Impaired memory and evidence of histopathology in CA1 pyramidal neurons through injection of Aβ1-42 peptides into the frontal cortices of rat

Introduction: Alzheimer's disease (AD) is one of the most common neurodegenerative disorders, which has much benefited from animal models to find the basics of its pathophysiology. In our previous work (Haghani, Shabani, Javan, Motamedi, & Janahmadi, 2012), a non-transgenic rat model of AD was used in electrophysiological studies. However, we did not investigate the histological aspects in the mentioned study. Methods: An AD model was developed through bilateral injection of amyloid-β peptides (Aβ) into the frontal cortices. Behavioral and histological methods were used to assess alterations in the memory and (ultra)structures. Furthermore, melatonin has been administered to assess its efficacy on this AD model. Results: Passive avoidance showed a progressive decline in the memory following Aβ injection. Furthermore, Nissl staining showed that Aβ neurotoxicity caused shrinkage of the CA1 pyramidal neurons. Neurodegeneration was clearly evident from Fluoro-jade labeled neurons in Aβ treated rats. Moreover, higher NF-κB immunoreactive CA1 pyramidal neurons were remarkably observed in Aβ treated rats. Ultrastructural analysis using electron microscopy also showed the evidence of subcellular abnormalities. Melatonin treatment in this model of AD prevented Aβ- induced increased NF-κB from immunoreaction and neurodegeneration. Discussion: This study suggests that injection of Aβ into the frontal cortices results in the memory decline and histochemical disturbances in CA1 pyramidal neurons. Furthermore, melatonin can prevent several histological changes induced by Aβ

THE EXPRESSION OF P53 AND MDM4 IN ORAL, LARYNGEAL AND CUTANEOUS SQUAMOUS CELL CARCINOMA; A COMPARATIVE STUDY

Background: P53 and MDM4 had been known to have dual mechanism depending on their localization. Nuclear p53 can bind to DNA and activate proapoptotic gene expression; cytoplasmic p53 can trigger transcription-independent apoptosis by directly interacting with Bcl-2 family members. Objectives: The aim of current study to evaluate and compare the expression of P53, MDM4 in oral , laryngeal and cutaneous SCC by microarray(TMA) and to investigate the correlation of expression of these markers with histopathological grading of tumor. Methods: One-hundred twenty paraffin embedded SCC sample of Iraqi patients collected during period 2009-2012, retrieved for TMA construction and the expression of P53 and MDM4 was examined by immunohistochemistry. Results: Data showed males with SCC were more than females ( 63.3%/76 , 36.7%/44). Most cancer types expressed both nuclear and cytoplasmic staining of P53 and MDM4 in different percentage, cutaneous Scc Nuclear/cytoplasm expression of P53 were ( 38.8%/94.6%), laryngeal (55%/90%), oral (36.8%/86.8%). Cutaneous SCC N/Cyt expression of MDM4 were (91.8%/72.9%), laryngeal (91.3%/76.3%), oral (97.5%/62.5%).There is no significant difference in expression of both protein markers and tumor types. Obvious significant correlation showed between tumor grading P53 nuclear expression. Conclusions: P53 and MDM4 were frequently overexpressed in SCC cases and there was a significant correlation between these markers. Nuclear p53 and cytoplasmic MDM4 overexpression can be considered as prognostic factor with tumour grading. High percentage MDM4 overexpression should be considered in their treatment

Gaps in the provision of spiritual care for terminally ill patients in Islamic societies - a systematic review

