Finite element modeling and experimental studies on mixed mode-I/III fracture specimens

In this study, finite element modeling and experimental studies on a mode-I/III specimen similar to the compact tension specimen are presented. By using bolts, the specimen is attached to two loading apparatus that allow different levels of mode-I/III loading by changing the loading holes. Specimens having two different thicknesses are analyzed and tested. Modeling, meshing and the solution of the problem involving the whole assembly, i.e., loading devices, bolts and the specimen, with contact mechanics are performed using ANSYSTM. Then, the mode-I/III specimen is analyzed separately using a submodeling approach, in which threedimensional enriched finite elements are used in FRAC3D solver to calculate the resulting stress intensity factors along the crack front. In all of the analyses, it is clearly shown that although the loading is in the mode-I and III directions, mode-II stress intensity factors coupled with mode-III are also generated due to rotational relative deformations of crack surfaces. The results show that the mode-II stress intensity factors change sign along the crack front and their magnitudes are close to the mode-III stress intensity factors. It is also seen that magnitudes of the mode-III stress intensity factors do not vary much along the crack front. Fracture experiments also performed and, using the stress intensity factors from the analyses and crack paths and surfaces are shown

Biosimilar filgrastim vs filgrastim: a multicenter nationwide observational bioequivalence study in patients with chemotherapy-induced neutropenia

Background: We studied the comparative effectiveness of biosimilar filgrastim vs original filgrastim in patients with chemotherapy-induced neutropenia.Patients and methods: This multicenter, observational study was conducted at 14 centers. The study included 337 patients experiencing neutropenia under chemotherapy. Patients were given either filgrastim 30 MIU or 48 MIU (Neupogen (R)) or biosimilar filgrastim 30 MIU (Leucostim (R)). Data regarding age, chemotherapeutic agents used, number of chemotherapy courses, previous diagnosis of neutropenia, neutrophil count of patients after treatment, medications used for the treatment of neutropenia, and duration of neutropenia were collected. Time to absolute neutrophil count (ANC) recovery was the primary efficacy measure.Results: Ambulatory and hospitalized patients comprised 11.3% and 45.1% of the enrolled patients, respectively, and a previous diagnosis of neutropenia was reported in 49.3% of the patients, as well. Neutropenia occurred in 13.7% (n=41), 45.5% (n=136), 27.4% (n=82), 11.4% (n=34), and 2.0% (n=6) of the patients during the first, second, third, fourth, and fifth cycles of chemotherapy, respectively. While the mean neutrophil count was 0.53 +/- 0.48 before treatment, a significant increase to 2.44 +/- 0.66 was observed after treatment (p=0.0001). While 90.3% of patients had a neutrophil count,1.49 before treatment, all patients had a neutrophil count >= 1.50 after treatment. Neutropenia resolved within <= 4 days of filgrastim therapy in 60.1%, 56.7%, and 52.6% of the patients receiving biosimilar filgrastim 30 MIU, original filgrastim 30 MIU, and original filgrastim 48 MIU, respectively. However, there was no significant difference between the three arms (p=0.468). Similarly, time to ANC recovery was comparable between the treatment arms (p=0.332).Conclusion: The results indicate that original filgrastim and biosimilar filgrastim have comparable efficacy in treating neutropenia. Biosimilar filgrastim provides a valuable alternative; however, there is need for further studies comparing the two products in different patient subpopulations

Epigenetic perturbations in the pathogenesis of mustard toxicity; hypothesis and preliminary results

Among the most readily available chemical warfare agents, sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. SM causes debilitating effects that can leave an exposed individual incapacitated for days to months; therefore delayed SM toxicity is of much greater importance than its ability to cause lethality. Although not fully understood, acute toxicity of SM is related to reactive oxygen and nitrogen species, oxidative stress, DNA damage, poly(ADP-ribose) polymerase (PARP) activation and energy depletion within the affected cell. Therefore several antioxidants and PARP inhibitors show beneficial effects against acute SM toxicity. The delayed toxicity of SM however, currently has no clear mechanistic explanation. One third of the 100,000 Iranian casualties are still suffering from the detrimental effects of SM in spite of the extensive treatment. We, therefore, made an attempt whether epigenetic aberrations may contribute to pathogenesis of mustard poisoning. Preliminary evidence reveals that mechlorethamine (a nitrogen mustard derivative) exposure may not only cause oxidative stress, DNA damage, but epigenetic perturbations as well. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to mutations, epimutations contribute to a variety of human diseases. Under light of preliminary results, the current hypothesis will focus on epigenetic regulations to clarify mustard toxicity and the use of drugs to correct possible epigenetic defects

