Aberrant expression of ALK and EZH2 in Merkel cell carcinoma

BACKGROUND: Distinct characteristic features categorize Merkel cell carcinoma (MCC) into two subgroups according to the Merkel cell polyomavirus infection. Many mutational studies on MCC have been carried out in recent years without identifying a prominent driver mutation. However, there is paucity reporting the expression of cancer genes at the RNA level in MCC tumors. In this study, we studied the RNA expression profiles of 26 MCC tumors, with a goal to identify prospective molecular targets that could improve the treatment strategies of MCC. METHODS: RNA expression of 50 cancer-related genes in 26 MCC tumors was analyzed by targeted amplicon based next-generation sequencing using the Ion Torrent technology and the expression compared with that of normal, non-cancerous skin samples. Sequencing data were processed using Torrent Suite Software. Expression profiles of MCV-negative and MCV-positive tumors were compared. Fluorescence in situ hybridization was performed to study ALK rearrangements and immunohistochemistry to study ALK expression in tumor tissue. RESULTS: ALK, CDKN2A, EZH2 and ERBB4 were overexpressed, and EGFR, ERBB2, PDGFRA and FGFR1 were underexpressed in MCC tumors compared to normal skin. In the MCV-negative tumors, MET, NOTCH1, FGFR3, and SMO were overexpressed and JAK3 and NPM1 were under-expressed compared to the MCV-positive tumors. CONCLUSIONS: High expression of ALK, CDKN2A and EZH2 was recorded in MCC tumors. No ALK fusion was seen by FISH analysis. Overexpression of EZH2 suggests its potential as a drug target in MCC.Peer reviewe

Minimizing the sum of flow times with batching and delivery in a supply chain

The aim of this thesis is to study one of the classical scheduling objectives that is of minimizing the sum of flow times, in the context of a supply chain network. We consider the situation that a supplier schedules a set of jobs for delivery in batches to several manufacturers, who in tum have to schedule and deliver jobs in batches to several customers. The individual problem from the viewpoint of supplier and manufacturers will be considered separately. The decision problem faced by the supplier is that of minimizing the sum of flow time and delivery cost of a set of jobs to be processed on a single machine for delivery in batches to manufacturers. The problem from the viewpoint of manufacturer is similar to the supplier's problem and the only difference is that the scheduling, batching and delivery decisions made by the supplier define a release date for each job, before which the manufacturer cannot start the processing of that job. Also a combined problem in the light of cooperation between the supplier and manufacturer will be considered. The objective of the combined problem is to find the best scheduling, batching, and delivery decisions that benefit the entire system including the supplier and manufacturer. Structural properties of each problem are investigated and used to devise a branch and bound solution scheme. Computational experience shows significant improvements over existing algorithms and also shows that cooperation between a supplier and a manufacturer reduces the total system cost of up to 12.35%, while theoretically the reduction of up to 20% can be achieved for special cases.EThOS - Electronic Theses Online ServiceGBUnited Kingdo

A Pilot Study on the Association of Lead, 8-Hydroxyguanine, and Malondialdehyde Levels in Opium Addicts’ Blood Serum with Illicit Drug Use and Non-Addict Persons

While a large body of literature has shown the health problems of illicit drug use, research is needed on how substance abuse impacts DNA damage and contaminants in blood, especially given Pb-contaminated opium. This pilot study aimed to evaluate the levels of lead (Pb), 8-hydroxy di-guanine (8-oxo-Gua), and malondialdehyde (MDA) in the blood serum of opium addicts and non-addict people. The current study is a case–control study with a cross-sectional design. A sample of 50 opium-addicted and non-addict adults were chosen for this study using convenience and random sampling methods. Participants were divided into two groups: addicts and non-addicts. The atomic absorption spectroscopy method was used to measure the quantity of Pb, and the Enzyme-Linked Immunosorbent Assay (ELISA) method was used to measure the amount of 8-oxo-Gua and MDA. The data were analyzed using an independent t-test. The results show that the amount of Pb in the blood serum of addicted women and men was higher than levels in non-addict men and women, for the study participants (p-value = 0.001). Blood levels were not significantly different between addicts and non-addicts for men or women for 8-oxo-Gua (p-value = 0.647 for women and p-value = 0.785 for men) and MDA (p-value = 0.867 for women and p-value = 0.995 for men). In general, addicts’ blood Pb levels were found to be substantially higher than those of normal non-addict persons in this pilot study. As a result, testing for blood Pb levels in addicts may be informative in instances when symptoms are inconclusive.</jats:p