Background. Islam has a profound concept about death and aftermath. Believing in living after death and resurrection is one of the three main principles of Islam. Since the increasing incidence of people in need of palliative care in developing countries and the fact that Muslims, who dominantly live in developing world, are very dependent on spirituality, describing the ways that spiritual care is described and provided in the Islamic context is highly demanded. This paper aims at delineating original research in this subject in a systematic manner. Method. Several medical databases were reviewed in a systematic manner to investigate original quantitative or qualitative researches about providing spiritual care in Muslim societies. Results. Searching main databases lead to identifying 84 articles alongside with 18 papers from hand searching, which all were reviewed by two investigators. Of this collection, only five papers met the criteria as being original research either quantitative or qualitative, published during the last 10 years. Cultural background plays an important role. Our findings conceded that very few papers are available in Islamic context about spiritual care at the end of life, where only three were quantitative. Research in this field, however, is rapidly growing compared with the previous year. Conclusion. While cancer is rapidly increasing specially in developing world, the need of terminally ill patients with other conditions should be equally considered. Spirituality in Islamic societies does exist profoundly, which needs more research especially in terminal life and even bereavement.Background. Islam has a profound concept about death and aftermath. Believing in living after death and resurrection is one of the three main principles of Islam. Since the increasing incidence of people in need of palliative care in developing countries and the fact that Muslims, who dominantly live in developing world, are very dependent on spirituality, describing the ways that spiritual care is described and provided in the Islamic context is highly demanded. This paper aims at delineating original research in this subject in a systematic manner. Method. Several medical databases were reviewed in a systematic manner to investigate original quantitative or qualitative researches about providing spiritual care in Muslim societies. Results. Searching main databases lead to identifying 84 articles alongside with 18 papers from hand searching, which all were reviewed by two investigators. Of this collection, only five papers met the criteria as being original research either quantitative or qualitative, published during the last 10 years. Cultural background plays an important role. Our findings conceded that very few papers are available in Islamic context about spiritual care at the end of life, where only three were quantitative. Research in this field, however, is rapidly growing compared with the previous year. Conclusion. While cancer is rapidly increasing specially in developing world, the need of terminally ill patients with other conditions should be equally considered. Spirituality in Islamic societies does exist profoundly, which needs more research especially in terminal life and even bereavement

Up-regulation of miR-381 inhibits NAD+ salvage pathway and promotes apoptosis in breast cancer cells

Nicotinamide phosphoribosyltransferase (NAMPT), a rate-limiting enzyme involved in nicotinamide adenine di- nucleotide (NAD) salvage pathway, is overexpressed in many human malignancies such as breast cancer. This enzyme plays a critical role in survival and growth of cancer cells. MicroRNAs (miRNAs) are among the most important regulators of gene expression, and serve as potential targets for diagnosis, prognosis, and therapy of breast cancer. Therefore, the aim of this study was to asse ss the effect of NAMPT inhibition by miR-381 on breast cancer cell survival. MCF-7 and MDA-MB-2 31 cancer cell lines were transfected with miR-381 mimic, inhibitor, and their corresponding negative controls (NCs). Subsequently, the level of NAMPT and NAD was assessed using real-time PCR, immuno-blotting, and enzymatic methods, resp ectively. In order to evalua te apoptosis, cells were labelled with Annexin V-FITC and propidium iodide and analyzed by flow cytometry. Bioinformatics analysis was performed to recognize whether NAMPT 3 ′ -untranslated region (UTR) is a direct target of miR-381 and the results were authenticated by the luciferase re porter assay using a vector containing the 3 ′ -UTR sequence of NAMPT. Our results revealed that the 3 ′ -UTR of NAMPT was a direct target of miR-381 and its up-regulation decreased NAMPT gene and protein expression, leading to a notable reduction in intracellular NAD and subse- quently cell survival and induction of apoptosis. It can be concluded that miR-381 has a vital role in tumor sup- pression by down-regulation of NAMPT, and it can be a promising candidate for breast cancer therapy

Total loss of MHC class I is an independent indicator of good prognosis in breast cancer

Tumours can be recognised by CTL and NK cells. CTL recognition depends on expression of MHC Class I loaded with peptides from tumour antigens. In contrast, loss of MHC Class I results in NK activation. In our study a large set of samples from patients with primary operable invasive breast cancer was evaluated for the expression of MHC Class I heavy and light by immunohistochemical staining of 439 breast carcinomas in a tissue microarray. Forty-seven percent (206 of 439) of breast carcinomas were considered negative for HLA Class I heavy chain (HC10), whereas lack of anti-β2m-antibody staining was observed in 39% (167 of 424) of tumours, with only 3% of the β2m-negative tumours expressing detectable HLA Class I heavy chain. Correlation with patient outcome showed direct relationship between patient survival and HLA-negative phenotype (log rank = 0.004). A positive relationship was found between the intensity of expression of MHC Class I light and heavy chains expression and histological grade of invasive tumour (p < 0.001) and Nottingham Prognostic Index (p < 0.001). To investigate whether HLA Class I heavy and light chains expression had independent prognostic significance, Cox multivariate regression analysis, including the parameters of tumour size, lymph node stage, grade and intensity of HC10 and anti-β2m staining, was carried out. In our analysis, lymph node stage (p < 0.001), tumour grade (p = 0.005) and intensity of MHC Class I light and heavy chains expression were shown to be independent prognostic factors predictive of overall survival (p-values HC10 = 0.047 and β2m = 0.018)

