Search results for: hepatocellular carcinoma cells

Authors: N. A. Kazemi Sefat, M. M. Mohammadi, J. Hadjati, S. Talebi, M. Ajami, H. Daneshvar

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Colorectal cancer metastases result in a significant number of cancer related deaths. Histone deacetylase (HDAC) inhibitors induce growth arrest and apoptosis in a variety of human cancer cells. Sodium butyrate (SB) is a short chain fatty acid, belongs to HDAC inhibitors which is released in the colonic lumen as a consequence of fiber fermentation. In this study, we are about to assess the effect of sodium butyrate on HCT116 human colorectal carcinoma cell line. The viability of cells was measured by microscopic morphologic study and MTT assay. After 48 hours, treatments more than 10 mM lead to cell injury in HCT116 by increasing cell granulation and decreasing cell adhesion (p>0.05). After 72 hours, treatments at 10 mM and more lead to significant cell injury (p<0.05). Our results may suggest that the gene expression which is contributed in cell proliferation and apoptosis has been changed under pressure of HDAC inhibition.

Keywords: colorectal cancer, sodium butyrate, cytotoxicity, MTT

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Authors: Katarzyna Lubecka, Kirsty Flower, Megan Beetch, Lucinda Kurzava, Hannah Buvala, Samer Gawrieh, Suthat Liangpunsakul, Tracy Gonzalez, George McCabe, Naga Chalasani, James M. Flanagan, Barbara Stefanska

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Hepatocellular carcinoma (HCC), the most prevalent type of primary liver cancer, is the second leading cause of cancer death worldwide. Late onset of clinical symptoms in HCC results in late diagnosis and poor disease outcome. Approximately 85% of individuals with HCC have underlying liver cirrhosis. However, not all cirrhotic patients develop cancer. Reliable early detection biomarkers that can distinguish cirrhotic patients who will develop cancer from those who will not are urgently needed and could increase the cure rate from 5% to 80%. We used Illumina-450K microarray to test whether blood DNA, an easily accessible source of DNA, bear site-specific changes in DNA methylation in response to HCC before diagnosis with conventional tools (pre-diagnostic). Top 11 differentially methylated sites were selected for validation by pyrosequencing. The diagnostic potential of the 11 pyrosequenced probes was tested in blood samples from a prospective cohort of cirrhotic patients. We identified 971 differentially methylated CpG sites in pre-diagnostic HCC cases as compared with healthy controls (P < 0.05, paired Wilcoxon test, ICC ≥ 0.5). Nearly 76% of differentially methylated CpG sites showed lower levels of methylation in cases vs. controls (P = 2.973E-11, Wilcoxon test). Classification of the CpG sites according to their location relative to CpG islands and transcription start site revealed that those hypomethylated loci are located in regulatory regions important for gene transcription such as CpG island shores, promoters, and 5’UTR at higher frequency than hypermethylated sites. Among 735 CpG sites hypomethylated in cases vs. controls, 482 sites were assigned to gene coding regions whereas 236 hypermethylated sites corresponded to 160 genes. Bioinformatics analysis using GO, KEGG and DAVID knowledgebase indicate that differentially methylated CpG sites are located in genes associated with functions that are essential for gene transcription, cell adhesion, cell migration, and regulation of signal transduction pathways. Taking into account the magnitude of the difference, statistical significance, location, and consistency across the majority of matched pairs case-control, we selected 11 CpG loci corresponding to 10 genes for further validation by pyrosequencing. We established that methylation of CpG sites within 5 out of those 10 genes distinguish cirrhotic patients who subsequently developed HCC from those who stayed cancer free (cirrhotic controls), demonstrating potential as biomarkers of early detection in populations at risk. The best predictive value was detected for CpGs located within BARD1 (AUC=0.70, asymptotic significance ˂0.01). Using an additive logistic regression model, we further showed that 9 CpG loci within those 5 genes, that were covered in pyrosequenced probes, constitute a panel with high diagnostic accuracy (AUC=0.887; 95% CI:0.80-0.98). The panel was able to distinguish pre-diagnostic cases from cirrhotic controls free of cancer with 88% sensitivity at 70% specificity. Using blood as a minimally invasive material and pyrosequencing as a straightforward quantitative method, the established biomarker panel has high potential to be developed into a routine clinical test after validation in larger cohorts. This study was supported by Showalter Trust, American Cancer Society (IRG#14-190-56), and Purdue Center for Cancer Research (P30 CA023168) granted to BS.

Keywords: biomarker, DNA methylation, early detection, hepatocellular carcinoma

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Authors: Hanan Alsaeid Alshenawy

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Background: Cervical dysplasia, which is potentially precancerous, has increased in young women. Detection of cervical is important for reducing morbidity and mortality in cervical cancer. This study analyzes the immunohistochemical expression of p16, HPV L1 capsid protein and Ki67 in cervical intraepithelial lesions and correlates them with lesion grade to develop a set of markers for diagnosis and detect the prognosis of cervical cancer precursors. Methods: 75 specimens were analyzed including 15 cases CIN 1, 28 CIN 2, 20 CIN 3, and 12 cervical squamous carcinoma, besides 10 normal cervical tissues. They were stained for p16, HPV L1 and Ki-67. Sensitivity, specificity, predictive values and accuracy were evaluated for each marker. Results: p16 expression increased during the progression from CIN 1 to carcinoma. HPV L1 positivity was detected in CIN 2 and decreased gradually as the CIN grade increased but disappear in carcinoma. Strong Ki-67 expression was observed with high grades CIN and carcinoma. p16, HPV L1 and Ki67 were sensitive but with variable specificity in detecting CIN lesions. Conclusions: p16, HPV L1 and Ki67 are useful set of markers in establishing the risk of high-grade CIN. They complete each other to reach accurate diagnosis and prognosis.

Keywords: p16, HPV L1, Ki67, CIN, cervical carcinoma

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Authors: Muhammad Umar Hassan

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Renal cell carcinoma is a subset of kidney cancer that arises in the lining of DCT and is present in parenchymal tissue. Diagnosis is based on lab reports, including urinalysis, renal function tests (RFTs), and electrolyte balance, along with imaging techniques. Organ failure and other complications have been commonly observed in these cases. Over the years, the presentation of patients has varied, so carcinoma was classified on the basis of site, shape, and consistency for detailed analysis. Lifestyle patterns and occupational history were inquired about and recorded. Methods: Data from 100 patients presenting to the oncology and nephrology department of Mayo Hospital in the year 2015-2020 were included in this retrospective study on a random basis. The study was specifically focused on three risk factors. Smoking, occupational exposures, and Hakim medicine are taken by the patient for any cause. After procurement of data, follow-up contacts of these patients were established, resulting in a detailed analysis of lifestyle. Conclusion: The inference drawn is a direct causal link between smoking, industrial workplace exposure, and Hakim medicine with the development of Renal Cell Carcinoma. It was shown in the majority of the patients and hence confirmed our hypothesis.

