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Decorated common ware from the Eastern Cenoman territory This paper examines the decorative patterns present in the coarse ware of the plains around Verona (inclu ding the town of Verona itself) between the 4th and the 1st centuries BC, in the period in which the Celtic tribe of the Cenomani settled in this area. Incised, impressed, and relief decorations are documented. The most significant motifs (dotted and notched decorations covering the entire surface of the vase) are related to the western Celtic Po Valley area. Some decorations, however, refer to the Veneto and the Magré culture areas. Decorated vases have been found both in settlements and in tombs. The decorations appear mainly on small vases with drinking function. The decorated vessels can almost all be dated between LT C2 and LT D2. The most numerous attestations date to LT D1. This increase, which can also be found in the territory of the Insubri, could come from the desire to emphasize one’s cultural tradition in a phase in which Rome’s political and cultural presence was becoming increasingly felt.

Introduction: Complement 3 glomerulopathy (C3G) is a rare inflammatory kidney disease mediated by dysregulation of the alternative complement pathway. No targeted therapy exists for this aggressive glomerulonephritis. Efficacy, safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) (measured by complement biomarkers) of iptacopan were assessed in patients with C3G. Methods: In this phase 2, multicenter, open-label, single-arm, nonrandomized study, adults with biopsy-proven, native kidney C3G (native cohort) and kidney transplant recipients with C3G recurrence (recurrent kidney transplant [KT] cohort) received iptacopan twice daily (bid) for 84 days (days 1–21: 10–100 mg; days 22–84: 200 mg). The primary end point was the urine protein-to-creatinine ratio (UPCR; native cohort) and the change in the C3 deposit score of kidney biopsy (recurrent KT cohort). The complement pathway measures included Wieslab assay, soluble C5b9, and serum C3 levels. Results: A total of 27 patients (16 native cohort and 11 recurrent KT cohort) were enrolled and all completed the study. In the native cohort, UPCR levels decreased by 45% from baseline to week 12 (P = 0.0003). In the recurrent KT cohort, the median C3 deposit score decreased by 2.50 (scale: 0–12) on day 84 versus baseline (P = 0.03). Serum C3 levels were normalized in most patients; complement hyperactivity observed pretreatment was reduced. Severe adverse events (AEs) included post-biopsy hematuria and hyperkalemia. No deaths occurred during the study. Conclusion: Iptacopan resulted in statistically significant and clinically important reductions in UPCR and normalization of serum C3 levels in the native cohort and reduced C3 deposit scores in the recurrent KT cohort with favorable safety and tolerability. (ClinicalTrials.gov identifier: NCT03832114).

Background: Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib. Patients and methods: Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as “no concomitant PPIs” or “concomitant PPIs”; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice. Results: A total of 128 patients were consecutively enrolled in the study; 78 belonged to the “no concomitant PPIs” group and 50 to the “concomitant PPIs” group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities. Conclusions: The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting.

A aplicação de acaricidas químicos tem sido a prática mais utilizada no controle do carrapato bovino Rhipicephalus microplus. Atualmente, essa estratégia de controle está apresentando uma eficácia limitada em populações específicas de carrapatos encontradas no ambiente de produção pecuária. Essa limitação está ligada principalmente ao desenvolvimento da resistência pelo uso extensivo de acaricidas químicos. Alternativas de manejo, combinando diferentes métodos ou empregando biocontroladores fúngicos, podem contribuir para melhorar o quadro atual. Em termos de pesquisa, o uso de biocontroladores apresenta grande potencial, sendo uma alternativa orgânica para o controle do carrapato. Nesta revisão, os aspectos gerais e atuais, relacionados ao controle do carrapato, são abordados, bem como a potencialidade e eficiência de métodos de menor impacto ambiental, os quais não são mais uma alternativa, mas uma necessidade imediata.