Overexpression and translocation of dynamin 2 promotes tumor aggressiveness in breast carcinomas

Dynamin 2 is a GTPase protein that has been implicated in cancer progression through its various roles such as endocytosis, morphogenesis, epithelial-mesenchymal transition (EMT), cellular contractions, and focal adhesion maturation. The increased expression levels of this molecule have been demonstrated with the development of several cancers such as prostate, pancreas, and bladder. However, its clinical significance in breast cancer is unclear yet. In the present study, the membranous, cytoplasmic, and nuclear expression levels of dynamin 2 molecule were evaluated for the first time, using immunohistochemistry (IHC) on tissue microarray (TMA) slides in 113 invasive breast cancer tissues. Moreover, afterward, the association between the dynamin 2 expression and clinicopathological features was determined. Our finding showed that, a higher nuclear expression of dynamin 2 is significantly associated with an increase in tumor stage (P = 0.05), histological grade (P = 0.001), and age of the patients (P = 0.03). In addition, analysis of the cytoplasmic expression levels of this molecule revealed that, there was a statistically significant difference between the expression levels of dynamin 2 among the different breast cancer subtypes (P = 0.003). Moreover, a significant association was found between the increased expression of dynamin 2 membranous and vascular invasion (VI) (P = 0.02). We showed that dynamin 2 protein expression has an association with more aggressive tumor behavior and more advanced disease in the patients with breast cancer; therefore, dynamin 2 molecule could be considered as an indicator of disease progression and aggressiveness

Evidence that the p53 negative / Bcl-2 positive phenotype is an independent indicator of good prognosis in colorectal cancer: A tissue microarray study of 460 patients

BACKGROUND: Advances in our understanding of the molecular biology of colorectal cancer have fuelled the search for novel molecular prognostic markers to complement existing staging systems. Markers assessed in combination may perform better than those considered individually. Using high-throughput tissue microarray technology, we describe the prognostic value of combined p53 / Bcl-2 status in colorectal cancer. PATIENTS AND METHODS: Tumour samples from 462 patients who underwent elective surgery to resect a primary colorectal cancer between 1994 and 2000 (mean follow-up of 75 months) were assembled in tissue microarray format. Clinico-pathological data including tumour grade, stage, vascular invasion status along with disease specific survival data has been collected prospectively. Immunohistochemical analysis of p53 and Bcl-2 expression was performed using antibodies DO-7 (p53) and 124 (Bcl-2), and results correlated with known clinico-pathological variables and outcomes. RESULTS: Abnormal nuclear p53 accumulation and Bcl-2 overexpression were detected in 221/445 (49.6%) and199/437 (45.5%) tumours respectively, with a significant inverse correlation between the two markers (p = 0.023). On univariate analysis no correlations were found between either marker and standard clinico-pathological variables, however nuclear p53 expression was associated with a significantly reduced survival (p = 0.024). Combined analysis of the two markers indicated that 112/432 (24.2%) cases displayed a p53(-)/Bcl-2(+) phenotype, this occurring more frequently in earlier stage tumours. Kaplan-Meier analysis revealed a significant survival advantage in these p53(-)/Bcl-2(+) tumours compared with the remaining cases (p = 0.0032). On multivariate analysis using the Cox proportional hazards model, neither p53 expression nor Bcl-2 expression alone were of independent prognostic significance, however the combined p53(-)/Bcl-2(+) phenotype was significantly associated with a good prognosis in this series (HR 0.659, 95%CI 0.452–0.959, p = 0.029). CONCLUSION: Patient stratification by combined p53 / Bcl-2 phenotype provides stage-independent prognostic information in colorectal cancer. Specifically, that up to a quarter of patients display a good prognosis p53(-)/Bcl-2(+) phenotype. This may indicate a more clinically indolent phenotype and a subset of patients for whom less aggressive adjuvant treatment appropriate

Evaluation of targetable biomarkers for chimeric antigen receptor T-cell (CAR-T) in the treatment of pancreatic cancer:a systematic review and meta-analysis of preclinical studies