Keywords: renal cell carcinoma, kidney cancer, clear cell carcinoma

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Authors: M. Pourshirazi, M. Esmaelifar, A. Aliahmadi, F. Yazdian, A. S. Hatamian Zarami, S. J. Ashrafi

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Medicinal fungi are the new potential source of drugs to improve the treatment of diseases with association to oxidative agents such as cancers. Monascus purpureus contains functional components potentially effective in improving human health. In the present work, ethanolic extract of Monascus purpureus (EEM) was evaluated for health improving potential mainly focusing on antioxidant and anticancer activities. Ferric ion reducing power (FRAP), scavenging of DPPH radicals and determining viability of breast carcinoma MCF-7 and cervical carcinoma HeLa cells with MTT assay were evaluated. Our data showed a significant antioxidant activity of EEM with 142.45 µg/ml inhibition concentration of 50% DPPH radicals and 2112.33 µg eq.Fe2+/mg extract of FRAP assay. These results might be caused by antioxidant components such as pigments and phenolic compounds. Further, the results demonstrated that EEM caused significant reduction in the viability of MCF-7 with IC50 of 7 µg/ml but not have good effect against viability of HeLa cells. Accordingly, Monascus purpureus is presented as a strong potential of breast cancer treatment. In further study, the mechanistic studies are needed to determine the mechanisms of anticancer activity of EEM.

Keywords: Monascus purpureus, antioxidant, cancer, ethanolic extract

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Authors: Laura Ulitzky, Dougbeh-Chris Nyan, Manuel M. Lafer, Erica Silberstein, Nicoleta Cehan, Deborah R. Taylor

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Hepatitis C virus (HCV)-associated hepatocellular carcinoma, fibrosis and cirrhosis are more frequent in men and postmenopausal women than in premenopausal women and women receiving hormone replacement therapy, suggesting that β-estradiol (estrogen) plays an innate role in preventing viral infection and liver disease. Estrogen classically acts through nuclear estrogen receptors or, alternatively, through the membrane-bound G-protein-coupled estrogen receptor (GPR30 or GPER). We observed a marked decrease in detectable virus when HCV-infected human hepatoma cells were treated with estrogen. The effect was mimicked by both Tamoxifen (Tam) and G1, a GPR30-specific agonist, and was reversed by the GPR30-specific antagonist, G15. Through GPR30, estrogen-mediated the down-regulation of occludin; a tight junction protein and HCV receptor, by promoting activation of matrix metalloproteinases (MMPs). Activated MMP-9 was secreted in response to estrogen, cleaving occludin in the extracellular Domain D, the motif required for HCV entry and spread. This pathway gives new insight into a novel innate immune pathway and the disparate host-virus responses to HCV demonstrated by the two sexes. Moreover, these data suggest that hormone replacement therapy may have beneficial antiviral properties for HCV-infected postmenopausal women and show promise for new antiviral treatments for both men and women.

Keywords: HCV, estrogen, occludin, MMPs

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Authors: Mohammed A. Abutalib

Abstract:

Papillary thyroid carcinoma (PTC) accounts for the most common type of thyroid cancer, a well-differentiated type. PTC is featured by biologically low-grade and less aggressive tumors with a survival rate of 10 years in most of the diagnosed cases. PTC can be presented with the involvement of cervical lymph nodes in about 50% of the patients, yet the distant spread is very uncommon. Herein, we discussed an early 50-year-old male patient with a history of PTC that presented to the emergency department complaining of shortness of breath and a radiological finding of hydrothorax. Cytologic examination, together with immune-histochemical staining and molecular studies of pleural effusion aspiration, concluded the definitive diagnosis of metastatic papillary thyroid carcinoma in the pleural space. PTC seldom causes metastatic niches in the pleural space, and this is a rare clinical presentation; nevertheless, a differential diagnosis of thyroid metastasis needs to be excluded.

Keywords: thyroid cancer, malignant pleural effusion, cytology aspiration, papillary thyroid carcinoma

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Authors: Loredana G. Marcu, David Marcu, Sanda M. Filip

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Advanced head and neck cancers are aggressive tumours, which require aggressive treatment. Treatment efficiency is often hindered by cancer cell repopulation during radiotherapy, which is due to various mechanisms triggered by the loss of tumour cells and involves both stem and differentiated cells. The aim of the current paper is to present in silico simulations of radiotherapy schedules on a virtual head and neck tumour grown with biologically realistic kinetic parameters. Using the linear quadratic formalism of cell survival after radiotherapy, altered fractionation schedules employing various treatment breaks for normal tissue recovery are simulated and repopulation mechanism implemented in order to evaluate the impact of various cancer cell contribution on tumour behaviour during irradiation. The model has shown that the timing of treatment breaks is an important factor influencing tumour control in rapidly proliferating tissues such as squamous cell carcinomas of the head and neck. Furthermore, not only stem cells but also differentiated cells, via the mechanism of abortive division, can contribute to malignant cell repopulation during treatment.

Keywords: radiation, tumour repopulation, squamous cell carcinoma, stem cell

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Authors: Kristina Jansen, Maximilian Lennartz, Patrick Lebok, Guido Sauter, Ronald Simon, David Dum, Stefan Steurer

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DOG1 (Discovered on GIST1) is a voltage-gated calcium-activated chloride and bicarbonate channel that is highly expressed in interstitial cells of Cajal and in gastrointestinal stromal tumors (GIST) derived from Cajal cells. To systematically determine in what tumor entities and normal tissue types DOG1 may be further expressed, a tissue microarray (TMA) containing 15,965 samples from 121 different tumor types and subtypes as well as 608 samples of 76 different normal tissue types were analyzed by immunohistochemistry. DOG1 immunostaining was found in 67 tumor types, including GIST (95.7%), esophageal squamous cell carcinoma (31.9%), pancreatic ductal adenocarcinoma (33.6%), adenocarcinoma of the Papilla Vateri (20%), squamous cell carcinoma of the vulva (15.8%) and the oral cavity (15.3%), mucinous ovarian cancer (15.3%), esophageal adenocarcinoma (12.5%), endometrioid endometrial cancer (12.1%), neuroendocrine carcinoma of the colon (11.1%) and diffuse gastric adenocarcinoma (11%). Low level-DOG1 immunostaining was seen in 17 additional tumor entities. DOG1 expression was unrelated to histopathological parameters of tumor aggressiveness and/or patient prognosis in cancers of the breast (n=1,002), urinary bladder (975), ovary (469), endometrium (173), stomach (233), and thyroid gland (512). High DOG1 expression was linked to estrogen receptor expression in breast cancer (p<0.0001) and the absence of HPV infection in squamous cell carcinomas (p=0.0008). In conclusion, our data identify several tumor entities that can show DOG1 expression levels at similar levels as in GIST. Although DOG1 is tightly linked to a diagnosis of GIST in spindle cell tumors, the differential diagnosis is much broader in DOG1 positive epithelioid neoplasms.

