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

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

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

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

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

Discovery of a magnetar candidate X-ray pulsar in the Large Magellanic Cloud

During a systematic search for new X-ray pulsators in the XMM-Newton archive, we discovered a high amplitude ($PF\simeq86\%$) periodic ($P\simeq7.25\,\mathrm{s}$) modulation in the X-ray flux of 4XMM J045626.3-694723 (J0456 hereafter), a previously unclassified source in the Large Magellanic Cloud (LMC). The period of the modulation is strongly suggestive of a spinning neutron star (NS). The source was detected only during one out of six observations in 2018-2022. Based on an absorbed power-law spectral model with photon slope of $\Gamma\simeq 1.9$, we derive a 0.3-10 keV luminosity of $L_\mathrm{X}\simeq2.7\times10^{34}$ erg cm$^{-2}$ s$^{-1}$ for a distance of 50 kpc. The X-ray properties of J0456 are at variance with those of variable LMC X-ray pulsars hosted in high-mass X-ray binary systems with a Be-star companion. Based on SALT spectroscopic observations of the only optical object that matches the X-ray uncertainty region, we cannot completely rule out that J0456 is a NS accreting from a late-type (G8-K3) star, an as-yet-unobserved binary evolutionary outcome in the MCs. We show that the source properties are in better agreement with those of magnetars. J0456 may thus be second known magnetar in the LMC after SGR 0526-66.Comment: 9 pages, 6 figures, 1 table. Accepted for publication in MNRA

A soft and transient ultraluminous X-ray source with 6-h modulation in the NGC 300 galaxy

We investigate the nature of CXOU J005440.5-374320 (J0054), a peculiar bright ($\sim$$4\times10^{39}$ erg/s) and soft X-ray transient in the spiral galaxy NGC 300 with a 6-hour periodic flux modulation that was detected in a 2014 Chandra observation. Subsequent observations with Chandra and XMM-Newton, as well as a large observational campaign of NGC 300 and its sources performed with the Swift Neil Gehrels Observatory, showed that this source exhibits recurrent flaring activity: four other outbursts were detected across $\sim$8 years of monitoring. Using data from the Swift/UVOT archive and from the XMM-Newton/OM and Gaia catalogues, we noted the source is likely associated with a bright blue optical/ultraviolet counterpart. This prompted us to perform follow-up observations with the Southern African Large Telescope in December 2019. With the multi-wavelength information at hand, we discuss several possibilities for the nature of J0054. Although none is able to account for the full range of the observed peculiar features, we found that the two most promising scenarios are a stellar-mass compact object in a binary system with a Wolf$-$Rayet star companion, or the recurrent tidal stripping of a stellar object trapped in a system with an intermediate-mass ($\sim1000$ $M_\odot$) black hole.Comment: 13 pages, 11 Figures, 3 Tables (the Table in appendix A will be available in the published version). Accepted for publication in A&

Probing the nature of the low state in the extreme ultraluminous X-ray pulsar NGC 5907 ULX1

NGC 5907 ULX1 is the most luminous ultra-luminous X-ray pulsar (ULXP) known to date, reaching luminosities in excess of 1e41 erg/s. The pulsar is known for its fast spin-up during the on-state. Here, we present a long-term monitoring of the X-ray flux and the pulse period between 2003-2022. We find that the source was in an off- or low-state between mid-2017 to mid-2020. During this state, our pulse period monitoring shows that the source had spun down considerably. We interpret this spin-down as likely being due to the propeller effect, whereby accretion onto the neutron star surface is inhibited. Using state-of-the-art accretion and torque models, we use the spin-up and spin-down episodes to constrain the magnetic field. For the spin-up episode, we find solutions for magnetic field strengths of either around 1e12G or 1e13G, however, the strong spin-down during the off-state seems only to be consistent with a very high magnetic field, namely, >1e13G. This is the first time a strong spin-down is seen during a low flux state in a ULXP. Based on the assumption that the source entered the propeller regime, this gives us the best estimate so far for the magnetic field of NGC 5907 ULX1.Comment: 10 pages, 1 figure, accepted for publication in A&

