cells up to 29%. The IC50 of Dox NPs and HP NPs was ~ 0.04-0.06 mg/mL and ~ 0.6-0.7 mg/mL, respectively. Significant decrease occurred in cyclin D1 expression by Dox NPs and HP NPs (P < 0.05). Exposure of KYSE-30 cells to combined treatments including both Dox and HP extract significantly increased the level of cyclin D1 expression as compared to those with individual treatments (P < 0.05). CONCLUSION: Dox NPs and HP NPs can successfully and specifically target ESCC cells through downregulation of cyclin D1. The simultaneous use of Dox and HP extract should be avoided for the treatment of ESCC.

Effects of estrogens and androgens on mitochondria under normal and pathological conditions.

Several lines of evidence have suggested that mitochondrial dysfunction plays a key role in neurodegeneration. The mitochondrial function is a potential target for steroid hormones, which could exert protective activities in the brain and other tissues. The decrease of some sex steroids with aging has been associated with deleterious effects on brain function and progression to neurodegenerative diseases. Recent in vitro and in vivo evidence provides the basis for this review on the interplay of sex steroids and mitochondrial defects in preventing or improving pathological events in the central nervous system (CNS). In this article, the role of mitochondria under normal and pathological states will be discussed. In addition, we will review studies conducted on steroidal compounds, which have neuroprotective effects targeting mitochondria. It has been shown that these compounds could exert both direct and indirect effects on mitochondria that promote or preserve mitochondrial function under pathological circumstances, such as acute brain injury and chronic neurodegeneration.

Curcumin: A naturally occurring autophagy modulator.

Autophagy is a self-degradative process that plays a pivotal role in several medical conditions associated with infection, cancer, neurodegeneration, aging, and metabolic disorders. Its interplay with cancer development and treatment resistance is complicated and paramount for drug design since an autophagic response can lead to tumor suppression by enhancing cellular integrity and tumorigenesis by improving tumor cell survival. In addition, autophagy denotes the cellular ability of adapting to stress though it may end up in apoptosis activation when cells are exposed to a very powerful stress. Induction of autophagy is a therapeutic option in cancer and many anticancer drugs have been developed to this aim. Curcumin as a hydrophobic polyphenol compound extracted from the known spice turmeric has different pharmacological effects in both in vitro and in vivo models. Many reports exist reporting that curcumin is capable of triggering autophagy in several cancer cells. In this review, we will focus on how curcumin can target autophagy in different cellular settings that may extend our understanding of new pharmacological agents to overcome relevant diseases.

Green synthesis of labeled CeO2 nanoparticles with 99mTc and its biodistribution evaluation in mice.

AIMS: The in vivo targeted diagnostic applications of biosynthetic Cerium oxide nanoparticles (CeO2-NPs), prepared by applying chitosan as a stabilizer, was explored by evaluating the cytotoxicity through MTT assay on WEHI 164 cell line, the Hemolytic activity of CeO2-NPs and biodistribution in rats. MAIN METHODS: The CeO2-NPs were characterized through the use of TGA/DTG, PXRD, FESEM, FTIR, and UV-Vis spectroscopy. The biodistribution of CeO2-NPs were determined by directly labeled nanoparticles with Technetium-99 m (99mTc) radioisotope (99mTc-CeO2-NPs). The labeling efficiency and stability of 99mTc-CeO2-NPs were also measured with Instant Thin Layer Chromatography (ITLC) method. The saturation study was investigated by 1 mCi of 99mTc-CeO2-NPs using different concentrations of WEHI 164 cells after 4 h of incubation. In vivo biodistribution study was performed by intravenous injection of 600 µCi/200 µL 99mTc-CeO2-NPs through rat's tail. KEY FINDINGS: CeO2-NPs seemed to have a low cytotoxic effect on WEHI 164 cell line and did not result in hemolysis. The biodistribution of CeO2-NPs has shown that a huge amount of 99mTc-CeO2-NPs was amassed in the living human organs, including liver, lung, spleen, stomach, and thyroid which shows the in vivo stability of the labeled conjugate. Herein, we have developed a facile, economical, and greener synthetic procedure applying Chitosan template. This green approach is comparable to conventional methods that utilize hazardous materials which are would be a suitable alternative to circumvent synthetic issues related to these materials. SIGNIFICANCE: The bio-applications of nano-sized CeO2-NPs were explored to find new horizon to use nanotechnology as the diagnostic tool.

Berberine: A potential adjunct for the treatment of gastrointestinal cancers?