Keywords: biomarker, DOG1, immunohistochemistry, tissue microarray

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Authors: Prajna Paramita Naik, Sujit Kumar Bhutia

Abstract:

Background: Regardless of the development multimodal treatment strategies, oral squamous cell carcinoma (OSCC) is often associated with a high rate of recurrence, metastasis and chemo- and radio- resistance. The present study inspected the relevance of CD44, ABCB1 and ADAM17 expression as a putative stem cell compartment in oral squamous cell carcinoma (OSCC) and deciphered the role of autophagy in regulating the expression of aforementioned proteins, stemness and chemoresistance. Methods: A retrospective analysis of CD44, ABCB1 and ADAM17 expression with respect to the various clinicopathological factors of sixty OSCC patients were determined via immunohistochemistry. The correlation among CD44, ABCB1 and ADAM17 expression was established. Sphere formation assay, flow cytometry and fluorescence microscopy were conducted to elucidate the stemness and chemoresistance nature of established cisplatin-resistant oral cancer cells (FaDu). The pattern of expression of CD44, ABCB1 and ADAM17 in parental (FaDu-P) and resistant FaDu cells (FaDu-CDDP-R) were investigated through fluorescence microscopy. Western blot analysis of autophagy marker proteins was performed to compare the status of autophagy in parental and resistant FaDu cell. To investigate the role of autophagy in chemoresistance and stemness, sphere formation assay, immunofluorescence and Western blot analysis was performed post transfection with siATG14 and the level of expression of autophagic proteins, mitochondrial protein and stemness-associated proteins were analyzed. The statistical analysis was performed by GraphPad Prism 4.0 software. p-value was defined as follows: not significant (n.s.): p > 0.05;*: p ≤ 0.05; **: p ≤ 0.01; ***: p ≤ 0.001; ****: p ≤ 0.0001 were considered statistically significant. Results: In OSCC, high CD44, ABCB1 and ADAM17 expression were significantly correlated with higher tumor grades and poor differentiation. However, the expression of these proteins was not related to the age and sex of OSCC patients. Moreover, the expression of CD44, ABCB1 and ADAM17 were positively correlated with each other. In vitro and OSCC tissue double labeling experiment data showed that CD44+ cells were highly associated with ABCB1 and ADAM17 expression. Further, FaDu-CDDP-R cells showed higher sphere forming capacity along with increased fraction of the CD44+ population and β-catenin expression FaDu-CDDP-R cells also showed accelerated expression of CD44, ABCB1 and ADAM17. A comparatively higher autophagic flux was observed in FaDu-CDDP-R against FaDu-P cells. The expression of mitochondrial proteins was noticeably reduced in resistant cells as compared to parental cells indicating the occurrence of autophagy-mediated mitochondrial degradation in oral cancer. Moreover, inhibition of autophagy was coupled with the decreased formation of orospheres suggesting autophagy-mediated stemness in oral cancer. Blockade of autophagy was also found to induce the restoration of mitochondrial proteins in FaDu-CDDP-R cells indicating the involvement of mitophagy in chemoresistance. Furthermore, a reduced expression of CD44, ABCB1 and ADAM17 was also observed in ATG14 deficient cells FaDu-P and FaDu-CDDP-R cells. Conclusion: The CD44+ ⁄ABCB1+ ⁄ADAM17+ expression in OSCC might be associated with chemoresistance and a putative CSC compartment. Further, the present study highlights the contribution of mitophagy in chemoresistance and confirms the potential involvement of autophagic regulation in acquisition of stem-like characteristics in OSCC.

Keywords: ABCB1, ADAM17, autophagy, CD44, chemoresistance, mitophagy, OSCC, stemness

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Authors: Dalia M. Abouelfadl, Noha N. Yassen, Marwa E. Shabana

Abstract:

Background: The evolution of immune therapy motivated many to study the relation between immune response and progression of cancer. Little is known about expression of PD-L1 (a newly evolving immunotherapeutic drug) in papillary thyroid carcinoma (PTC) arising de-novo and PTC arising on top of autoimmune thyroiditis (Hashimoto's (HT) and lymphocytic thyroiditis (LT)). The aim of this work is to study the alteration of expression of PD-L1 in PTCs arising from de-novo or on top of HT OR LT using immunohistochemistry and image analyser system. Method: 100 paraffin blocks for PTC cases were collected retrospectively for staining using PD-L1 rabbit monoclonal antibody (BIOCARE-ACI 3171 A, C). The antibody expression is measured digitally using Image Analyzer Leica Qwin 3000, and the membranous and cytoplasmic expression of PD-L1 in tumor cells was considered positive. The results were correlated with tumor grade, size, and LN status. Results: The study samples consisted of 41 cases of PTC arising De novo, 36 cases on top of HT, and 23 on top of LT. Expression of PD-L1 was highest among the PTC-HL group (25 case-69%) followed by PTC-TL group (14 case-60.8%) then de-novo PTC (19 case-46%) with P Value < 0.05. PD-L1 expression correlated with nodal metastasis and was not relevant to tumor size or grade. Conclusion: The severity of the immune response in tumor microenvironment directly influences PTC prognosis. The anti PD-L1 Ab can be a very successful therapeutic agent for PTC arising on top of HT.

Keywords: carcinoma, Hashimoto's, lymphocytic, papillary, PD-L1, thyroiditis

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Authors: Liu Xiaohan

Abstract:

Epstein–Barr virus (EBV) is a human herpesvirus and is closely related to many malignancies of lymphocyte and epithelial origins, such as gastric cancer, Burkitt’s lymphoma, and nasopharyngeal carcinoma (NPC). NPC is a malignant epithelial tumor which is 100% associated with EBV latent infection. Most of the NPC cases are densely populated in southern China, especially in Guangdong and Hong Kong. To our knowledge, overexpression of pro-inflammatory cytokines may result in a loss of balance of the immune system and cause damage to human bodies. Interleukin-6 (IL6) is a pro-inflammatory cytokine which plays an important role in tumor progression. In addition, gene expression is regulated by both transcriptional and post-transcriptional pathways, while post-transcriptional regulation is an important mechanism to modulate the mature mRNA level in mammalian cells. AU-rich element binding factor 1 (AUF1)/heterogeneous nuclear RNP D (hnRNP D) is known for its function in destabilizing mRNAs, including cytokines and cell cycle regulators. Previous studies have found that overexpression of hnRNP D would lead to tumorigenesis. In this project, our aim is to determine the role played by hnRNP D in EBV-infected cells and how our anti-EBV agents can affect the function of hnRNP D. The results of this study will provide a new insight into how the pro-inflammatory cytokine expression can be regulated by EBV.