Effects of aircraft noise on annoyance, sleep disorders, and blood pressure among adult residents near the Orio al Serio International Airport (BGY), Italy

Introduzione: Il rumore aeroportuale pu\uf2 causare effetti extra-uditivi quali annoyance, disturbi del sonno, ipertensione, patologie cardiovascolari e alterazioni delle abilit\ue0 cognitive nei bambini. Obiettivi: Condurre un\u2019indagine trasversale tra gli adulti residenti in prossimit\ue0 dell\u2019Aeroporto Internazionale di Orio al Serio (BGY), per studiare l\u2019associazione tra rumore aeroportuale, annoyance, disturbi del sonno, pressione arteriosa e ipertensione. Metodi: Soggetti di et\ue0 45-70 anni sono stati suddivisi, sulla base della residenza, in tre zone acustiche di rumore aeroportuale: <60 (Riferimento), 60-65 (Zona A) e 65-75 dBA (Zona B). Un campione di soggetti \ue8 stato invitato a sottoporsi a intervista e misurazioni della pressione arteriosa. Per analizzare variabili quantitative e categoriche, sono stati utilizzati modelli di regressione lineare multipla e di Poisson robusta, rispettivamente. Risultati: Tra giugno e settembre 2013 sono stati reclutati 400 soggetti (166 nella Zona di Riferimento, 164 nella Zona A e 70 nella Zona B). Rispetto al riferimento, sono stati rilevati elevati punteggi di annoyance (diurni e notturni) nelle Zone A (+2,7) e B (+4,0) (p<0,001) e circa il doppio di soggetti fortemente infastiditi in entrambe le zone (p<0,001). Anche i disturbi del sonno riferiti nel mese precedente erano pi\uf9 frequenti nelle Zone A e B. I disturbi del sonno considerati complessivamente corrispondevano a 19,9% nella Zona di Riferimento, 29,9% nella Zona A e 35,7% nella Zona B (p<0,001). Conclusioni: \uc8 stata evidenziata una forte associazione tra rumore aeroportuale, annoyance e disturbi del sonno. Non \ue8 stata riscontrata alcuna relazione con i livelli di pressione arteriosa e la prevalenza di ipertensione.Background: Aircraft noise may cause several non-auditory health effects, including annoyance, sleep disorders, hypertension, cardiovascular diseases, and impaired cognitive skills in children. Objectives: To perform a cross-sectional study among adult residents near the Orio al Serio International Airport (BGY), Italy to investigate the association between aircraft noise, annoyance, sleep disorders, blood pressure levels, and prevalence of hypertension. Methods: Residential addresses of subjects aged 45-70 years were geocoded and classified in three groups according to noise levels: <60 (Reference), 60-65 (Zone A), and 65-75 dBA (Zone B). A sample of subjects was invited to undergo a personal interview and blood pressure measurements. Multiple linear and robust Poisson regression models were used to analyze quantitative and categorical variables, respectively. Results: Between June and September 2013, we enrolled 400 subjects (166 in the Reference Zone, 164 in Zone A, and 70 in Zone B). Compared to the Reference Zone, we found elevated adjusted annoyance scores (day and night) in Zone A (+2.7) and Zone B (+4.0) (p<0.001) and about doubled proportions of severely annoyed subjects (p<0.001). Reported sleep disorders in the previous month were also more frequent in Zones A and B. Sleep disorders in general were 19.9% in the Reference Zone, 29.9% in Zone A, and 35.7% in Zone B (p<0.001). Conclusions: We found a strong association between aircraft noise levels, annoyance, and sleep disorders among adult residents near the Orio al Serio International Airport. We found no relationship with blood pressure levels and prevalence of hypertension