Abstract Background FOLFIRINOX is a pillar first-line regimen in the treatment of pancreatic cancer. Historically, biliary tract cancer (BTC) and pancreatic cancer have been treated similarly with gemcitabine alone or combined with a platinum compound. With growing evidence supporting the role of fluoropyrimidines in the treatment of BTC, we aimed at assessing the outcomes of patients (pts) with BTC on frontline FOLFIRINOX. Methods We retrospectively analyzed data of all our consecutive patients with locally advanced (LA) or metastatic (M) BTC who were registered to receive FOLFIRINOX as a first-line therapy between 12/2013 and 11/2017 at Paul Brousse university hospital. The main endpoints were Overall Survival (OS), Time-to-Progression (TTP), best Objective Response Rate (ORR), Disease Control rate (DCR), secondary macroscopically-complete resection (res) and incidence of severe (grade 3–4) toxicity (tox). Results There were 17 male (40%) and 25 female (60%) pts. aged 36 to 84 years (median: 67). They had PS of 0 (55%) or 1 (45%), and intrahepatic cholangiocarcinoma (CCA) (21 pts., 50%), gallbladder carcinoma (8 pts., 19%), perihilar CCA (7 pts., 17%), distal CCA (4 pts., 10%) and ampulloma (2 pts., 5%). BTC was LA or M in 10 (24%) and 32 pts. (76%) respectively. Biliary stent was placed in 14 pts. (33%). A median of 10 courses was given with median treatment duration of 6 months. There were no untoward toxicity issues, with no febrile neutropenia, emergency admission for toxicity or toxic death. We observed 12 partial responses (29%) and 19 disease stabilisations (45%). Six patients (14%) underwent secondary R0-R1 resection. Median TTP was 8 months [95%CL, 6–10] and median OS was 15 months [13–17]. Patients undergoing secondary resection displayed a 3-y disease-free rate of 83%. Conclusions First-line FOLFIRINOX offers promising results in patients with LA and M-BTC. It deserves prospective evaluation to further improve outcomes for advanced BTC.

The present work focuses on Nd3+-Yb3+ co-doping of bare and Sr-substituted hydroxyapatite nanoparticles and their chemical, structural and optical characterization. An energy transfer between Nd3+ and Yb3+ centers was found, generating an efficient down-shifting process, where Nd3+ absorbs at a low near-infrared wavelength and Yb3+ emits at its characteristic 2F7/2 → 2F5/2 transition. The energy transfer was found to be more efficient in Sr-substituted than in bare hydroxyapatite nanoparticles. The synthesized Nd3+-Yb3+ doped hydroxyapatite nanoparticles can potentially find applications not only as diagnostic near-infrared down-shifting agent but also as nanosystem for near-infrared photoactivated treatment.

The state of health (SOH) is among the most important parameters to be monitored in lithium-ion batteries (LIB) because it is used to know the residual functionality in any condition of aging. The paper focuses on the application of the extended Kalman filter (EKF) for the identification of the parameters of a cell model, which are required for the correct estimation of the SOH of the cell. This article proposes a methodology for tuning the covariance matrices of the EKF by using an optimization process based on genetic algorithms (GA). GAs are able to solve the minimization problems for the non-linear functions, and they are better than other optimization algorithms such as gradient descent to avoid the local minimum. To validate the proposed method, the cell parameters obtained from the EKF are compared with a reference model, in which the parameters have been determined with proven procedures. This comparison is carried out with different cells and in the whole range of the cell’s SOH, with the aim of demonstrating that a single tuning procedure, based on the proposed GA process, is able to guarantee good accuracy in the estimation of the cell parameters at all stages of the cell’s life.

The human 80S ribosome is the cellular nucleoprotein nanomachine in charge of protein synthesis that is profoundly affected during cancer transformation by oncogenic proteins and provides cancerous proliferating cells with proteins and therefore biomass. Indeed, cancer is associated with an increase in ribosome biogenesis and mutations in several ribosomal proteins genes are found in ribosomopathies, which are congenital diseases that display an elevated risk of cancer. Ribosomes and their biogenesis therefore represent attractive anti-cancer targets and several strategies are being developed to identify efficient and specific drugs. Homoharringtonine (HHT) is the only direct ribosome inhibitor currently used in clinics for cancer treatments, although many classical chemotherapeutic drugs also appear to impact on protein synthesis. Here we review the role of the human ribosome as a medical target in cancer, and how functional and structural analysis combined with chemical synthesis of new inhibitors can synergize. The possible existence of oncoribosomes is also discussed. The emerging idea is that targeting the human ribosome could not only allow the interference with cancer cell addiction towards protein synthesis and possibly induce their death but may also be highly valuable to decrease the levels of oncogenic proteins that display a high turnover rate (MYC, MCL1). Cryo-electron microscopy (cryo-EM) is an advanced method that allows the visualization of human ribosome complexes with factors and bound inhibitors to improve our understanding of their functioning mechanisms mode. Cryo-EM structures could greatly assist the foundation phase of a novel drug-design strategy. One goal would be to identify new specific and active molecules targeting the ribosome in cancer such as derivatives of cycloheximide, a well-known ribosome inhibitor.

