Search

Gastrointestinal (GI) malignancies are a major global health burden, with high mortality rates. The identification of novel therapeutic strategies is crucial to improve treatment and survival of patients. The poly (ADP-ribose) polymerase (PARP) enzymes involved in the DNA damage response (DDR) play major roles in the development, progression and treatment response of cancer, with PARP inhibitors (PARPi) currently used in the clinic for breast, ovarian, fallopian, primary peritoneal, pancreatic and prostate cancers with deficiencies in homologous recombination (HR) DNA repair. This article examines the current evidence for the role of the DDR PARP enzymes (PARP1, 2, 3 and 4) in the development, progression and treatment response of GI cancers. Furthermore, we discuss the role of HR status as a predictive biomarker of PARPi efficacy in GI cancer patients and examine the pre-clinical and clinical evidence for PARPi and cytotoxic therapy combination strategies in GI cancer. We also include an analysis of the genomic and transcriptomic landscape of the DDR PARP genes and key HR genes (BRCA1, BRCA2, ATM, RAD51, MRE11, PALB2) in GI patient tumours (n = 1744) using publicly available datasets to identify patients that may benefit from PARPi therapeutic approaches.

The hippocampus in mammalian brain varies in size across individuals. Here, Hibar and colleagues perform a genome-wide association meta-analysis to find six genetic loci with significant association to hippocampus volume.

Background: Lead is a common environmental and occupational pollutant which induced multiorgans dysfunction. The present study was designed to investigate the hepatoprotective effects of turmeric (TUR) and/or vitamin C (Vit-C) alone or together against lead acetate toxicity and to explore novel molecular pathways. Method: Acute hepatotoxicity was induced by lead acetate (100 mg/kg/day, i.p.) in male rats, and the effect of TUR (200 mg/kg/day, orally) and/or Vit-C (250 mg/kg/day, orally) along with lead acetate for 7 days was studied. Results: Lead acetate increased serum alanine transaminase, aspartate transaminase, lactate dehydrogenase, hepatic lipid peroxidation and nitric oxide; while, hepatic superoxide dismutase and glutathione activities were downregulated. Hepatic Bcl-2-associated X (Bax) and B-cell lymphoma-2 (Bcl-2) proteins expressions were altered and hepatic DNA damaged was increased as well. Liver/body weight ratio was decreased. Hematoxylin and eosin demonstrated that lead acetate induced focal areas of massive hepatic degeneration of the hepatocytes. Treatment with both antioxidants ameliorated all the altered parameters and induced marked improvement of liver architecture. Conclusion: The combination of TUR and Vit-C has shown the most protective effects against lead acetate-induced hepatotoxicity.

The aim of the current study is to assess the effectiveness of milk thistle seeds (Mth) in combination with Taraxacum officinale ( Tof ) and/or Camellia sinensis ( Csin ) against tetrachloromethane (Tcm) renotoxicity in rats. Tetrachloromethane was injected in a single dose, followed by 1-month treatments with Mth, Tof , and Csin alone or in combination. Serum urea, uric acid, and creatinine levels were significantly increased matched with the control group. Masson trichrome stain revealed increase in the deposition of fibrous tissue in the interstitium between the tubules and the renal corpuscles. Immunohistochemical analysis of kidney tissues revealed that Tcm induced an increase in the immune response of tumor growth factor β (TGF-β) and Janus kinase (JAK) protein expressions and cysteine–aspartic acid protease 3 (caspase 3), while B-cell lymphoma 2 (Bcl2) was downregulated. Treatment with the antioxidants in question either alone or in combination ameliorated all kidney function parameters and showed mild immune reactivity toward TGF-β and JAK protein expressions in blood vessels and glomeruli in the kidney tissues and downregulated caspase 3 and activated Bcl2 protein expression. The combination regimen of the 3 antioxidants showed the most significant renoprotective effect. This was also confirmed histopathologically. It was concluded that the antioxidant mixture is considered as a promising candidate toward renal dysfunction and immune reactivity induced by Tcm and other toxicants.