Evaluation of the Effect of Day and Night Temperature Fluctuations in different Seasons of the Year on the Fruit Formation of Sweet Pepper (Capsicum annuum L.) Lines

Introduction Capsicum is a plant sensitive to temperature fluctuations at day and night, and temperature changes strongly affect the quality of the fruit. Identification of tolerant genotypes to temperature fluctuations that naturally produce parthenocarp and marketable fruit is important for use in breeding programs and the production of hybrids with appropriate fruit weight and size and high marketability. Materials and Methods In order to evaluate the reaction of the lines related to three populations of sweet pepper (A: red fruit, B: orange fruit and C: yellow fruit) obtained from five generations of self-polination (by generation management by single-seed bulk method), a greenhouse factorial experiment was conducted based on a completely randomized design with three different temperature conditions including optimal day and night temperature (day temperature 25± 2 and night temperature 20 ± 2 °C), low night temperature (day temperature 25± 2 and night temperature 11± 2 °C) and high day temperature (day temperature 40± 2 and night temperature 20 ± 2 °C). For this purpose, 100 lines from each population were planted in three separate greenhouses with the mentioned temperatures. Percentage of seedless fruit lines per population or Parthenocarp fruits (including seedless fruits that had at least 50% by weight of seeded and natural fruits and other seedless fruits that were deformed and small in size (knot) were removed), height Plant, day to ripening and number of fruit lobes per 100 lines of each population were measured in three different temperature conditions. Due to the fact that the lines within each population were different from the other population lines, so the data analysis was performed as a complex sequential-factorial design. Also, due to the importance of fruit characteristics in seedless fruit lines and seeded fruits, analysis of variance of these lines in a completely randomized design (15 treatments in 3 replications) using SAS v software 9.2 was performed and the comparison of the mean of the evaluated traits was performed using Duncan's multiple range test at 5% probability level.   Results and Discussion The results showed that under optimal temperature conditions, all lines had good growth and no parthenocarpic plants were observed in the evaluated populations, but day and night temperature fluctuations outside the optimal temperature range caused significant changes in plant growth, fruit development. And seeds were formed. The effect of high day temperature on the evaluated characteristics was less than low night temperature. With a sharp drop in night temperature, population A produced the highest percentage of seedless fruit plants. The percentage of parthenocarp lines of populations B and C were significantly lower than population A at low night and daytime temperatures. Population C was less affected by adverse day and night temperatures than the other two populations. Fruit size, fruit weight and fruit shape index, which are the most important determinants of fruit marketing, were strongly affected by day and night temperature fluctuations. In all three populations evaluated, fruit length was significantly negatively affected by low night temperature more than high day temperature, which resulted in distortion of fruit shape index. Fruit shape index, which is the result of the ratio of length to diameter of fruit, in marketable fruits is 1-1.02. As the fruit length increases and the fruit diameter remains constant or decreases, the shape index increases from 1.02, and as the fruit diameter increases with decreasing fruit length, which is usually achieved under cold stress conditions, this number decreases below one. Based on the results, the three populations evaluated had different fruit lengths under optimal temperature conditions, which, with the proportion of fruit diameter to length, the fruit shape index was normal and produced marketable fruits. By decreasing the night temperature below the optimum growth temperature, fruit length decreased sharply in the three evaluated populations, and this decrease was greater in seedless fruits. According to Table 2, the highest percentage of fruit length reduction at low night temperature was observed in population A and in seedless fruits. In this temperature condition, fruit length decreased by 43% in seedless fruits and 17.5% in seeded fruits. The lowest decrease in fruit length at low night temperature was related to population C. Fruit length in seeded and non-seeded fruits of this population decreased by 12 and 24%, respectively. However, the percentage of fruit reduction in the total populations evaluated was 13.90 and 33.69% on average in seeded and seedless fruits, respectively. Although the length of the fruit was less affected by the high temperature during the day than the low temperature at night, but the trend of fruit length changes in these temperature conditions was similar to the low temperature at night. The average decrease in fruit length in the total population in seeded and seedless fruits was 10.41 and 31.52%, respectively, with population C having the least and population A having the most effect from unfavorable daytime temperature. Fruit weight was also affected by the unfavorable temperature of day and night, but the negative effect of low night temperature on fruit weight was more than the unfavorable temperature of the day. According to the results, the percentage of fruit weight loss in seeded and seedless fruits at low temperature at night was 21.19 and 50.06%, respectively, and at high temperature at day, 15.98 and 50.12%. As the results show, seedless fruits had the same effect of unfavorable temperature day and night and showed the highest percentage of weight loss. Also, fruit weight in population C showed the least effect of adverse temperature day and night and no significant difference was observed between populations B and A. Expression is associated with undesirable traits that can be due to the coherence of traits or pleiotropic effects of parthenocarpic genes or physiological or molecular changes. Although in population C the number of lines with Parthenocarp fruit was 1%, but Parthenocarp fruits consisting of size and shape index are more suitable than the other two populations. The C population also showed a low percentage of Knot fruits as well as slight differences in fruit weight and shape at low temperature at night and high temperature at day. Based on the results, the three populations evaluated have different potentials in terms of reacting to adverse low temperatures at night and high temperatures during the day, and this potential can be used in future research and breeding programs to produce hybrids that tolerate temperature fluctuations