Keywords: interleukin 6 (IL6), epstein-barr virus (EBV), nasopharyngeal carcinoma (NPC, epstein-barr nuclear antigen-1 (EBNA1)

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Authors: Laila Seada, Ashraf Ibrahim, Amjad Al Shammari

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Background and Objectives: Breast carcinoma is the most common cancer of females in Hail region, accounting for 31% of all diagnosed cancer cases followed by thyroid carcinoma (25%) and colorectal carcinoma (13%). Methods: In the present retrospective study, all cases of breast lesions received at the histopathology department in King Khalid Hospital, Hail, during the period from May 2011 to April 2016 have been retrieved from department files. For all cases, a trucut biopsy, lumpectomy, or modified radical mastectomy was available for histopathologic diagnosis, while 105/140 (75%) had, as well, preoperative fine needle aspirates (FNA). Results: 49 cases out of 140 (35%) breast lesions were carcinomas: 44/49 (89.75%) was invasive ductal, 2/49(4.1%) invasive lobular carcinomas, 1/49(2.05%) intracystic low grade papillary carcinoma and 2/49 (4.1%) ductal carcinoma in situ (DCIS). Mean age for malignant cases was 45.06 (+/-10.58): 32.6% were below the age of 40 and 30.6 below 50 years, 18.3% below 60 and 16.3% below 70 years. For the benign group, mean age was 32.52 (+/10.5) years. Benign lesions were in order of frequency: 34 fibroadenomas, 14 fibrocystic disease, 12 chronic mastitis, five granulomatous mastitis, three intraductal papillomas, and three benign phyllodes tumor. Tubular adenoma, lipoma, skin nevus, pilomatrixoma, and breast reduction specimens constituted the remaining specimens. Conclusion: Breast lesions are common in our series and invasive carcinoma accounts for more than 1/3^rd of the lumps, with 63.2% incidence in pre-menopausal ladies, below the age of 50 years. FNA as a non-invasive procedure, proved to be an effective tool in diagnosing both benign and malignant/suspicious breast lumps and should continue to be used as a first assessment line of palpable breast masses.

Keywords: age incidence, breast carcinoma, fine needle aspiration, hail region

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Authors: Diwei Lin, Amanda Jh. Tan

Abstract:

We present a very rare case of de novo large cell neuroendocrine carcinoma of the prostate (LCNEC) in an 84-year-old male on a background of high-grade, muscle-invasive transitional cell carcinoma of the bladder. While NE tumours account for 1% to 5% of all cases of prostate cancer and scattered NE cells can be found in 10% to 100% of prostate adenocarcinomas, pure LCNEC of the prostate is extremely rare. Most LCNEC of the prostate is thought to originate by clonal progression under the selection pressure of therapy and refractory to long-term hormonal treatment for adenocarcinoma of the prostate. De novo LCNEC is only described in case reports and is thought to develop via direct malignant transformation. Limited data in the English literature makes it difficult to accurately predict the prognosis of LCNEC of the prostate. However, current evidence suggesting that increasing NE differentiation in prostate adenocarcinoma is associated with a higher stage, high-grade disease, and a worse prognosis.

Keywords: large cell neuroendocrine cancer, prostate cancer, refractory cancer, medical and health sciences

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Authors: Ahlam H. Mahmoud, Samir F. Zohny, Ibrahim H. Boraia, Faten S. Bayoumic, Eman Eissa

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Hepatocellular carcinoma is one of the most common cancers worldwide and is known to be resistant to conventional chemotherapy. Therefore, we aimed to assess the Salsola inermis extract as a novel chemopreventive and/or therapeutic agent against N-nitrosodiethylamine (DNE)/phenobarbital (PB)-induced hepatocarcinogenesis in rats. Adult male Wistar albino rats were divided into five groups: group1 rats were served as normal controls; group 2 rats were injected intraperitoneally with S. inermis extract (100 mg/kg body weight/day) for 20 weeks; group 3 rats were subjected to two-phase hepatocarcinogenic regimen (initiation of hepatocarcinogenesis was performed by a single intraperitoneal injection of DEN at a dose of 200 mg/kg body weight, 2 weeks later, the carcinogenic effect was promoted by supplementation of rats with 0.05% PB for 16 weeks); group 4 rats were injected intraperitoneally with S. inermis extract 2 weeks prior to the injection of DEN, the daily injection of S. inermis extract was then continued for 18 weeks along with two-phase hepatocarcinogenic regimen (chemoprevention group); and group 5 rats were subjected to the two-phase hepatocarcinogenic regimen, and then, the animals were injected intraperitoneally with S. inermis extract for 4 weeks (treatment group). The activities of serum liver enzymes and levels of total bilirubin, conjugated bilirubin, α-fetoprotein, vascular endothelial growth factor (VEGF) and soluble intercellular adhesion molecule-1 (sICAM-1) in serum were decreased in chemopreventive and treated rats compared with DEN/PB-administered rats. Interestingly, the serum levels of total protein and albumin were normalized in chemopreventive and treated rats. Moreover, the majority of chemopreventive and treated rats showed an almost normal histological pattern of liver. In conclusion, S. inermis extract possessed chemopreventive and therapeutic activities against hepatocarcinogenesis in rats partially through the inhibition of VEGF and sICAM-1.

Keywords: Salsola inermis extract, hepatocarcinogenesis, α–fetoprotein, VEGF, sICAM-1

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Authors: Rolivhuwa Bishop Ramagoma1*, Lynn Cairncross1, , Saartjie Roux1

Abstract:

According to the world health organisation, colon cancer is among the most common cancers diagnosed in both men and women. Specifically, it is the second leading cause of cancer related deaths accounting for over 860 000 deaths worldwide in 2018. Currently, chemotherapy has become an essential component of most cancer treatments. Despite progress in cancer drug development over the previous years, traditional chemotherapeutic drugs still have low selectivity for targeting tumour tissues and are frequently constrained by dose-limiting toxicity. The creation of nanoscale delivery vehicles capable of directly directing treatment into cancer cells has recently caught the interest of researchers. Herein, the development of peptide-functionalized polyethylene glycol gold nanoparticles (Peptide-PEG-AuNPs) as a cellular probe and delivery agent is described, with the higher aim to develop a specific diagnostic prototype and assess their specificity not only against cell lines but primary human cells as well. Gold nanoparticles (AuNPs) were synthesized and stabilized through chemical conjugation. The synthesized AuNPs were characterized, stability in physiological solutions was assessed, their cytotoxicity against colon carcinoma and non-carcinoma skin fibroblasts was also studied. Furthermore, genetic effect through real-time polymerase chain reaction (RT-PCR), localization and uptake, peptide specificity were also determined. In this study, different peptide-AuNPs were found to have preferential toxicity at higher concentrations, as revealed by cell viability assays, however, all AuNPs presented immaculate stability for over 3 months following the method of synthesis. The final obtained peptide-PEG-AuNP conjugates showed good biocompatibility in the presence of high ionic solutions and biological media and good cellular uptake. Formulation of colon cancer specific targeting peptide was successful, additionally, the genes/pathways affected by the treatments were determined through RT-PCR. Primary cells study is still on going with promising results thus far.

Keywords: nanotechnology, cancer, diagnosis, therapeutics, gold nanoparticles.

