Human cancer genomes harbor the mutational signature of tobacco-specific nitrosamines NNN and NNK.

Tobacco usage is linked to multiple cancer types and accounts for a quarter of all cancer-related deaths. Tobacco smoke contains various carcinogenic compounds, including polycyclic aromatic hydrocarbons (PAH), though the mutagenic potential of many tobacco-related chemicals remains largely unexplored. In particular, the highly carcinogenic tobacco-specific nitrosamines NNN and NNK form pre-mutagenic pyridyloxobutyl (POB) DNA adducts. In the study presented here, we identified genome-scale POB-induced mutational signatures in cell lines and rat tumors, while also investigating their role in human cancer. These signatures are characterized by T>N and C>T mutations forming from specific POB adducts damaging dT and dC residues. Analysis of 2,780 cancer genomes uncovered POB signatures in ∼180 tumors; from cancer types distinct from the ones linked to smoking-related signatures SBS4 and SBS92. This suggests that, unlike PAH compounds, the POB pathway may contribute uniquely to the mutational landscapes of certain hematological malignancies and cancers of the kidney, breast, prostate and pancreas.

Effects of abrupt and gradual light/dark switching on growth performance, behavior, villus development, meat characteristics, and immunity of broilers.

The aim of this study is to determine the effect of abrupt and gradual light/dark switching on growth performance, behavior, villus development, meat characteristics, and immunity of broilers. A total of 270 daily male broiler chicks were used in the experiment. The study comprised three groups based on whether the transitions between light and dark periods were abrupt or gradual. No significant differences were observed among the examined groups in terms of body weight, weight gain, mortality rate, feeding, pecking, relaxing, and feather preening behaviors, carcass, and breast meat quality characteristics. Total body weight gain, total feed consumption, total feed utilization ratio, and mortality rates of broilers during the 6-week fattening period did not differ compared to the abrupt transition. Broilers in the group with gradual transition exhibited less movement, more sitting, and sleeping behaviors. It was determined that the IgG was higher in the gradual transition group. The transitions between light and dark periods influenced the characteristics of thigh meat. Villus height and crypt depth were higher in the group where a 1-h gradual transition was applied. As a conclusion, gradual transition is more appropriate in broiler rearing.

Efficacy of mono- and multistrain synbiotics supplementation in modifying performance, caecal fermentation, intestinal health, meat and bone quality, and some blood biochemical indices in broilers.

The superiority of synbiotics in terms of their biological effects depends primarily on a suitable combination of both components, pro-biotic and pre-biotic. The present study was conducted to compare the efficacy of mono- and multistrain synbiotics on overall performance, caecal fermentation, intestinal health, meat and bone quality along with some blood biochemical indices in broilers. A total of 231, 1-day-old male Ross 308, broiler chicks were randomly assigned to three experimental groups using 11 replicates each and seven chicks/replicate. The dietary treatments included control group with no synbiotic supplementation, monostrain (Maflor) and multistrain (Maflor plus) synbiotic groups with 1 g/kg of added synbiotics each. Synbiotics feeding significantly improved animal performance with a clear impact on meat quality in terms of low-fat, optimum ultimate pH24, higher water holding capacity, and lower drip and cooking losses. Of the two synbiotics, multistrain seemed to have responded better in modifying small intestinal epithelia and fermentation metabolites, although both synbiotics were comparable in reducing the pathogen load. Load-bearing capacity of both leg bones (femur and tibia) was also enhanced with synbiotics supplementation, which was also reflected in their mineral profile. The blood serum biochemical analysis showed a reduction in circulating cholesterol and triglycerides levels and an increment in IgA and IgG concentrations. In conclusion, the remarkable efficacy of tested synbiotics in providing higher growth, better meat quality in tandem with the optimum gut environment, lower pathogen load, healthy epithelia, immunomodulation, hypocholesterolemic, and hypotriglyceridemic effects affirms their great potential to be used as feed additives in broiler diets. Contrary to our expectations, the effectiveness of a mono-strain in comparison to multistrain synbiotic in improving almost all the features investigated was also notable. Further evaluation under challenging conditions should be explicitly conducted to achieve more comprehensive results.

Sepiolite as an effective supplement for low-protein diets with the constant energy-protein ratio in broilers.