Application of Nanobiotechnology for Early Diagnosis of SARS-CoV-2 Infection in the COVID-19 Pandemic

Abstract: A most discussed topic of the new decade, COVID-19 is an infectious disease caused by the recently discovered SARS-CoV-2. With an exceedingly high transmission rate, COVID-19 has affected almost all the countries in the world. Absent any vaccine or specific treatment, the humanity is left with nothing but the legacy method of quarantine. However, quarantine can only be effective when combined with early diagnosis of suspected cases. With their high sensitivity and unmatched specificity, biosensors have become an area of interest for development of novel diagnostic methods. Compared to the more traditional diagnostics, nanobiotechnology introduces biosensors as different diagnostics with greater versatility in application. Today, a growing number of analytes are being accurately identified by these nanoscopic sensing machines. Several reports of validated application with real samples further strengthen this idea. As of recent, there has been a rise in the number of studies on portable biosensors. Despite the slow progression, certain devices with embedded biosensors have managed to be of diagnostic value in several countries. The perceptible increase in development of mobile platforms has revolutionized the healthcare delivery system in the new millennium. The present article reviews the most recent advancements in development of diagnostic nanobiosensors and their application in the clinical fields. Key points: � There is no specific treatment for highly transmissible SARS-CoV-2. � Early diagnosis is critical for control of pandemic. � Highly sensitive/specific nanobiosensors are emerging assets against COVID-19. © 2021, The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature

Overexpression of HMGA1 promotes anoikis resistance and constitutive Akt activation in pancreatic adenocarcinoma cells

HMGA1 proteins are architectural transcription factors that are overexpressed by pancreatic adenocarcinomas. Roles of HMGA1 in mediating the malignant phenotype of this cancer are poorly understood. We tested the hypothesis that overexpression of HMGA1 promotes resistance to anoikis (apoptosis induced by anchorage deprivation) in pancreatic cancer cells. HMGA1 cDNA was stably transfected into MiaPaCa2 human pancreatic adenocarcinoma cells (which have low baseline expression levels of HMGA1). Cells were grown in suspension on PolyHEMA-coated plates and their susceptibility to anoikis was assayed using flow cytometry. Overexpression of HMGA1 was associated with marked reductions in susceptibility to anoikis in concert with increases in Akt phosphorylation (Ser473) and in Akt kinase activity and with reductions in caspase 3 activation. Inhibition of phosphoinositidyl-3 (PI3-K)/Akt pathway with either the small molecule inhibitor LY294002 or dominant-negative Akt resulted in reversal of anoikis resistance induced by HMGA1 overexpression. Further, RNA interference-mediated HMGA1 silencing in MiaPaCa2 and BxPC3 (a human pancreatic adenocarcinoma cell line with high baseline levels of HMGA1 expression) cells resulted in significant increases in susceptibility to anoikis. Our findings suggest HMGA1 promotes anoikis resistance through a PI3-K/Akt-dependent mechanism. Given the putative associations between anoikis resistance and metastatic potential, HMGA1 represents a potential therapeutic target in pancreatic adenocarcinoma

Frequent overexpression of HMGA1 and 2 in gastroenteropancreatic neuroendocrine tumours and its relationship to let-7 downregulation