Acute and delayed sulfur mustard toxicity; novel mechanisms and future studies

Sulfur mustard (SM), also known as mustard gas, has been the most widely used chemical weapon. The toxicity of SM as an incapacitating agent is of much greater importance than its ability to cause lethality. Acute toxicity of SM is related to reactive oxygen and nitrogen species, DNA damage, poly(ADP-ribose) polymerase activation and energy depletion within the affected cell. Therefore melatonin shows beneficial effects against acute SM toxicity in a variety of manner. It scavenges most of the oxygen- and nitrogen-based reactants, inhibits inducible nitric oxide synthase, repairs DNA damage and restores cellular energy depletion. The delayed toxicity of SM however, currently has no mechanistic explanation. We propose that epigenetic aberrations may be responsible for delayed detrimental effects of mustard poisoning. Epigenetic refers to the study of changes that influence the phenotype without causing alteration of the genotype. It involves changes in the properties of a cell that are inherited but do not involve a change in DNA sequence. It is now known that in addition to genetic mutations, epimutations can also involve in the pathogenesis of a variety of human diseases. Several actions of melatonin are now delineated by epigenetic actions including modulation of histone acetylation and DNA methylation. Future studies are warranted to clarify whether epigenetic mechanisms are involved in pathogenesis of delayed sulfur mustard toxicity and melatonin alleviates delayed toxicity of this warfare agent

Molecular, genetic and epigenetic pathways of peroxynitrite-induced cellular toxicity

Oxidative stress plays a key role in the pathogenesis of cancer and many metabolic diseases; therefore, an effective antioxidant therapy would be of great importance in these circumstances. Nevertheless, convincing randomized clinical trials revealed that antioxidant supplementations were not associated with significant reduction in incidence of cancer, chronic diseases and all-cause mortality. As oxidation of essential molecules continues, it turns to nitro-oxidative stress because of the involvement of nitric oxide in pathogenesis processes. Peroxynitrite damages via several distinctive mechanisms; first, it has direct toxic effects on all biomolecules and causes lipid peroxidation, protein oxidation and DNA damage. The second mechanism involves the induction of several transcription factors leading to cytokine-induced chronic inflammation. Finally, it causes epigenetic perturbations that exaggerate nuclear factor kappa-B mediated inflammatory gene expression. Lessons-learned from the treatment of several chronic disorders including pulmonary diseases suggest that, chronic inflammation and glucocorticoid resistance are regulated by prolonged peroxynitrite production

Finite element modeling and experimental studies on mixed mode-I/III fracture specimens

In this study, finite element modeling and experimental studies on a mode-I/III specimen similar to the compact tension specimen are presented. By using bolts, the specimen is attached to two loading apparatus that allow different levels of mode-I/III loading by changing the loading holes. Specimens having two different thicknesses are analyzed and tested. Modeling, meshing and the solution of the problem involving the whole assembly, i.e., loading devices, bolts and the specimen, with contact mechanics are performed using ANSYSTM. Then, the mode-I/III specimen is analyzed separately using a submodeling approach, in which threedimensional enriched finite elements are used in FRAC3D solver to calculate the resulting stress intensity factors along the crack front. In all of the analyses, it is clearly shown that although the loading is in the mode-I and III directions, mode-II stress intensity factors coupled with mode-III are also generated due to rotational relative deformations of crack surfaces. The results show that the mode-II stress intensity factors change sign along the crack front and their magnitudes are close to the mode-III stress intensity factors. It is also seen that magnitudes of the mode-III stress intensity factors do not vary much along the crack front. Fracture experiments also performed and, using the stress intensity factors from the analyses and crack paths and surfaces are shown