The present study aimed to examine the influence of sepiolite on growth performance, meat quality, intestinal health, some blood parameters, and digestibility of nutrients in broilers fed low-protein diets with the constant energy-protein ratio. A total of 252, daily male broiler chicks were allocated to four treatment groups further divided into 9 replicates each containing 7 chicks. Low-protein diets having a constant energy-protein ratio were formulated by lowering protein and energy levels of the control group diet by 5%. Sepiolite was used at the level of 1% in the diets. After 42 days of trial, total feed consumption, total body weight gain, total feed conversion ratio, and carcass yield were not influenced by reducing protein, sepiolite supplementation, and interaction between low-protein-low-energy diet and sepiolite. Reducing protein in the diets led to reducing the digestibility of nutrients, increasing ileal viscosity, decreasing villus height, villus surface area in duodenum and jejunum, and increasing abdominal fat and ether extract, cooking losses, total oxidant status, and oxidative status index in breast meat. Sepiolite supplementation to low-protein diets increased crude protein digestibility, reduced viscosity, increased villus height/crypt depth values and reduced cooking losses, and increased water holding capacity in breast meat. Blood serum biochemical parameters and minerals were not affected by sepiolite supplementation to low-protein diets. Therefore, it is concluded that sepiolite can be added as a beneficial supplement in broiler diets as well as in low-protein diets with a constant energy-protein ratio.

A Highly Efficacious PS Gene Editing System Corrects Metabolic and Neurological Complications of Mucopolysaccharidosis Type I.

Our previous study delivered zinc finger nucleases to treat mice with mucopolysaccharidosis type I (MPS I), resulting in a phase I/II clinical trial (ClinicalTrials.gov: NCT02702115). However, in the clinical trial, the efficacy needs to be improved due to the low transgene expression level. To this end, we designed a proprietary system (PS) gene editing approach with CRISPR to insert a promoterless α-l-iduronidase (IDUA) cDNA sequence into the albumin locus of hepatocytes. In this study, adeno-associated virus 8 (AAV8) vectors delivering the PS gene editing system were injected into neonatal and adult MPS I mice. IDUA enzyme activity in the brain significantly increased, while storage levels were normalized. Neurobehavioral tests showed that treated mice had better memory and learning ability. Also, histological analysis showed efficacy reflected by the absence of foam cells in the liver and vacuolation in neuronal cells. No vector-associated toxicity or increased tumorigenesis risk was observed. Moreover, no off-target effects were detected through the unbiased genome-wide unbiased identification of double-stranded breaks enabled by sequencing (GUIDE-seq) analysis. In summary, these results showed the safety and efficacy of the PS in treating MPS I and paved the way for clinical studies. Additionally, as a therapeutic platform, the PS has the potential to treat other lysosomal diseases.

Effect of autologous growth factors on apoptosis and thickness of the outer nuclear layer in an experimental retinal degeneration model.

Retinal pigment epithelium and photoreceptor cells are a microenvironment where 90 different peptides are synthesized for transduction, visual cycle, intracellular electron transport chain, and removal of metabolic wastes. Depending on the inheritance pattern, either mutant proteins accumulate inside the cells or the energy cycle is disrupted. Disruption of homeostasis causes the cells to switch to the dormant phase; if the improper conditions last longer, then apoptosis eventually develops resulting in a loss of visual function. In neural tissues, growth factors such as neural growth factor, brain-derived neurotrophic factor, ciliary neurotrophic factor, and insulin-like growth factor are regulatory peptides for intracellular energy cycle and intracellular digestion. In this study, it has been shown histopathologically that autologous growth factors can prevent apoptosis and prevent loss of outer retinal thickness in the retinal degeneration model created with sodium iodate.

Mesenchymal stem cell transplantation in polytrauma: Evaluation of bone and liver healing response in an experimental rat model.