Metformin, a widely used anti-diabetic molecule, has attracted a strong interest in the last 10 years as a possible new anti-cancer molecule. Metformin acts by interfering with mitochondrial respiration, leading to an activation of the AMPK tumor-suppressive pathway to promote catabolic-energy saving reactions and block anabolic ones that are associated with abnormal cell proliferation. Metformin also acts at the organism level. In type 2 diabetes patients, metformin reduces hyperglycemia and increases insulin sensitivity by enhancing insulin-stimulated glucose uptake in muscles, liver, and adipose tissue and by reducing glucose output by the liver. Lowering insulin and insulin-like growth factor 1 (IGF-1) levels that stimulate cancer growth could be important features of metformin's mode of action. Despite continuous progress in treatments with the use of targeted therapies and now immunotherapies, acute leukemias are still of very poor prognosis for relapse patients, demonstrating an important need for new treatments deriving from the identification of their pathological supportive mechanisms. In the last decade, it has been realized that if cancer cells modify and reprogram their metabolism to feed their intense biochemical needs associated with their runaway proliferation, they develop metabolic addictions that could represent attractive targets for new therapeutic strategies that intend to starve and kill cancer cells. This Mini Review explores the anti-leukemic potential of metformin and its mode of action on leukemia metabolism.

Elena Verzoni, Paolo Grassi, Isabella Testa, Roberto Iacovelli, Pamela Biondani, Enrico Garanzini , Filippo De Braud, Giuseppe ProcopioDepartment of Medical Oncology 1, Fondazione IRCCS Istituto Nazionale Tumori, Milan, ItalyAbstract: Antiangiogenesis options have evolved rapidly in the last few years, with an increasing number of agents currently approved by the US Food and Drug Administration and European Medicines Agency. Angiogenesis inhibitors have been shown to be very effective for the treatment of metastatic renal cancer cell. Axitinib is a third-generation inhibitor of vascular endothelial growth factor receptor and is currently being developed for the treatment of various malignancies. The pharmacokinetic properties of axitinib may have a selective therapeutic effect, with minimal adverse reactions and enhanced safety. In a large Phase III study of previously treated patients with metastatic renal cell carcinoma, axitinib achieved a longer progression-free survival than sorafenib with an acceptable safety profile and good quality of life. This review focuses on the pharmacology, pharmacokinetics, and clinical activity of axitinib in the current treatment of renal cell carcinoma. The role of axitinib in the adjuvant and/or neoadjuvant setting needs to be evaluated in further clinical trials.Keywords: axitinib, renal cell carcinoma, vascular endothelial growth factor receptor, angiogenesis

Mesenchymal-epithelial transition (MET) is a member of a distinct subfamily of heterodimeric receptor tyrosine kinase receptors that specifically binds the hepatocyte growth factor (HGF). Binding to HGF leads to receptor dimerization/multimerization and phosphorylation, resulting in its catalytic activation. MET activation drives the malignant progression of several tumor types, including colorectal cancer (CRC), by promoting signaling cascades that mainly result in alterations of cell motility, survival, and proliferation. MET is aberrantly activated in many human cancers through various mechanisms, including point mutations, gene amplification, transcriptional up-regulation, or ligand autocrine loops. MET promotes cell scattering, invasion, and protection from apoptosis, thereby acting as an adjuvant pro-metastatic gene for many tumor types. In CRC, MET expression confers more aggressiveness and worse clinical prognosis. With all of this rationale, inhibitors that target the HGF/MET axis with different types of response have been developed. HGF and MET are new promising targets to understand the pathogenesis of CRC and for the development of new, targeted therapies.