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Authors: N. Ahmadi, H. Yousefnia, A. Bahrami-Samani

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Chitosan is a natural and biodegradable polysaccharide with special characteristic for application in intracavital therapy. 166Ho-chitosan has been reported for the treatment of hepatocellular carcinoma and RSV with promising results. The aim of this study was to prepare 186/188Re-chitosan for radiosynovectomy purposes and investigate the probability of its leakage from the knee joint. 186/188Re was produced by neutron irradiation of the natural rhenium in a research reactor. Chemical processing was performed to obtain (186/188Re)-NaReO4- according to the IAEA manual. A stock solution of chitosan was prepared by dissolving in 1 % acetic acid aqueous solution (10 mg/mL). 1.5 mL of this stock solution was added to the vial containing the activity and the mixture was stirred for 5 min in the room temperature. The radiochemical purity of the complex was checked by the ITLC method, showing the purity of higher than 98%. Distribution of the radiolabeled complex was determined after intra-articular injection into the knees of rats. Excellent retention was observed in the joint with approximately no activity in the other organs.

Keywords: chitosan, leakage, radiosynovectomy, rhenium

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Authors: Shangqing Song, Bin Xu, Yajun Cheng, Zhong Wang

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miRNAs derived from exosomes exist in a body fluid such as urine were regarded as potential biomarkers for various human cancers diagnosis and prognosis, as mature miRNAs can be steadily preserved by exosomes. However, its potential value in clear cell renal cell carcinoma (ccRCC) diagnosis and prognosis remains unclear. In the present study, differentially expressed miRNAs from urinal exosomes were identified by next-generation sequencing (NGS) technology. The 16 differentially expressed miRNAs were identified between ccRCC patients and healthy donors. To explore the specific diagnosis biomarker of ccRCC, we validated these urinary exosomes from 70 early-stage renal cancer patients, 30 healthy people and other urinary system cancers, including 30 early-stage prostate cancer patients and 30 early-stage bladder cancer patients by qRT-PCR. The results showed that urinary exosome miR-30c-5p could be stably amplified and meanwhile the expression of miR-30c-5p has no significant difference between other urinary system cancers and healthy control, however, expression level of miR-30c-5p in urinary exosomal of ccRCC patients was lower than healthy people and receiver operation characterization (ROC) curve showed that the area under the curve (AUC) values was 0.8192 (95% confidence interval was 0.7388-0.8996, P= 0.0000). In addition, up-regulating miR-30c-5p expression could inhibit renal cell carcinoma cells growth. Lastly, HSP5A was found as a direct target gene of miR-30c-5p. HSP5A depletion reversed the promoting effect of ccRCC growth casued by miR-30c-5p inhibitor, respectively. In conclusion, this study demonstrated that urinary exosomal miR-30c-5p is readily accessible as diagnosis biomarker of early-stage ccRCC, and miR-30c-5p might modulate the expression of HSPA5, which correlated with the progression of ccRCC.

Keywords: clear cell renal cell carcinoma, exosome, HSP5A, miR-30c-5p

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Authors: Vanja Misic, Mohamed El-Mogy, Yousef Haj-Ahmad

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Endonuclease G (EndoG) is a well conserved mitochondrio-nuclear nuclease with dual lethal and vital roles in the cell. The aim of our study was to examine whether EndoG exerts its nuclease activity on exogenous DNA substrates such as plasmid DNA (pDNA), considering their importance in gene therapy applications. The effects of EndoG knockdown on pDNA stability and levels of encoded reporter gene expression were evaluated in the cervical carcinoma HeLa cells. Transfection of pDNA vectors encoding short-hairpin RNAs (shRNAs) reduced levels of EndoG mRNA and nuclease activity in HeLa cells. In physiological circumstances, EndoG knockdown did not have an effect on the stability of pDNA or the levels of encoded transgene expression as measured over a four day time-course. However, when endogenous expression of EndoG was induced by an extrinsic stimulus, targeting of EndoG by shRNA improved the perceived stability and transgene expression of pDNA vectors. Therefore, EndoG is not a mediator of exogenous DNA clearance, but in non-physiological circumstances it may non-specifically cleave intracellular DNA regardless of its origin. These findings make it unlikely that targeting of EndoG is a viable strategy for improving the duration and level of transgene expression from non-viral DNA vectors in gene therapy efforts.

Keywords: EndoG, silencing, exogenous DNA stability, HeLa cells

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Authors: R. Stalin, D. Karthick, H. Haseena Banu, T. P. Sachidanandam, P. Shanthi

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Background: Breast cancer is emerging as one of the leading cause of cancer related deaths and hence there arises the need to look out for drugs which are more targets specific with minimal side effects. In recent times, there is a shift towards alternative medicine due to low cost and less side effects. Siddha system of medicine is one the oldest system of medicine practiced against various ailments. Tridham (TD) is a herbal formulation prepared in our laboratory consisting of Terminalia chebula, Elaeocarpus ganitrus and Prosopis cineraria in a definite ratio (TD) and its anticancer potential is evaluated in terms of induction of apoptosis. Objective: The present study was designed to investigate the anti proliferative effect of TD and 1,2,3,4,6-penta-O-galloyl-b-D-glucose (PGG), a pure compound isolated from TD on human mammary carcinoma cell line (MCF-7). Materials and Methods: Cell viability was studied using MTT analysis and trypan blue staining. Mitochondrial membrane potential was studied using DAPI staining. The protein and mRNA expressions of pro-apoptotic and anti- apoptotic markers namely Bax, Bad, Bcl-2 and caspases were also assessed by Western Blotting and RT PCR. Results: Viability studies of TD and PGG treated MCF-7 cells showed an inhibition in cell growth in time and dose dependent manner. The alteration in mitochondrial membrane potential was restored through treatment with TD and PGG which was confirmed by DAPI staining. The protein and mRNA expression of pro-apoptotic markers was found to be significantly increased in TD and PGG treated cells with a concomitant decrease in anti-apoptotic markers. Conclusion: The results of the study suggest that TD and PGG exhibit their anticancer effect through its membrane stabilizing property and activation of apoptotic cascade in MCF-7 cells.

