Measurement and testing problems experienced during FAA's emissions testing of general aviation piston engines

The importance of measuring accurate air and fuel flows as well as the importance of obtaining accurate exhaust pollutant measurements were emphasized. Some of the problems and the corrective actions taken to incorporate fixes and/or modifications were identified

Finite element simulation of semi-finishing turning of Electron Beam Melted Ti6Al4V under dry and cryogenic cooling

open6noIn the last few years, important step forwards have been made on Finite Element Simulation of machining operations. Wrought Ti6Al4V alloy has been deeply investigated both numerically and experimentally due to its wide application in the industry. Recently, Additive Manufacturing technologies as the Electron Beam Melting and the Direct Melting Laser Sintering are more and more employed in the production of biomedical and aeronautical components made of Ti6Al4V alloy. Fine acicular microstructures are generated by the application of additive manufacturing technologies, affecting the mechanical properties and the machinability. By the consequence, this peculiarity has to be considered in modelling the material behaviour. In this work, a numerical analysis of cylindrical external turning on Electron Beam Melted (EBM) Ti6Al4V alloy is presented. A Johnson-Cook constitutive equation was implemented as a flow stress model and adapted with respect to the wrought Ti6Al4V alloy. The model was calibrated and validated through the cutting forces and temperatures measurements acquired under dry and cryogenic lubricating conditions.openBordin, A; Imbrogno, S.; Rotella, G.; Bruschi, S.; Ghiotti, A.; Umbrello, D.Bordin, Alberto; Imbrogno, S.; Rotella, G.; Bruschi, Stefania; Ghiotti, Andrea; Umbrello, D

Relocation consequences on an ophthalmology consultation service from an inpatient to outpatient facility

Importance This study shows that relocation of an academic ophthalmology residency program from an inpatient to an outpatient setting in western New York does not affect the consult volume but affects management patterns and follow-up rates. Objective To investigate the effects on the ophthalmology consultation service of an academic program with relocation from a Regional Level-1 Trauma center to an outpatient facility. Design Consultation notes from 3 years before and 3 years after the University at Buffalo’s (UB) Department of Ophthalmology relocation from a Regional Level-1 Trauma center (Erie County Medical Center) to an outpatient facility (Ross Eye Institute) were obtained from hospital electronic medical records and analyzed. Setting Hospitalized care and institutional practice. Participants All inpatient or Emergency Room Ophthalmology consultation patients from the Department of Ophthalmology at UB from 2004 to 2010 (1,379 patients). Exposures None, this was a retrospective chart review. Main outcome measures Patient demographics, reason for consult, diagnoses, and ophthalmic procedures performed by the UB Department of Ophthalmology before and after its relocation. Results Relocation to the outpatient facility did not affect consult volume (P=0.15). The number of consults focusing on ophthalmic conditions, as a percentage of the yearly total, rose 460% (P=0.0001), while systemic condition consults with ocular manifestations fell 83% (P=0.0001). Consults for ocular trauma decreased 65% (P=0.0034). Consults ending with a diagnosis of “normal exam” fell, as a percentage of the yearly total (56%, P=0.0023), while diagnoses of new ocular conditions rose 17% (P=0.00065). The percentage of consults for Medicaid patients fell 12% (P=0.0001), while those for privately insured patients rose 15% (P=0.0001). The number of ophthalmic procedures did not change, but postconsult patient follow-up fell from 23% at the Erie County Medical Center clinic to 2% after the move to Ross Eye Institute, a ≥97% decrease. Conclusion and relevance Relocation of UB’s academic Ophthalmology program from an inpatient department to an outpatient facility had no effect on its consultation patient or procedure volume, but it significantly affected the nature of consult diagnoses and decreased outpatient follow-up by \u3e90% at the latter location. Many hospitals are creating separate outpatient facilities that may experience similar obstacles

Vertebral artery dissection in term pregnancy after cervical spine manipulation: a case report and review the literature