Background: diagnostic radiology field workers are at elevated risk level for systemic and oral diseases like periodontal diseases. This study was aimed to estimate the periodontal condition and salivary flow rate among diagnostic radiology workers. Material and method: The sample for this study consisted of a study group radiographers (forty subjects) working for 5 years at least and control group consisted of nurses and laboratory workers away from radiation (forty subjects) in Baghdad hospitals. All the 80 subjects aged 30-40 year-old and looking healthy without systemic diseases. Plaque, gingival, periodontal pocket depth and clinical attachment loss indices were used for recording the periodontal conditions. Under standardized conditions, collection of unstimulated salivary samples was done and salivary flow rate was measured. Results: Although not significant statistically (p>0.01), analysis of the present study data showed that plaque and gingival indices were higher among radiographers. While periodontal pocket depth and clinical attachment loss were higher among radiographers than control group with statistically highly significant difference (p

Background: The consequences of excess copper in human tissue are the alterations in the oxidative stress markers and peroxidative damage of membrane lipids. Unselective copper binding may be the clue to damaging impact to protein construction and hence modifying their biological functions. The aim of this study is to match the hepatoprotective efficacy of curcumin (CM) or nanocurcumin (NCM) with that of desferrioxamine (DSF; standard heavy metal chelator) against toxic doses of copper sulphate (CuSO 4 ). Method: All treatments were given simultaneously with CuSO 4 for 7 days. Result: CuSO 4 administration elevated serum alanine transaminase, and hepatic nitric oxide (NO), lipid peroxide, and caspase-3 as well as protein expression of cytochrome P4502E1, and nuclear factor-κB (NF-κB) and Bax gene expressions. On the other hand, hepatic levels of reduced glutathione, superoxide dismutase, and interleukin-10 were decreased, whereas DNA degradation was increased as well compared with the control group. The administration of the aforementioned antioxidants ameliorated all the previous altered measured parameters. Interestingly, NCM achieved the most pronounced hepatoprotective effect nearly equivalent to that of DSF. Conclusion: It was concluded that NCM is considered a promising candidate against CuSO 4 toxicity, and cytochrome P450, NF-κB, and Bax are involved in its toxicity and treatment.

The purpose of this study was to examine students' creativity when writing open-ended stories--across ethnicity, gender, and grades. Participants were 139 students, including 67 males and 72 females, from urban and rural areas of the southwestern United States. The students were in third, fourth, and fifth grades and included three ethnicities: White, Mexican American, and Navajo. Written stories were selected from the Discovering Intellectual Strengths and Capabilities while Observing Varied Ethnic Responses (DISCOVER) project's archives. Creative products were scored by using the Consensual Assessment Technique (CAT) by five experts. No significant differences were found between boys and girls; also, no significant differences were found across the three grade levels. The differences among the three ethnic groups were significant: the White students were more creative. Future researchers should focus on implementing comprehensive teaching methods to meet all students' needs (e.g., the DISCOVER project). Teachers who work at schools with minority students should establish an early childhood program for teaching English as a Second Language (ESL) to help young students use the language and adapt to the culture.

Convolutional neural networks (CNN) are relational with grid-structures and spatial dependencies for two-dimensional images to exploit location adjacencies, color values, and hidden patterns. Convolutional neural networks use sparse connections at high-level sensitivity with layered connection complying indiscriminative disciplines with local spatial mapping footprints. This fact varies with architectural dependencies, insight inputs, number and types of layers and its fusion with derived signatures. This research focuses this gap by incorporating GoogLeNet, VGG-19, and ResNet-50 architectures with maximum response based Eigenvalues textured and convolutional Laplacian scaled object features with mapped colored channels to obtain the highest image retrieval rates over millions of images from versatile semantic groups and benchmarks. Time and computation efficient formulation of the presented model is a step forward in deep learning fusion and smart signature capsulation for innovative descriptor creation. Remarkable results on challenging benchmarks are presented with a thorough contextualization to provide insight CNN effects with anchor bindings. The presented method is tested on well-known datasets including ALOT (250), Corel-1000, Cifar-10, Corel-10000, Cifar-100, Oxford Buildings, FTVL Tropical Fruits, 17-Flowers, Fashion (15), Caltech-256, and reported outstanding performance. The presented work is compared with state-of-the-art methods and experimented over tiny, large, complex, overlay, texture, color, object, shape, mimicked, plain and occupied background, multiple objected foreground images, and marked significant accuracies.