Keywords: apoptosis, mammary carcinoma, MCF-7, penta galloyl glucose, Tridham

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Authors: Badawia Ibrahim, Iman Hussein, Samar El Sheikh, Fatma Abou Elkasem, Hazem Abo Ismael

Abstract:

Background: Response of breast carcinoma to neoadjuvant chemotherapy (NAC) varies regarding many factors including hormonal receptor status. Breast cancer is a heterogenous disease with different outcomes, hence a need arises for new markers predicting the outcome of NAC especially for the triple negative group when estrogen, progesterone receptors and Her2/neu are negative. FOXP3 is a promising target with unclear role. Aim: To examine the value of FOXP3 expression in locally advanced triple negative breast cancer tumoral cells as well as tumor infiltrating lymphocytes (TILs) and to elucidate its relation to the extent of NAC response. Material and Methods: Forty five cases of immunohistochemically confirmed to be triple negative breast carcinoma were evaluated for NAC (Doxorubicin, Cyclophosphamide AC x 4 cycles + Paclitaxel x 12 weeks, patients with ejection fraction less than 60% received Taxotere or Cyclophosphamide, Methotrexate, Fluorouracil CMF) response in both tumour and lymph nodes status according to Miller & Payne's and Sataloff's systems. FOXP3 expression in tumor as well as TILs evaluated in the pretherapy biopsies was correlated with NAC response in breast tumor and lymph nodes as well as other clinicopathological factors. Results: Breast tumour cells showed FOXP3 positive cytoplasmic expression in (42%) of cases. High FOXP3 expression percentage was detected in (47%) of cases. High infiltration by FOXP3+TILs was detected in (49%) of cases. Positive FOXP3 expression was associated with negative lymph node metastasis. High FOXP3 expression percentage and high infiltration by FOXP3+TILs were significantly associated with complete therapy response in axillary lymph nodes. High FOXP3 expression in tumour cells was associated with high infiltration by FOXP3+TILs. Conclusion: This result may provide evidence that FOXP3 marker is a good prognostic and predictive marker for triple negative breast cancer (TNBC) indicated for neoadjuvant chemotherapy and can be used for stratifications of TNBC cases indicated for NAC. As well, this study confirmed the fact that the tumour cells and the surrounding microenvironment interact with each other and the tumour microenvironment can influence the treatment outcomes of TNBC.

Keywords: breast cancer, FOXP3 expression, prediction of neoadjuvant chemotherapy effect, triple negative

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Authors: Maierhaba Mijiti

Abstract:

Objective：The aim is to understand the relationship between the expression level of the long-non-coding RNA LINC AC008063 and the clinicopathological parameters of patients with head and neck squamous cell carcinoma (HNSCC), and to clarify the biological function of LINC AC008063 in HNSCC cells. Moreover, it provides a potential biomarker for the diagnosis, treatment, and prognosis evaluation of HNSCC. Methods: The expression level of LINC AC008063 in the HNSCC was analyzed using transcriptome sequencing data from the TCGA (The cancer genome atlas) database. The expression levels of LINC AC008063 in human embryonic lung diploid cells 2BS, human immortalized keratinocytes HACAT, HNSCC cell lines CAL-27, Detroit562, AMC-HN-8, FD-LSC-1, FaDu and WSU-HN30 were determined by real-time quantitative PCR (qPCR). RNAi (RNA interference) was introduced for LINC AC008063 knockdown in HNSCC cell lines, the localization and abundance analysis of LINC AC008063 was determined by RT-qPCR, and the biological functions were examined by CCK-8, clone formation, flow cytometry, transwell invasion and migration assays, Seahorse assay. Results: LINC AC008063 was upregulated in HNSCC tissue (P<0.001), and verified b CCK-8, clone formation, flow cytometry, transwell invasion and migration assays, Seahorse assayy qPCR in HNSCC cell lines. The survival analysis revealed that the overall survival rate (OS) of patients with high LINC AC008063 expression group was significantly lower than that in the LINC AC008063 expression group, the median survival times for the two groups were 33.10 months and 61.27 months, respectively (P=0.002). The clinical correlation analysis revealed that its expression was positively correlated with the age of patients with HNSCC (P<0.001) and positively correlated with pathological state (T3+T4＞T1+T2, P=0.03). The RT-qPCR results showed that LINC AC008063 was mainly enriched in cytoplasm (P=0.01). Knockdown of LINC AC008063 inhibited proliferation, colony formation, migration and invasion; the glycolytic capacity was significantly decreased in HNSCC cell lines (P＜0.05). Conclusion: High level of LINC AC008063 was associated with the malignant progression of HNSCC as well as promoting the important biological functions of proliferation, colony formation, migration and invasion; in particular, the glycolytic capacity was decreased in HNSCC cells. Therefore, LINC AC008063 may serve as a potential biomarker for HNSCC and a distinct molecular target to inhibit glycolysis.

Keywords: head and neck squamous cell carcinoma, oncogene, long non-coding RNA, LINC AC008063, invasion and metastasis

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Authors: Zohra Salim

Abstract:

Objective: To access the relationship of primary tumor thickness with cervical lymphadenopathy in squamous cell carcinoma of buccal mucosa. Methodology: A cross-sectional observational study was carried out on 80 Patients with biopsy-proven oral squamous cell carcinoma of buccal mucosa at Dow University of Health Sciences. All the study participants were treated with wide local excision of the primary tumor with elective neck dissection. Patients with prior head and neck malignancy or those with prior radiotherapy or chemotherapy were excluded from the study. Data was entered and analyzed on SPSS 21. Chi-squared test with 95% C.I and 80% power of the test was used to evaluate the relationship of tumor depth with cervical lymph nodes. Results: 50 participants were male, and 30 patients were female. 30 patients were in the age range of 20-40 years, 36 patients in the range of 40-60 years, while 14 patients were beyond age 60 years. Tumor size ranged from 0.3cm to 5cm with a mean of 2.03cm. Tumor depth ranged from 0.2cm to 5cm. 20% of the participants reported with tumor depth greater than 2.5cm, while 80% of patients reported with tumor depth less than 2.5cm. Out of 80 patients, 27 reported with negative lymph nodes, while 53 patients reported with positive lymph nodes. Conclusion: Our study concludes that relationship exists between the depth of primary tumor and cervical lymphadenopathy in squamous cell carcinoma of buccal mucosa.

Keywords: squamous cell carcinoma, tumor depth, cervical lymphadenopathy, buccal mucosa

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Authors: Bharti Arora, Michael Chen, Steven Lun

Abstract:

Plasmacytoid urothelial carcinoma (PUC) of the bladder is a rare and aggressive subtype of urothelial carcinoma that usually presents at an advanced clinical stage, has a predilection for early metastatic potential and is associated with poor prognosis. The first reported case of PUC was in 1991 and approximately 100 cases were reported in the literature worldwide. We present a case of a 43 year old female presenting with a 3-month history of urgency and frequency. Failing medical management of her urinary symptoms with anticholinergic medication, she underwent a diagnostic cystoscopy which revealed an erythematous and indurated bladder. Bladder biopsies of these regions revealed plasmacytoid urothelial carcinoma. Pre-operative staging scans were clear of any metastatic disease and the patient subsequently underwent a radical cystectomy and pelvic clearance with the formation of ileal conduit for urinary diversion. Histology confirmed plasmacytoid urothelial carcinoma with involvement of right upper vagina and focally positive margins in soft tissue at right and left sides of bladder. She received adjuvant chemotherapy but passed away within a year from disease progression. PUC can present atypically and our case highlights the role of cystoscopy in patients with persistent urinary symptoms. By reviewing the literature on PUC, we aim to raise awareness and improve understanding of this rare bladder cancer subtype amongst urologists.