Background: Vertebral artery dissection is an uncommon, but potentially fatal, vascular event. This case aimed to describe the pathogenesis and clinical presentation of vertebral artery dissection in a term pregnant patient. Moreover, we focused on the differential diagnosis, reviewing the available evidence. Case presentation: A 39-year-old Caucasian woman presented at 38 + 4 weeks of gestation with a short-term history of vertigo, nausea, and vomiting. Symptoms appeared a few days after cervical spine manipulation by an osteopathic specialist. Urgent magnetic resonance imaging of the head was obtained and revealed an ischemic lesion of the right posterolateral portion of the brain bulb. A subsequent computed tomography angiographic scan of the head and neck showed a right vertebral artery dissection. Based on the correlation of the neurological manifestations and imaging findings, a diagnosis of vertebral artery dissection was established. The patient started low-dose acetylsalicylic acid and prophylactic enoxaparin following an urgent cesarean section. Conclusion: Vertebral artery dissection is a rare but potential cause of neurologic impairments in pregnancy and during the postpartum period. It should be considered in the differential diagnosis for women who present with headache and/or vertigo. Women with a history of migraines, hypertension, or autoimmune disorders in pregnancy are at higher risk, as well as following cervical spine manipulations. Prompt diagnosis and management of vertebral artery dissection are essential to ensure favorable outcomes

Constitutive activation of the DNA damage response pathway as a novel therapeutic target in diffuse large B-cell lymphoma

The recent finding that MYC-driven cancers are sensitive to inhibition of the DNA damage response (DDR) pathway, prompted us to investigate the role of DDR pathway as therapeutic target in diffuse large B-cell lymphoma (DLBCL), which frequently overexpresses the MYC oncogene. In a preliminary immunohistochemical study conducted on 99 consecutive DLBCL patients, we found that about half of DLBCLs showed constitutive expression of the phosphorylated forms of checkpoint kinases (CHK) and CDC25c, markers of DDR activation, and of phosphorylated histone H2AX (?H2AX), marker of DNA damage and genomic instability. Constitutive ?H2AX expression correlated with c-MYC levels and DDR activation, and defined a subset of tumors characterised by poor outcome. Next, we used the CHK inhibitor PF-0477736 as a tool to investigate whether the inhibition of the DDR pathway might represent a novel therapeutic approach in DLBCL. Submicromolar concentrations of PF-0477736 hindered proliferation in DLBCL cell lines with activated DDR pathway. These results were fully recapitulated with a different CHK inhibitor (AZD-7762). Inhibition of checkpoint kinases induced rapid DNA damage accumulation and apoptosis in DLBCL cell lines and primary cells. These data suggest that pharmacologic inhibition of DDR through targeting of CHK kinases may represent a novel therapeutic strategy in DLBCL

Prexasertib, a Chk1/Chk2 inhibitor, increases the effectiveness of conventional therapy in B-/T- cell progenitor acute lymphoblastic leukemia

During the last few years many Checkpoint kinase 1/2 (Chk1/Chk2) inhibitors have been developed for the treatment of different type of cancers. In this study we evaluated the efficacy of the Chk 1/2 inhibitor prexasertib mesylate monohydrate in B-/T- cell progenitor acute lymphoblastic leukemia (ALL) as single agent and in combination with other drugs. The prexasertib reduced the cell viability in a dose and time dependent manner in all the treated cell lines. The cytotoxic activity was confirmed by the increment of apoptotic cells (Annexin V/Propidium Iodide staining), by the increase of \u3b3H2A.X protein expression and by the activation of different apoptotic markers (Parp-1 and pro-Caspase3 cleavage). Furthermore, the inhibition of Chk1 changed the cell cycle profile. In order to evaluate the chemo-sensitizer activity of the compound, different cell lines were treated for 24 and 48 hours with prexasertib in combination with other drugs (imatinib, dasatinib and clofarabine). The results from cell line models were strengthened in primary leukemic blasts isolated from peripheral blood of adult acute lymphoblastic leukemia patients. In this study we highlighted the mechanism of action and the effectiveness of prexasertib as single agent or in combination with other conventional drugs like imatinib, dasatinib and clofarabine in the treatment of B-/T-ALL