The molecular pathogenesis of gastroenteropancreatic (GEP) neuroendocrine tumours (NETs) remains to be elucidated. High-mobility group A (HMGA) proteins play important roles in the regulation of transcription, differentiation, and neoplastic transformation. In this study, the expression of HMGA1 and HMGA2 was studied in 55 GEP NETs. Overexpression of HMGA1 and 2 was frequently detected in GEP NETs compared with normal tissues. Nuclear immunostaining of HMGA1 and 2 was observed in GEP NETs (38 of 55, 69%; 40 of 55, 73%, respectively). High-mobility group A2 expression increased from well-differentiated NET (WNET) to well-differentiated neuroendocrine carcinoma (WNEC) and poorly differentiated NEC (PNEC) (P<0.005) and showed the highest level in stage IV tumours (P<0.01). In WNECs, the expression of HMGA1 and 2 was significantly higher in metastatic tumours than those without metastasis (P<0.05). Gastroenteropancreatic NETs in foregut showed the highest level of HMGA1 and 2 expressions. MIB-1 labelling index (MIB-1 LI) correlated with HMGA1 and 2 overexpression (R=0.28, P<0.05; R=0.434, P<0.001; respectively) and progressively increased from WNETs to WNECs and PNECs (P<0.001). Let-7 expression was addressed in 6 normal organs, 30 tumour samples, and 24 tumour margin non-tumour tissues. Compared with normal tissues, let-7 downregulation was frequent in NETs (19 of 30, 63%). Higher expression of HMGA1 and 2 was frequently observed in tumours with let-7 significant reduction (53, 42%, respectively). The reverse correlation could be detected between HMGA1 and let-7 (P<0.05). Our findings suggested that HMGA1 and 2 overexpression and let-7 downregulation might relate to pathogenesis of GEP NETs

ILSF, A THIRD GENERATION LIGHT SOURCE LABORATORY IN IRAN

Abstract The Iranian Light Source Facility (ILSF) project is a first large scale accelerator facility which is currently under planning in Iran. On the basis of the present design, circumference of the 3 GeV storage ring is 297.6 m. Beam current and natural beam emittance are 400 mA and 3.278 nm.rad respectively. The facility will be built on a land of 50 hectares area in the city of Qazvin, located 150 km West of Tehran. The city is surrounded by many universities, research centers and industrial companies. The design and construction of prototype items such as radio frequency solid state amplifier, dipole magnets, highly stable magnet power supplies and girders have already begun. Site selection studies, including geotechnical and seismological measurements are being performed. Conceptual Design Report, CDR, as the first milestone of the project was published in October 2012

HMGA1 drives stem cell, inflammatory pathway, and cell cycle progression genes during lymphoid tumorigenesis

<p>Abstract</p> <p>Background</p> <p>Although the <it>high mobility group A1 </it>(<it>HMGA1</it>) gene is widely overexpressed in diverse cancers and portends a poor prognosis in some tumors, the molecular mechanisms that mediate its role in transformation have remained elusive. <it>HMGA1 </it>functions as a potent oncogene in cultured cells and induces aggressive lymphoid tumors in transgenic mice. Because HMGA1 chromatin remodeling proteins regulate transcription, <it>HMGA1 </it>is thought to drive malignant transformation by modulating expression of specific genes. Genome-wide studies to define HMGA1 transcriptional networks during tumorigenesis, however, are lacking. To define the HMGA1 transcriptome, we analyzed gene expression profiles in lymphoid cells from <it>HMGA1a </it>transgenic mice at different stages in tumorigenesis.</p> <p>Results</p> <p>RNA from lymphoid samples at 2 months (before tumors develop) and 12 months (after tumors are well-established) was screened for differential expression of > 20,000 unique genes by microarray analysis (Affymetrix) using a parametric and nonparametric approach. Differential expression was confirmed by quantitative RT-PCR in a subset of genes. Differentially expressed genes were analyzed for cellular pathways and functions using Ingenuity Pathway Analysis. Early in tumorigenesis, HMGA1 induced inflammatory pathways with NFkappaB identified as a major node. In established tumors, HMGA1 induced pathways involved in cell cycle progression, cell-mediated immune response, and cancer. At both stages in tumorigenesis, HMGA1 induced pathways involved in cellular development, hematopoiesis, and hematologic development. Gene set enrichment analysis showed that stem cell and immature T cell genes are enriched in the established tumors. To determine if these results are relevant to human tumors, we knocked-down HMGA1 in human T-cell leukemia cells and identified a subset of genes dysregulated in both the transgenic and human lymphoid tumors.</p> <p>Conclusions</p> <p>We found that <it>HMGA1 </it>induces inflammatory pathways early in lymphoid tumorigenesis and pathways involved in stem cells, cell cycle progression, and cancer in established tumors. <it>HMGA1 </it>also dyregulates genes and pathways involved in stem cells, cellular development and hematopoiesis at both early and late stages of tumorigenesis. These results provide insight into <it>HMGA1 </it>function during tumor development and point to cellular pathways that could serve as therapeutic targets in lymphoid and other human cancers with aberrant <it>HMGA1 </it>expression.</p

Research priorities for global food security under extreme events

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