Over the last decade, the field of imaging genomics has combined high-throughput genotype data with quantitative magnetic resonance imaging (QMRI) measures to identify genes associated with brain structure, cognition, and several brain-related disorders. Despite its successful application in different psychiatric and neurological disorders, the field has yet to be advanced in epilepsy. In this article we examine the relevance of imaging genomics for future genetic studies in epilepsy from three perspectives. First, we discuss prior genome-wide genetic mapping efforts in epilepsy, considering the possibility that some studies may have been constrained by inherent theoretical and methodological limitations of the genome-wide association study (GWAS) method. Second, we offer a brief overview of the imaging genomics paradigm, from its original inception, to its role in the discovery of important risk genes in a number of brain-related disorders, and its successful application in large-scale multinational research networks. Third, we provide a comprehensive review of past studies that have explored the eligibility of brain QMRI traits as endophenotypes for epilepsy. While the breadth of studies exploring QMRI-derived endophenotypes in epilepsy remains narrow, robust syndrome-specific neuroanatomical QMRI traits have the potential to serve as accessible and relevant intermediate phenotypes for future genetic mapping efforts in epilepsy.

The lack of sentiment resources in poor resource languages poses challenges for the sentiment analysis in which machine learning is involved. Cross-lingual and semi-supervised learning approaches have been deployed to represent the most common ways that can overcome this issue. However, performance of the existing methods degrades due to the poor quality of translated resources, data sparseness and more specifically, language divergence. An integrated learning model that uses a semi-supervised and an ensembled model while utilizing the available sentiment resources to tackle language divergence related issues is proposed. Additionally, to reduce the impact of translation errors and handle instance selection problem, we propose a clustering-based bee-colony-sample selection method for the optimal selection of most distinguishing features representing the target data. To evaluate the proposed model, various experiments are conducted employing an English-Arabic cross-lingual data set. Simulations results demonstrate that the proposed model outperforms the baseline approaches in terms of classification performances. Furthermore, the statistical outcomes indicate the advantages of the proposed training data sampling and target-based feature selection to reduce the negative effect of translation errors. These results highlight the fact that the proposed approach achieves a performance that is close to in-language supervised models.

Doxorubicin (DOX) is a cytotoxic anthracycline antibiotic and one of the important chemotherapeutic agents for different types of cancers. DOX treatment is associated with adverse effects, particularly cardiac dysfunction. This study examined the cardioprotective effects of carvedilol (CAR) and/or resveratrol (RES) and liposomal RES (LIPO-RES) against DOX-induced cardiomyopathy, pointing to their modulatory effect on oxidative stress, inflammation, S100A1 and sarco/endoplasmic reticulum calcium ATPase2a (SERCA2a). Rats received CAR (30 mg/kg) and/or RES (20 mg/kg) or LIPO-RES (20 mg/kg) for 6 weeks and were challenged with DOX (2 mg/kg) twice per week from week 2 to week 6. DOX-administered rats exhibited a significant increase in serum creatine kinase-MB (CK-MB), troponin-I and lactate dehydrogenase (LDH) along with histological alterations, reflecting cardiac cell injury. Cardiac toll-like receptor 4 (TLR-4), inducible nitric oxide synthase (iNOS), tumor necrosis factor (TNF)-α and interleukin (IL)-6 protein expression were up-regulated, and lipid peroxidation was increased in DOX-administered rats. Treatment with CAR, RES or LIPO-RES as well as their alternative combinations ameliorated all observed biochemical and histological alterations with the most potent effect exerted by CAR/LIPO-RES. All treatments increased cardiac antioxidants, and the expression of S100A1 and SERCA2a. In conclusion, the present study conferred new evidence on the protective effects of CAR and its combination with either RES or LIPO-RES on DOX-induced inflammation, oxidative stress and calcium dysregulation.