Gastrointestinal cancers are among the most prevalent cancers in the general population. Despite effective early diagnostics and intervention, the gastrointestinal cancer-related mortality still remains elevated. Berberine (BBR) is a benzyl tetra isoquinoline alkaloid exracted from several plants. BBR is nontoxic to human normal cells, but suppresses the growth of different tumor cells: melanoma, epidermoid carcinoma, hepatoma, oral carcinoma, glioblastoma, prostatic carcinoma, and gastric carcinoma. In particular, BBR seems to suppress the proliferation of gastrointestinal cancers in a number of preclinical models. Several mechanisms of action have been hypothesized and demonstrated: immunomodulation, inhibition of topoisomerase enzymes, suppression of the EGF receptor, Her2/neu, and the VEGF receptor, induction of p53, Cip1/p21, Kip1/p27, Rb expression, induction of apoptosis (by regulation of MMPs pathway, caspases, Bax, and Smac/DIABLO), inhibition of arylamin N-acetyltransferase activity, and regulation of microRNAs expression. The aim of this review is to summarize the pharmacological effects of BBR on animal and human gastrointestinal cancers.

Protective effects of curcumin against doxorubicin-induced toxicity and resistance: A review.

Doxorubicin (DOX)-induced toxicity and resistance are major obstacles in chemotherapeutic approaches. Despite effective in the treatment of numerous malignancies, some clinicians have voiced concern that DOX has the potential to cause debilitating consequences in organ tissues, especially the heart. The mechanisms of toxicity and resistance are respectively related to induction of reactive oxygen species (ROS) and up-regulation of ATP-binding cassette (ABC) transporter. Curcumin (CUR) with several biological and pharmacological properties is expected to restore DOX-mediated impairments to tissues. This review is intended to address the current knowledge on DOX adverse effects and CUR protective actions in the heart, kidneys, liver, brain, and reproductive organs. Coadministration of CUR and DOX is capable of ameliorating DOX toxicity pertained to antioxidant, apoptosis, autophagy, and mitochondrial permeability.

Cadmium-induced toxicity is rescued by curcumin: A review.

Cadmium (Cd) is one of the most common environmental and occupational heavy metals with extended distribution. Exposure to Cd may be associated with several deleterious consequences on the liver, bones, kidneys, lungs, testes, brain, immunological, and cardiovascular systems. Overproduction of reactive oxygen species (ROS) as the main mechanism behind its toxicity causes oxidative stress and subsequent damages to lipids, proteins, and DNA. Therefore, antioxidants along with chelating agents have shown promising outcomes against Cd-induced toxicity. Curcumin with various beneficial effects and medical efficacy has been evaluated for its inhibitory activities against biological impairments caused by Cd. Thus, this article is intended to address the effectiveness of curcumin against toxicity following Cd entry. Curcumin can afford to attenuate lipid peroxidation, glutathione depletion, alterations in antioxidant enzyme, and so forth through scavenging and chelating activities or Nrf2/Keap1/ARE pathway induction. © 2017 BioFactors, 43(5):645-661, 2017.

Validity of immunohistochemistry method in predicting HER-2 gene status and association of clinicopathological variables with it in invasive breast cancer patients.

Human epidermal growth factor receptor-2 is an important and prognostic factors and one of the most targeted proteins in breast cancer's therapy. There is no globally accepted method for determining its status. Here, we aimed to evaluate the immunohistochemistry method validity in predicting HER-2 status by Fluorescence in situ hybridization method and investigate some clinicopathological variables association with HER-2 amplification. A total of 190 HER-2 2+ and 3+ by immunohistochemistry (IHC) invasive breast cancer cases were enrolled in this study. Fluorescence in situ hybridization (FISH) was performed for these cases using FDA criteria and the association between clinicopathological variables and HER-2 status evaluated. Study consisted of 190 invasive breast cancer patients (160 HER-2 2+ and 30 HER-2 3+). HER-2 FISH amplification according to FDA criteria was found 27.5% (44/160 patients) in HER-2 2+ patients and 83.3% (25/30 patients) in HER-2 3+ patients. Tumors with HER-2 amplification were more likely to be ER-negative (51.0% vs 31.2%, p = 0.013) and PR-negative (52.9% vs 27.0%, p < 0.001). This study showed that immunohistochemistry is not a good method for evaluating HER-2 status and decision-making about trastuzumab therapy even with 3+ score patients. However, this result may not be too strong for IHC 3+ cases due to the limited number of these patients in this study.

Expression of Bcl-2 and epithelial growth factor receptor proteins in keratocystic odontogenic tumor in comparison with dentigerous cyst and ameloblastoma.