PURPOSE: Trauma is the most common cause of death of young people in the world. As known, mesenchymal stem cells (MSCs) accelerate tissue regeneration mechanisms. In our study, we aimed to investigate the effects of MSCs transplantation on the healing of liver and bone tissue by considering trauma secondary inflammatory responses. METHODS: 56 adult Wistar-albino rats were divided into two groups: the polytrauma (liver and bone) (n = 28), and the liver trauma group (n = 28). At 36 h and 5th day after surgery, both rats with polytrauma and with isolated liver injury received either intravenous (IV) or intraperitoneal (IP) injections of MSCs (one million cells per kg body weight). Untreated groups received IV and IP saline injections. At day 21 after surgery, liver, tibia and fibula of the subjects were excised and evaluated for histopathologic and histomorphometric examination. Additionally, whole blood count (white blood cells, hemoglobin and platelets), C-reactive protein (CRP), glucose, alanine aminotransferase (ALT), aspartate aminotransferase (AST), albumin, blood gas, and trauma markers interleukin-1B (IL-1B), interleukin-6 (IL-6), and tumor necrosis factor alpha (TNF alpha) levels were investigated. RESULTS: In general, MSC transplantations were well tolerated by the subjects. It was found that ALT, CRP, albumin were significantly lower in rats which received MSCs (p < 0.001). Inflammation of the liver and bone tissue in the MSC-injected rats were significantly lower than that of the untreated groups. CONCLUSIONS: Herewith we have shown that MSC infusion in posttraumatic rats leads to less aggressive and more effective consequences on liver and bone tissue healing. Human MSC treatment for trauma is still in early stages of development; thus standard protocols, and patient inclusion criteria should be established beforehand clinical trials.

Microbiological and Histopathological Effects of Nasal Packing Containing Probiotics on Nasal Mucosa.

BACKGROUND: Nasal packing is frequently used after surgical interventions to prevent bleeding and synecchia formation and for the treatment of diseases such as epistaxis. One of the most morbid complications of nasal packing applications is the toxic shock syndrome (TSS). Owing to the microbiological structure of nasal mucosa, antibiotics are administered to all patients who are applied nasal packages for prevention of TSS. AIM: The aim of this study is the evaluation of microbiological and histopathological changes taking place in nasal mucosa with nasal packing containing probiotics. METHODS: Three groups were formed with 6 rats in each group. The nasal packings with the same characteristics were applied to nasal cavities of rats in all 3 groups. In group 1, only nasal packs were used. Probiotics or parenteral antibiotics were not used. In group 2, parenteral antibiotics were used along with nasal packs. In group 3, nasal packs with probiotics containing Lactobacillus strains were applied. No parenteral antibiotics were used. After 3 days packages were removed and nasal cavity was irrigated with saline. Both packages and irrigation materials were analyzed for microbiological content. After scarification, nasal and paranasal structures were examined for histopathological changes. RESULTS: In group 3 statistically the total bacteria load was significantly lower in comparison to the other groups. However, in the histopathological evaluation of the mucosa of rats in group 3, bleeding and inflammation findings were significantly higher statistically. CONCLUSIONS: It has been determined that the total microbiological load significantly decreases with the application of packing containing probiotics. So, the use of probiotics along with nasal packings is promising to prevent unnecessary use of medications.

Imaging and surgical outcomes of spinal tumors in 18 dogs and one cat.

Clinical and magnetic resonance imaging (MRI) findings, histological appearances and surgical outcomes of 18 dogs and one cat with spinal tumors are presented. Medical records of the cases admitted for spinal disorders were reviewed, and cases of spinal tumors that were diagnosed by MRI and confirmed by histological examination were included in this study. T1 weighted, T2 weighted and contrast enhanced T1 weighted images were taken and interpreted to evaluate the spinal tumors. The tumors were diagnosed as: meningioma (n = 6), ependymoma (n = 1), nerve sheath tumor (n = 4), metastatic spinal tumor (n = 3), osteosarcoma (n = 2), osteoma (n = 1), rhabdomyosarcoma (n = 1), and nephroblastoma (n = 1). Thirteen cases underwent surgical operation and the remaining six cases were euthanized at the request of the owners. The neurological status of the surgical cases did not deteriorate, except for one dog that showed ependymoma in the early period after the operation. These results indicate the potential for surgical gross total tumor removal of vertebral tumors to provide better quality of life and surgical collection of histological specimens for definitive diagnosis. For effective case management, dedicated MRI examination is important to accurate evaluation of the spinal tumors, and surgical treatment is useful for extradural and intradural-extramedullary spinal tumors.