Therapeutic implications of intratumor heterogeneity for TP53 mutational status in Burkitt lymphoma

Therapeutic implications of intra-tumor heterogeneity are still undefined. In this study we report a genetic and functional analysis aimed at defining the mechanisms of chemoresistance in a 43-year old woman affected by stage IVB Burkitt lymphoma with bulky abdominal masses and peritoneal effusion. The patient, despite a transient initial response to chemotherapy with reduction of the bulky masses, rapidly progressed and died of her disease. Targeted TP53 sequencing found that the bulky mass was wild-type whereas peritoneal fluid cells harbored a R282W mutation. Functional studies on TP53 mutant cells demonstrated an impaired p53-mediated response, resistance to ex vivo doxorubicin administration, overexpression of DNA damage response (DDR) activation markers and high sensitivity to pharmacologic DDR inhibition. These findings suggest that intra-tumor heterogeneity for TP53 mutational status may occur in MYC-driven cancers, and that DDR inhibitors could be effective in targeting hidden TP53 mutant clones in tumors characterized by genomic instability and prone to intra-tumor heterogeneity

Synergism through WEE1 and CHK1 inhibition in acute lymphoblastic leukemia

Introduction: Screening for synthetic lethality markers has demonstrated that the inhibition of the cell cycle checkpoint kinases WEE1 together with CHK1 drastically affects stability of the cell cycle and induces cell death in rapidly proliferating cells. Exploiting this finding for a possible therapeutic approach has showed efficacy in various solid and hematologic tumors, though not specifically tested in acute lymphoblastic leukemia. Methods: The efficacy of the combination between WEE1 and CHK1 inhibitors in B and T cell precursor acute lymphoblastic leukemia (B/T-ALL) was evaluated in vitro and ex vivo studies. The efficacy of the therapeutic strategy was tested in terms of cytotoxicity, induction of apoptosis, and changes in cell cycle profile and protein expression using B/T-ALL cell lines. In addition, the efficacy of the drug combination was studied in primary B-ALL blasts using clonogenic assays. Results: This study reports, for the first time, the efficacy of the concomitant inhibition of CHK1/CHK2 and WEE1 in ALL cell lines and primary leukemic B-ALL cells using two selective inhibitors: PF-0047736 (CHK1/CHK2 inhibitor) and AZD-1775 (WEE1 inhibitor). We showed strong synergism in the reduction of cell viability, proliferation and induction of apoptosis. The efficacy of the combination was related to the induction of early S-phase arrest and to the induction of DNA damage, ultimately triggering cell death. We reported evidence that the efficacy of the combination treatment is independent from the activation of the p53-p21 pathway. Moreover, gene expression analysis on B-ALL primary samples showed that Chek1 and Wee1 are significantly co-expressed in samples at diagnosis (Pearson r = 0.5770, p = 0.0001) and relapse (Pearson r= 0.8919; p = 0.0001). Finally, the efficacy of the combination was confirmed by the reduction in clonogenic survival of primary leukemic B-ALL cells. Conclusion: Our findings suggest that the combination of CHK1 and WEE1 inhibitors may be a promising therapeutic strategy to be tested in clinical trials for adult ALL

Pancreatic Ductal Adenocarcinoma Associated with Autoimmune Pancreatitis

Autoimmune pancreatitis (AIP), in contrast to other benign chronic pancreatic diseases, can be cured with immunosuppressant drugs, thus the differentiation of AIP from pancreatic cancer is of particular interest in clinical practice. There is the possibility that some patients with AIP may develop pancreatic cancer, and this possibility contributes to increasing our difficulties in differentiating AIP from pancreatic cancer. We herein report the case of a 70-year-old man in whom pancreatic adenocarcinoma and AIP were detected simultaneously. We must carefully monitor AIP patients for the simultaneous presence of pancreatic cancer, even when a diagnosis of AIP is confirmed