Gastric pH changes by proton-pump-inhibitors (PPIs) were found to affect progression-free survival (PFS) in metastatic breast cancer (mBC) patients treated with palbociclib. The current study was aimed at investigating whether the same effect could occur in patients treated with ribociclib. Patients with hormone-positive/HER-2-negative mBC candidates for first-line treatment with ribociclib were enrolled in this retrospective-cohort study. Patients were classified as "no concomitant PPIs" or "concomitant PPIs"; PPI administration covered the entire or not less than 2/3 of treatment with ribociclib. All clinical interventions were made according to clinical practice. A total of 128 patients were consecutively enrolled in the study; 78 belonged to the "no concomitant PPIs" group and 50 to the "concomitant PPIs" group. One hundred and six patients were endocrine-sensitive and received ribociclib and letrozole, while 22 were endocrine-resistant and were treated with ribociclib and fulvestrant. The most prescribed PPI was lansoprazole. According to PFS, patients taking PPIs had a PFS almost superimposable to those assuming ribociclib and endocrine therapy alone (35.3 vs. 49.2 months, p = 0.594). No difference in PFS was observed in estrogen-sensitive or estrogen-resistant mBC in the presence or absence of concomitant PPI treatment (p = 0.852). No correlation with adverse events was found including grade>2 hematological toxicities. The present study supports the hypothesis that the concomitant use of PPIs does not compromise the efficacy of ribociclib in a real-life setting. • Changes of gastric pH by PPIs may significantly affect the bioavailability of tyrosine kinase inhibitors. • Our findings support the hypothesis that long-term treatment with PPI does not compromise the efficacy of ribociclib. • Consistent with our results, data from the literature show no effect of gastric pH changes on ribociclib pharmacokinetics. [ABSTRACT FROM AUTHOR]

Background Stomatocytoses are a group of inherited autosomal dominant hemolytic anemias and include overhydrated hereditary stomatocytosis, dehydrated hereditary stomatocytosis, hereditary cryohydrocytosis and familial pseudohyperkalemia.Design and Methods We report a novel variant of hereditary stomatocytosis due to a de novo band 3 mutation (p. G796R-band3 CEINGE) associated with a dyserythropoietic phenotype. Band 3 genomic analysis, measurement at of hematologic parameters and red cell indices and morphological analysis of bone marrow were carried out. We then evaluated the red cell membrane permeability and ion transport systems by functional studies of the patient’s erythrocytes and Xenopus oocytes transfected with mutated band 3. We analyzed the red cell membrane tyrosine phosphorylation profile and the membrane association of the tyrosine kinases Syk and Lyn from the Src-family-kinase group, since the activity of the membrane cation transport pathways is related to cyclic phosphorylation-dephosphorylation events.Results The patient showed mild hemolytic anemia with circulating stomatocytes together with signs of dyserythropoiesis. Her red cells displayed increased Na+ content with decreased K+content and abnormal membrane cation transport activities. Functional characterization of band 3 CEINGE in Xenopus oocytes showed that the mutated band 3 is converted from being an anion exchanger (Cl−, HCO3−) to being a cation pathway for Na+ and K+. Increased tyrosine phosphorylation of some red cell membrane proteins was observed in diseased erythrocytes. Syk and Lyn membrane association was increased in the patient’s red cells compared to in normal controls, indicating perturbation of phospho-signaling pathways involved in cell volume regulation events.Conclusions Band 3 CEINGE alters function from that of anion exchange to cation transport, affects the membrane tyrosine phosphorylation profile, in particular of band 3 and stomatin, and its presence during red cell development likely contributes to dyserythropiesis.

Cystic fibrosis (CF) is one of the most common fatal autosomal recessive disorders in the Caucasian population caused by mutations of gene for the cystic fibrosis transmembrane conductance regulator (CFTR). New experimental therapeutic strategies for CF propose a diet supplementation to affect the plasma membrane fluidity and to modulate amplified inflammatory response. The objective of this study was to evaluate the efficacy of 5-methyltetrahydrofolate (5-MTHF) and vitamin B12 supplementation for ameliorating cell plasma membrane features in pediatric patients with cystic fibrosis.A single arm trial was conducted from April 2004 to March 2006 in an Italian CF care centre. 31 children with CF aged from 3 to 8 years old were enrolled. Exclusion criteria were diabetes, chronic infections of the airways and regular antibiotics intake. Children with CF were supplemented for 24 weeks with 5-methyltetrahydrofolate (5-MTHF, 7.5 mg /day) and vitamin B12 (0.5 mg/day). Red blood cells (RBCs) were used to investigate plasma membrane, since RBCs share lipid, protein composition and organization with other cell types. We evaluated RBCs membrane lipid composition, membrane protein oxidative damage, cation content, cation transport pathways, plasma and RBCs folate levels and plasma homocysteine levels at baseline and after 24 weeks of 5-MTHF and vitamin B12 supplementation. In CF children, 5-MTHF and vitamin B12 supplementation (i) increased plasma and RBC folate levels; (ii) decreased plasma homocysteine levels; (iii) modified RBC membrane phospholipid fatty acid composition; (iv) increased RBC K(+) content; (v) reduced RBC membrane oxidative damage and HSP70 membrane association.5-MTHF and vitamin B12 supplementation might ameliorate RBC membrane features of children with CF.ClinicalTrials.gov NCT00730509.