Keywords: urology, bladder cancer, plasmacytoid urothelial cancer, literature review

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Authors: E. Locatelli, I. Monaco, R. C. Martin, Y. Li, R. Pini, M. Chiariello, M. Comes Franchini

Abstract:

Despite the many advantages of application of nanomaterials in the field of nanomedicine, increasing concerns have been expressed on their potential adverse effects on human health. There is urgency for novel green strategies toward novel materials with enhanced biocompatibility using safe reagents. Photothermal ablation therapy, which exploits localized heat increase of a few degrees to kill cancer cells, has appeared recently as a non-invasive and highly efficient therapy against various cancer types; anyway new agents able to generate hyperthermia when irradiated are needed and must have precise biocompatibility in order to avoid damage to healthy tissues and prevent toxicity. Recently, there has been increasing interest in magnesium as a biomaterial: it is the fourth most abundant cation in the human body, and it is essential for human metabolism. However magnesium nanoparticles (Mg NPs) have had limited diffusion due to the high reduction potential of magnesium cations, which makes NPs synthesis challenging. Herein, we report the synthesis of Mg NPs and their surface functionalization for the obtainment of a stable and biocompatible nanomaterial suitable for photothermal ablation therapy against cancer. We synthesized the Mg crystals by reducing MgCl2 with metallic lithium and exploiting naphthalene as an electron carrier: the lithium–naphthalene complex acts as the real reducing agent. Firstly, the nanocrystal particles were coated with the ligand 12-ethoxy ester dodecanehydroxamic acid, and then entrapped into water-dispersible polymeric micelles (PMs) made of the FDA-approved PLGA-b-PEG-COOH copolymer using the oil-in-water emulsion technique. Lately, we developed a more straightforward methodology by introducing chitosan, a highly biocompatible natural product, at the beginning of the process, simultaneously using lithium–naphthalene complex, thus having a one-pot procedure for the formation and surface modification of MgNPs. The obtained MgNPs were purified and fully characterized, showing diameters in the range of 50-300 nm. Notably, when coated with chitosan the particles remained stable as dry powder for more than 10 months. We proved the possibility of generating a temperature rise of a few to several degrees once MgNPs were illuminated using a 810 nm diode laser operating in continuous wave mode: the temperature rise resulted significant (0-15 °C) and concentration dependent. We then investigated potential cytotoxicity of the MgNPs: we used HN13 epithelial cells, derived from a head and neck squamous cell carcinoma and the hepa1-6 cell line, derived from hepatocellular carcinoma and very low toxicity was observed for both nanosystems. Finally, in vivo photothermal therapy was performed on xenograft hepa1-6 tumor bearing mice: the animals were treated with MgNPs coated with chitosan and showed no sign of suffering after the injection. After 12 hours the tumor was exposed to near-infrared laser light. The results clearly showed an extensive damage to tumor tissue after only 2 minutes of laser irradiation at 3Wcm-1, while no damage was reported when the tumor was treated with the laser and saline alone in control group. Despite the lower photothermal efficiency of Mg with respect to Au NPs, we consider MgNPs a promising, safe and green candidate for future clinical translations.

Keywords: chitosan, magnesium nanoparticles, nanomedicine, photothermal therapy

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Authors: Paiwan Buachan, Maneekarn Namsa-Aid, Suchada Jongrungruangchok, Foengchat Jarintanan, Wanlaya Uthaisang-Tanechpongtamb

Abstract:

Lung cancer or pulmonary carcinoma is the uncontrolled growth of abnormal cells in one or both of the lungs. These abnormal cells can spread to other organs of the body through lymphatic system or bloodstream which is called metastatic stage that leading cause of cancer death. Terrein (C₈H₁₀O₃; MW= 154.06 kDa) is a secondary bioactive fungal metabolite, which was isolated from the Aspergillus terreus. In this study, we investigated the effects of terrein on the inhibition of human lung cancer cell proliferation and metastasis. The A549 human non-small cell lung cancer cell line was used as a model. Terrein significantly inhibited lung cancer cell proliferation measuring by a colorimetric MTT assay (IC₅₀ 0.32 mM) and significantly inhibited metastatic processes including migration, invasion, and adhesion that determined by wound healing assay, transwell assay, and adhesion assay, respectively. These findings indicate that terrein could be a potential therapeutic agent for lung cancer.

Keywords: terrein, lung cancer, anticancer, antimetastatic

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Authors: Karen Boaz, C. R. Charan

Abstract:

Background: The infiltration of tumour stroma by eosinophils, Tumor-Associated Tissue Eosinophilia (TATE), is known to modulate the progression of Oral Squamous Cell Carcinoma (OSCC). Eosinophils have direct tumoricidal activity by release of cytotoxic proteins and indirectly they enhance permeability into tumor cells enabling penetration of tumoricidal cytokines. Also, eosinophils may promote tumor angiogenesis by production of several angiogenic factors. Identification of eosinophils in the inflammatory stroma has been proven to be an important prognosticator in cancers of mouth, oesophagus, larynx, pharynx, breast, lung, and intestine. Therefore, the study aimed to correlate TATE with clinical and histopathological variables, and blood eosinophil count to assess the role of TATE as a prognosticator in Oral Squamous Cell Carcinoma (OSCC). Methods: Seventy two biopsy-proven cases of OSCC formed the study cohort. Blood eosinophil counts and TNM stage were obtained from the medical records. Tissue sections (5µm thick) were stained with Haematoxylin and Eosin. The eosinophils were quantified at invasive tumour front (ITF) in 10HPF (40x magnification) with an ocular grid. Bryne’s grading of ITF was also performed. A subset of thirty cases was also assessed for association of TATE with recurrence, involvement of lymph nodes and surgical margins. Results: 1) No statistically significant correlation was found between TATE and TNM stage, blood eosinophil counts and most parameters of Bryne’s grading system. 2) Statistically significant relation of intense degree of TATE was associated with the absence of distant metastasis, increased lympho-plasmacytic response and increased survival (diseasefree and overall) of OSCC patients. 3) In the subset of 30 cases, tissue eosinophil counts were higher in cases with lymph node involvement, decreased survival, without margin involvement and in cases that did not recur. Conclusion: While the role of eosinophils in mediating immune responses seems ambiguous as eosinophils support cell-mediated tumour immunity in early stages while inhibiting the same in advanced stages, TATE may be used as a surrogate marker for determination of prognosis in oral squamous cell carcinoma.