BACKGROUND: Keratocystic odontogenic tumor (KCOT) is a developmental odontogenic cyst on which various investigations have been focused due to its biological activities, high tendency to recur and different growth mechanisms in comparison with other cystic lesions. Previous studies have shown different biological and proliferative activities for the lining epithelium of KCOT. The aim of this study was immunohistochemical evaluation of Bcl-2 and epidermal growth factor receptor (EGFR) expression in KCOT compared with dentigerous cyst and ameloblastoma. MATERIALS AND METHODS: Formalin-fixed and paraffin-embedded tissue sections of 16 cases of KCOT, 16 cases of dentigerous cyst and 16 cases of ameloblastoma were immunohistochemically analyzed to determine Bcl-2 and EGFR proteins' expression. Biotin-Stereotavidin method was used. It was observed by two oral pathologists separately, and the data were analyzed by Mann-Whitney and Kruskul-Wallis. P < 0.05 was considered as significant. RESULTS: Regardless of staining intensity, all cases of ameloblastoma and KCOT except dentigerous cases were positively stained for Bcl-2. Expression of Bcl-2 was higher in the peripheral layer of ameloblastoma and basal layer of KCOT. Furthermore, all cases of ameloblastoma and dentigerous cysts except KCOT samples were positively stained for EGFR. Expression of EGFR was higher in the peripheral layer of ameloblastoma and basal layer of dentigerous cysts. CONCLUSION: According to the expression of - Bcl-2 in ameloblastoma and KCOT, and no expression of EGFR in KCOT, it can be concluded that the biological activity and growth mechanisms of KCOT are different compared with other cystic lesions. However, the aggressive potential of KCOT is not as severe as that of a neoplasm such as ameloblastoma.

The significance of clinicopathological aspects of tumor for the detection of liver micrometastasis in patients with colorectal cancer.

BACKGROUND: Colorectal tumor is one of the main causes of death in our country. The aim of the present study was to determine the clinicopathological aspects of tumor and the presence of hepatic micrometastasis in patients with colorectal cancer (CRC). MATERIALS AND METHODS: Forty two patients with CRC were evaluated in the study surgical treatment was performed and liver biopsy was taken for the evaluation of micrometastasis by immunohistochemistry and polymerase chain reaction. The variables that have been evaluated were: Patient's gender, patients age at the time of diagnosis, size and location of tumor, tumor-node-metastasis stage and grade of the primary tumor, lymph node involvement, lymphovascular and neural invasion, presence of macrometastasis and carcinoembryonic antigen level prior to surgery. After 1 year patients were called and asked to come back to the clinic for elective colonoscopy to evaluate the surgical site for recurrence of tumor and survival. All variables were compared between patients in whom liver micrometastasis were present in comparison with patients without liver micrometastasis. RESULTS: Of the studied patients (6 with positive micrometatsis and 36 without micrometstasis), 38 were alive after 1 year (6 with positive micrometatsis and 32 without micrometstasis) and the difference was not significant between groups with or without micrometastasis (P = 0.52). In four of survived patients colonoscopy was abnormal, however this difference was not also significant between groups (P = 0.59). CONCLUSION: Clinicopathologic aspect of tumor was not different in CRC patients with and without hepatic micrometastasis.

Micrometastasis in non-small-cell lung cancer: Detection and staging.

BACKGROUND: The clinical relevance of bone marrow micrometastasis (BMM) in non-small-cell lung cancer is undetermined, and the value of such analyses in advanced stage patients has not been clearly assessed previously. This study was conducted to estimate the accuracy of both polymerase chain reaction (PCR) and immunohistochemistry (IHC) in micrometastases detection and determine the best site for bone marrow biopsy in order to find micrometastasis. METHODS: This prospective cross-sectional study was performed in the Department of Thoracic Surgery, Alzahra University Hospital from September 2008 to June 2009. To evaluate the bone marrow, a 3-cm rib segment and an aspirated specimen from the iliac bone prior to tumor resection were taken. PCR and IHC were performed for each specimen to find micrometastasis. RESULTS: Of 41 patients, 14 (34%) were positive for BMM by PCR compared with two positive IHC (4.8%). All BMMs were diagnosed in rib segments, and iliac specimens were all free from metastatic lesion. Our data showed no significant association between variables such as age, sex, histology, tumor location, side of tumor, involved lobe, smoking, or weight loss and presence of BMM. CONCLUSION: PCR could use as a promising method for BMM detection. BMM in a sanctuary site (rib) is not associated with advanced stages of lung cancer. In addition, when predictor variables such as age, sex, histology, tumor location, smoking, or weight loss are analyzed, no correlation can be found between micrometastasis prevalence and any of those variables.

Evaluation of ARG protein expression in mature B cell lymphomas compared to non-neoplastic reactive lymph node.

The participation of Abl-Related Gene (ARG) is demonstrated in pathogenesis of different human malignancies. However there is no conclusive evidence on ARG expression level in mature B cell lymphomas. In this study we evaluated ARG protein expression in Follicular Lymphoma (FL), Burkitt's Lymphoma (BL) and Diffused Large B Cell Lymphoma (DLBCL) in comparison with non-neoplastic lymph nodes. Semi-quantitative fluorescent ImmunoHistoChemistry was applied on 14, 7 and 4 patients with DLBCL, FL and BL respectively, adding to 4 normal and 4 reactive lymph nodes. The mean ratio of ARG/GAPDH expression was significantly different (p<0.00) between lymphomas and control samples, with DLBCL having the highest ARG expression amongst all. Over expression of ARG was seen in FL and BL, with FL expressing statistically more ARG than BL. Moreover, the ARG/GAPDH expression ratio increased from DLBCL stage I towards stage VI, all showing significantly more ARG expression than FL and BL (in all cases p<0.00).