The present study aimed to explore the efficiency of N-acetyl cysteine (NACC) or thymoquinone (TMQ) alone or in combination in the downregulation of inflammatory molecule expression and decreasing hepatic injury in response to sodium fluoride (SF). Sodium fluoride upregulated serum alanine and aspartate transferases activities, tumor necrosis factor α and hepatic malondialdehyde and nitric oxide levels, and the expression of cyclooxygenase 2, nuclear factor κB cell, and signal transducer and activator of transcription 3. In contrast, hepatic glutathione level, superoxide dismutase activity, and nuclear factor erythroid 2-related factor 2 expression were decreased. However, the concurrent treatment with antioxidants, alone or in combination, modulated the levels of these parameters. Histopathological examination revealed that SF treatment resulted in focal areas of massive hepatic degeneration and many degenerated hepatocytes, whereas the treatment with TMQ or NACC exhibited moderate improvement in cellular degeneration of the liver with many abnormal cells. Rats receiving a combination of TMQ and NACC showed marked improvement in cellular degeneration of liver with apparently normal hepatic architecture with very few degenerated hepatocytes. The results also revealed that the combination of TMQ and NACC is the most effective regimen in ameliorating SF toxicity, suggesting their efficacy against the toxicity of fluoride compounds. Their activities might be mediated via multiple molecular pathways.

Background: Copper is an essential element that is used widely in agriculture as fungicides and insecticides; for example, it is used to control schistosomiasis and as an antiseptic and germicide. Copper sulfate (CuSO 4 ) induces multiorgan dysfunction through the stimulation of reactive oxygen species and oxidative stress. Despite the numerous pharmacological effects of curcumin (CUR), its pharmacokinetic properties are less promising. Hence, there is an urgent need for novel, effective strategies to attenuate heavy metal toxicity and consequently improve the treatment efficiency. Liposomal curcumin (L-CUR) improves the dissolution, stability, and bioavailability of treatment agents. This study compared the efficacy of CUR and L-CUR with that of desferrioxamine (DES), which is a heavy metal chelator against CuSO 4 hepatotoxicity. Methods: All treatments with the aforementioned antioxidants were administered for 7 days along with CuSO 4 . Serum levels of alanine aminotransferase, aspartate transaminase, lactate dehydrogenase, and C-reactive protein, hepatic nitric oxide (NO), and lipid peroxides (malondialdehyde) were measured; protein expression of cyclooxygenase 2 and DNA fragmentation were evaluated. Histopathological examinations were also conducted. Results: A toxic dose of CuSO 4 induced elevations in the previously measured parameters; these increases were reduced by the tested antioxidants , whereas glutathione (GSH) and superoxide dismutase (SOD) levels were decreased. Treatment with the antioxidants in question modulated these levels. Liposomal CUR has more hepatoprotective efficiency than CUR, and its efficacy was similar to that of DES. The histopathological examinations confirmed these results. Conclusions: Liposomal CUR may be useful for the prevention of CuSO 4 -induced liver injury. Cyclooxygenase 2 protein expression and DNA fragmentation were involved in CuSO 4 toxicity and treatment.

Propionic acid (PRA) is a metabolic end-product of enteric bacteria in the gut, and it is commonly used as a food preservative. Despite the necessity of PRA for immunity in the body, excessive exposure to this product may result in disruptive effects. The purpose of this study is to examine the hepatoprotective effects of acetyl-L-carnitine (A-CAR) and liposomal-coenzyme Q10 (L-CoQ10) against PRA-induced injury. Liver injury in rats was induced by oral administration of PRA, and A-CAR and L-CoQ10 were administered concurrently with PRA for 5 days. Oxidative stress, inflammatory, apoptotic, and fibrotic biomarkers were analyzed; the histology of liver tissue was assessed as well to further explore any pathological alterations. PRA caused significant increases in the levels of serum liver enzymes and hepatic oxidative stress, inflammatory, and apoptotic biomarker levels, along with histopathological alterations. Concurrent treatment with A-CAR and/or L-CoQ10 with PRA prevented tissue injury and decreased the levels of oxidative stress, proinflammatory cytokines, and apoptotic markers. Additionally, A-CAR and/or L-CoQ10 modulated the expression of high-mobility group box-1, cytokeratin-18, transforming growth factor-beta1, and SMAD3 in liver tissue. In conclusion, A-CAR and/or L-CoQ10 showed hepatoprotective efficacy by reducing oxidative stress, the inflammatory response, apoptosis, and fibrosis in liver tissue. [ABSTRACT FROM AUTHOR]