One of the cutting edge techniques for treating cancer is the use of the patient's immune system to prevail cancerous disease. The versatility of the chimeric antigen receptor (CAR) T-cell approach in conjugation with promising treatments in haematological cancer has led to countless cases of research literature for the treatment of solid cancer. A systematic search of online databases as well as gray literature and reference lists of retrieved studies were carried out up to March 2019 to identify experimental animal studies that investigated the antigens targeted by CAR T-cell for pancreatic cancer treatment. Studies were evaluated for methodological quality using the SYstematic Review Center for Laboratory Animal Experimentation bias risk tool (SYRCLE's ROB tool). Pooled cytotoxicity ratio/percentage and 95% confidence intervals were calculated using the inverse-variance method while random-effects meta-analysis was used, taking into account conceptual heterogeneity. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I2 statistic using Stata 13.0. Of the 485 identified studies, 56 were reviewed in-depth with 16 preclinical animal studies eligible for inclusion in the systematic review and 11 studies included in our meta-analysis. CAR immunotherapy significantly increased the cytotoxicity assay (percentage: 65%; 95% CI: 46%, 82%). There were no evidence for significant heterogeneity across studies [P = 0.38 (Q statistics), I2 = 7.14%] and for publication bias. The quality assessment of included studies revealed that the evidence was moderate to low quality and none of studies was judged as having a low risk of bias across all domains. CAR T-cell therapy is effective for pancreatic cancer treatment in preclinical animal studies. Further high-quality studies are needed to confirm our finding and a standard approach of this type of studies is necessary according to our assessment.</p

Evaluation of targetable biomarkers for chimeric antigen receptor T-cell (CAR-T) in the treatment of pancreatic cancer:a systematic review and meta-analysis of preclinical studies

One of the cutting edge techniques for treating cancer is the use of the patient's immune system to prevail cancerous disease. The versatility of the chimeric antigen receptor (CAR) T-cell approach in conjugation with promising treatments in haematological cancer has led to countless cases of research literature for the treatment of solid cancer. A systematic search of online databases as well as gray literature and reference lists of retrieved studies were carried out up to March 2019 to identify experimental animal studies that investigated the antigens targeted by CAR T-cell for pancreatic cancer treatment. Studies were evaluated for methodological quality using the SYstematic Review Center for Laboratory Animal Experimentation bias risk tool (SYRCLE's ROB tool). Pooled cytotoxicity ratio/percentage and 95% confidence intervals were calculated using the inverse-variance method while random-effects meta-analysis was used, taking into account conceptual heterogeneity. Heterogeneity was assessed with the Cochran Q statistic and quantified with the I2 statistic using Stata 13.0. Of the 485 identified studies, 56 were reviewed in-depth with 16 preclinical animal studies eligible for inclusion in the systematic review and 11 studies included in our meta-analysis. CAR immunotherapy significantly increased the cytotoxicity assay (percentage: 65%; 95% CI: 46%, 82%). There were no evidence for significant heterogeneity across studies [P = 0.38 (Q statistics), I2 = 7.14%] and for publication bias. The quality assessment of included studies revealed that the evidence was moderate to low quality and none of studies was judged as having a low risk of bias across all domains. CAR T-cell therapy is effective for pancreatic cancer treatment in preclinical animal studies. Further high-quality studies are needed to confirm our finding and a standard approach of this type of studies is necessary according to our assessment.</p

Tumor Matrix Stiffness Provides Fertile Soil for Cancer Stem Cells

Matrix stiffness is a mechanical characteristic of the extracellular matrix (ECM) that increases from the tumor core to the tumor periphery in a gradient pattern in a variety of solid tumors and can promote proliferation, invasion, metastasis, drug resistance, and recurrence. Cancer stem cells (CSCs) are a rare subpopulation of tumor cells with self-renewal, asymmetric cell division, and differentiation capabilities. CSCs are thought to be responsible for metastasis, tumor recurrence, chemotherapy resistance, and consequently poor clinical outcomes. Evidence suggests that matrix stiffness can activate receptors and mechanosensor/mechanoregulator proteins such as integrin, FAK, and YAP, modulating the characteristics of tumor cells as well as CSCs through different molecular signaling pathways. A deeper understanding of the effect of matrix stiffness on CSCs characteristics could lead to development of innovative cancer therapies. In this review, we discuss how the stiffness of the ECM is sensed by the cells and how the cells respond to this environmental change as well as the effect of matrix stiffness on CSCs characteristics and also the key malignant processes such as proliferation and EMT. Then, we specifically focus on how increased matrix stiffness affects CSCs in breast, lung, liver, pancreatic, and colorectal cancers. We also discuss how the molecules responsible for increased matrix stiffness and the signaling pathways activated by the enhanced stiffness can be manipulated as a therapeutic strategy for cancer