Keywords: tumour-associated tissue eosinophilia, oral squamous cell carcinoma, prognosticator, tumoral immunity

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Authors: Ching-Yi Yiu, Hui-Chen Hsu

Abstract:

Objectives: Head and neck cancer (HNC) is a big global health problem in the world. Despite the development of diagnosis and treatment, the overall survival of HNC is still low. The well recognition of the interaction of the host immune system and cancer cells has led to realizing the processes of tumor initiation, progression and metastasis. Many systemic inflammatory responses have been shown to play a crucial role in cancer progression. The pre and post-treatment nutritional and immunological status of HNC patients is a reliable prognostic indicator of tumor outcomes and survivors. Methods: Between July 2020 to June 2022, We have enrolled 60 HNC patients, including 59 males and 1 female, in Chi Mei Medical Center, Liouying, Taiwan. The age distribution was from 37 to 81 years old (y/o), with a mean age of 57.6 y/o. We evaluated the pre-and post-treatment nutritional and immunological status of these HNC patients with body weight, body weight loss, body mass index (BMI), whole blood count including hemoglobin (Hb), lymphocyte, neutrophil and platelet counts, biochemistry including prealbumin, albumin, c-reactive protein (CRP), with the time period of before treatment, post-treatment 3 and 6 months. We calculated the neutrophil-to-lymphocyte ratio (NLR) and platelet-to-lymphocyte ratio (PLR) to assess how these biomarkers influence the outcomes of HNC patients. Results: We have carcinoma of the hypopharynx in 21 cases with 35％, carcinoma of the larynx in 9 cases, carcinoma of the tonsil and tongue every 6 cases, carcinoma soft palate and tongue base every 5 cases, carcinoma of buccal mucosa, retromolar trigone and mouth floor every 2 cases, carcinoma of the hard palate and low lip each 1 case. There were stage I 15 cases, stage II 13 cases, stage III 6 cases, stage IVA 10 cases, and stage IVB 16 cases. All patients have received surgery, chemoradiation therapy or combined therapy. We have wound infection in 6 cases, 2 cases of pharyngocutaneous fistula, flap necrosis in 2 cases, and mortality in 6 cases. In the wound infection group, the average BMI is 20.4 kg/m2; the average Hb is 12.9 g/dL, the average albumin is 3.5 g/dL, the average NLR is 6.78, and the average PLR is 243.5. In the PC fistula and flap necrosis group, the average BMI is 21.65 kg/m2; the average Hb is 11.7 g/dL, the average albumin is 3.15 g/dL, average NLR is 13.28, average PLR is 418.84. In the mortality group, the average BMI is 22.3 kg/m2; the average Hb is 13.58 g/dL, the average albumin is 3.77 g/dL, the average NLR is 6.06, and the average PLR is 275.5. Conclusion: HNC is a big challenging public health problem worldwide, especially in the high prevalence of betel nut consumption area Taiwan. Besides the definite risk factors of smoking, drinking and betel nut related, the other biomarkers may play significant prognosticators in the HNC outcomes. We concluded that the average BMI is less than 22 kg/m2, the average Hb is low than 12.0 g/dL, the average albumin is low than 3.3 g/dL, the average NLR is low than 3, and the average PLR is more than 170, the surgical complications and mortality will be increased, and the prognosis is poor in HNC patients.

Keywords: nutritional, immunological, neutrophil-to-lymphocyte ratio, paltelet-to-lymphocyte ratio.

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Authors: Manohar Salla, Mark S. Butler, Ruby Pelingon, Geraldine Kaeslin, Daniel E. Croker, Janet C. Reid, Jong Min Baek, Paul V. Bernhardt, Elizabeth M. J. Gillam, Matthew A. Cooper, Avril A. B. Robertson

Abstract:

MCC950 is a potent and selective inhibitor of the NOD-like receptor pyrin domain-containing protein 3 (NLRP3) inflammasome that shows early promise for treatment of inflammatory diseases. The identification of major metabolites of lead molecule is an important step during drug development process. It provides an information about the metabolically labile sites in the molecule and thereby helping medicinal chemists to design metabolically stable molecules. To identify major metabolites of MCC950, the compound was incubated with human liver microsomes and subsequent analysis by (+)- and (−)-QTOF-ESI-MS/MS revealed a major metabolite formed due to hydroxylation on 1,2,3,5,6,7-hexahydro-s-indacene moiety of MCC950. This major metabolite can lose two water molecules and three possible regioisomers were synthesized. Co-elution of major metabolite with each of the synthesized compounds using HPLC-ESI-SRM-MS/MS revealed the structure of the metabolite (±) N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. Subsequent synthesis of individual enantiomers and coelution in HPLC-ESI-SRM-MS/MS using a chiral column revealed the metabolite was R-(+)- N-((1-hydroxy-1,2,3,5,6,7-hexahydro-s-indacen-4-yl)carbamoyl)-4-(2-hydroxypropan-2-yl)furan-2-sulfonamide. To study the possible cytochrome P450 enzyme(s) responsible for the formation of major metabolite, MCC950 was incubated with a panel of cytochrome P450 enzymes. The result indicated that CYP1A2, CYP2A6, CYP2B6, CYP2C9, CYP2C18, CYP2C19, CYP2J2 and CYP3A4 are most likely responsible for the formation of the major metabolite. The biological activity of the major metabolite and the other synthesized regioisomers was also investigated by screening for for NLRP3 inflammasome inhibitory activity and cytotoxicity. The major metabolite had 170-fold less inhibitory activity (IC50-1238 nM) than MCC950 (IC50-7.5 nM). Interestingly, one regioisomer had shown nanomolar inhibitory activity (IC50-232 nM). However, no evidence of cytotoxicity was observed with any of these synthesized compounds when tested in human embryonic kidney 293 cells (HEK293) and human liver hepatocellular carcinoma G2 cells (HepG2). These key findings give an insight into the SAR of the hexahydroindacene moiety of MCC950 and reveal a metabolic soft spot which could be blocked by chemical modification.

Keywords: Cytochrome P450, inflammasome, MCC950, metabolite, microsome, NLRP3

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Authors: Otilia Ruxandra Vasile, Ecaterina Andronescu, Cristina Daniela Ghitulica, Bogdan Stefan Vasile, Roxana Trusca, Eugeniu Vasile, Alina Maria Holban, Carmen Mariana Chifiriuc, Florin Iordache, Horia Maniu

Abstract:

Engineered powders offer great promise in several applications, but little information is known about cytotoxicity effects. The aim of the current study was the synthesis and cytotoxicity examination of silver powders using pyrosol method at temperatures of 600°C, 650°C and 700°C, respectively sol-gel method and calcinations at 500°C, 600°C, 700°C and 800°C. We have chosen to synthesize and examine silver particles cytotoxicity due to its use in biological applications. The synthesized Ag powders were characterized from the structural, compositional and morphological point of view by using XRD, SEM, and TEM with SAED. In order to determine the influence of the synthesis route on Ag particles cytotoxicity, different sizes of micro and nanosilver synthesized powders were evaluated for their potential toxicity. For the study of their cytotoxicity, cell cycle and apoptosis have been done analysis through flow cytometry on human colon carcinoma cells and mesenchymal stem cells and through the MTT assay, while the viability and the morphological changes of the cells have been evaluated by using cloning studies. The results showed that the synthesized silver nanoparticles have displayed significant cytotoxicity effects on cell cultures. Our synthesized silver powders were found to present toxicity in a synthesis route and time-dependent manners for pyrosol synthesized nanoparticles; whereas a lower cytotoxicity has been measured after cells were treated with silver nanoparticles synthesized through sol-gel method.

Keywords: Ag, cytotoxicity, pyrosol method, sol-gel method

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