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

Polycaprolactone multicore-matrix particle for the simultaneous encapsulation of hydrophilic and hydrophobic compounds produced by membrane emulsification and solvent diffusion processes

Co-encapsulation of drugs in the same carrier, as well as the development of microencapsulation processes for biomolecules using mild operating conditions, and the production of particles with tailored size and uniformity are major challenges for encapsulation technologies. In the present work, a suitable method consisting of the combination of membrane emulsification with solvent diffusion is reported for the production of multi-core matrix particles with tailored size and potential application in multi-therapies. In the emulsification step, the production of a W/O/W emulsion was carried out using a batch Dispersion Cell for formulation testing and subsequently a continuous azimuthally oscillating membrane emulsification system for the scaling-up of the process to higher capacities. In both cases precise and gentle control of droplet size and uniformity of the W/O/W emulsion was achieved, preserving the encapsulation of the drug model within the droplet. Multi-core matrix particles were produced in a post emulsification step using solvent diffusion. The compartmentalized structure of the multicore-matrix particle combined with the different chemical properties of polycaprolactone (matrix material) and fish gelatin (core material) was tested for the simultaneous encapsulation of hydrophilic (copper ions) and hydrophobic (α-tocopherol) test components. The best operating conditions for the solidification of the particles to achieve the highest encapsulation efficiency of copper ions and α-tocopherol of 99 (±4)% and 93(±6)% respectively were found. The multi-core matrix particle produced in this work demonstrates good potential as a co-loaded delivery system

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

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

Atypical presentation of acute idiopathic megacolon in a 14-year-old patient

In clinical practice the term "megacolon" is used to indicate a marked dilatation of the cecum and the sigmoid colon (>12 and 6.5 cm, respectively) (1). From a clinical standpoint, a megacolon can be classified as chronic or acute depending on its clinical presentation. Chronic megacolon typically refers to a congenital disorder in which the enteric nervous system (ENS) supplying the colon does not develop properly, thereby leaving the distal segments of the viscus without myenteric and submucosal ganglia (i.e. Hirschsprung's disease) (2). Other cases of non-aganglionic chronic megacolon can be secondary to variety of conditions such as Chagas' disease and neurodegenerative diseases (e.g. Parkinson's and Alzheimer's diseases), leading to or associated with ENS abnormalities (3). The acute form of megacolon, also referred to as Ogilvie's syndrome, is characterized by a predominant involvement of the cecum and right colon usually affecting elderly patients undergoing surgery (e.g. orthopedic procedures) or taking medications altering gut motility (e.g. opioids or antidepressants) (4). Some forms of acute megacolon, however, can be idiopathic in origin since no underlying etiology can be identified. Patients with acute idiopathic megacolon usually have a longstanding history of constipation, often accompanied by laxative abuse, and their clinical presentation is characterized by abdominal distension and severe pain with radiological evidence of stool impacted in the colon and rectum (1, 4). The case herein reported represents an unusual form of acute idiopathic megacolon characterized by massive descending and sigmoid colon distension complicated with a volvulus in a 14-year-old boy with no Hirschsprung's disease. In addition, just to increase the peculiarity of this case report, the patient had an unremarkable clinical record, and never suffered from chronic constipation in the past

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&

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

Is the pancreas affected in patients with septic shock? A prospective study

Hyperamylasemia can be observed anecdotally during the course of severe sepsis or septic shock. This study aimed to investigate the possibility of pancreatic involvement in patients with septic shock using serum pancreatic enzyme determinations and imaging techniques in 21 consecutive patients with septic shock and 21 healthy subjects as controls. METHODS: The serum activity of pancreatic amylase and lipase was assayed initially in all subjects and 24 and 48 hours after the initial observation in the 21 patients with septic shock. All patients also underwent radiological examination to detect pancreatic abnormalities. RESULTS: The serum activity of pancreatic amylase was significantly higher in the 21 patients with septic shock than in the 21 control subjects during the study period, while the serum activity of lipase was similar to that of the control subjects. Amylase and lipase serum activity did not significantly changed throughout the study period in the 21 patients with septic shock. None of the patients with pancreatic hyperenzymemia had clinical signs or morphological alterations compatible with acute pancreatitis. CONCLUSION: The presence of pancreatic hyperenzymemia in septic shock patients is not a biochemical manifestation of acute pancreatic damage, and the management of these patients should be dependent on the clinical situation and not merely the biochemical result