Surface structuring of medical implants has been shown to reduce the rejection rate of medical devices inserted inside living tissue. Several studies have shown that by texturing the surface of medical implants at micro/nanoscale it is possible to foster cell adhesion. The surface texturing of medical devices poses many challenges in terms of cost and time when the nano texturing process is performed directly on the part surface. A viable solution for mass production of polymer based surface enhanced medical devices is achieved via injection molding. However, nano structuring of micro injection molding molds, requires techniques enabling processing of complex surfaces, small curvature radii and with high aspect ratios. Furthermore the accessibility of all surfaces to be structured and the processing time are the main concerns and limiting factors on the selection of the structures dimensions and geometries. In this work, two different process chains are analyzed for the nano structuring of a bone micro plug. The first method relies on a chemical deposition process in order to produce a semi random structure on the entire mold surface of the medical component. The characteristic size of the structures is controlled by acting on the deposition parameters. The second process, relies on laser structuring of the mold components by producing Laser-Induced Periodic Surface Structures (LIPSS).The two process chains are compared and an evaluation of the applicability in different production scenarios presented, with specific focus on surface accessibility, nano structures uniformity and applicability to surfaces with complex geometry [ABSTRACT FROM AUTHOR]

Many mechanical components require mirror–like surface appearance. When the application concerns the manufacturing of steel dies and moulds, material removal processes are the preferential choice in order to achieve the wanted dimensions and surface topography. In particular, ball milling is used in all those cases that require the machining of free form surfaces. When mirror-like surface appearance is in focus in such components, the final machining operations consists in a very shallow cut. The theoretical surface roughness (kinematic surface topography) that can be achieved in a finishing operation by ball end milling is orders of magnitude below the actual surface roughness. Beside runout and machine tool positioning errors, the quality of the cutting tools is a key factor in determining the surface topography. The combination of shallow depth of cut together with the finite size of the cutting edge radius of the tool are responsible for the occurrence of material smearing phenomena. Smearing, consisting in the accumulation of plastically deformed material over the surface, is particularly detrimental for the aesthetic functionality of machined components because it is responsible of the "foggy" appearance. In order to minimize the occurrence of the smeared material it is necessary to have a good understanding of the causes of the smearing formation process. The aim of this paper is the description and quantification of the smearing phenomena for ball end milling operations. The location of the smeared material is determined through SEM image analysis and related with the direction of the cutting speed and milling strategy. Subsequently the volume of the smeared material is quantified through a combination of confocal microscopy and SEM image analysis. Based on the volumetric analysis of the smeared material a new method for determining the Minimum Uncut Chip Thickness for the material is proposed. [ABSTRACT FROM AUTHOR]

Surface generation in machining processes is affected by a complex interaction between cutting edge and workpiece material, leading to surface artefacts, so that the surface topography deviates considerably from the kinematic one. This paper shows how to model such interaction, taking into account cutting edge topography, material deformation and cutting edge trajectory errors to achieve a reliable prediction of surface topography generation in ball end milling. The model is experimentally validated in upward raster ball end milling of copper and tool steel. [ABSTRACT FROM AUTHOR]

Selective laser melting (SLM) is often applied in the production of steel moulds with high wear resistance and conformal cooling channels for advanced thermal management. The surface finishing of such moulds is crucial, especially if it is intended for the moulding of plastic parts with aesthetic functionality. The surface quality of such metal 3D printed moulds is typically refined by means of subsequent material removal processes, but this is often hindered by residual porosity and inhomogeneity in the metal structure of the 3D-printed part. In this paper an indirect tooling process chain for production of mould inserts is proposed. The process chain aims at exploiting the good replication capability of electroformed nickel, to copy mirror-like substrates. The bulky part of the insert is produced by means of SLM that shows a considerably higher material deposition rate. The thermal input is controlled throughout the process chain to prevent deleterious grains growth in the nickel layer. The roughness of the nickel surface is measured after the selective etching of the substrate and compared with the substrate roughness before the nickel deposition, showing good replication of the master surface. The proposed process chain overcomes the problems related to the deposition of thick electroformed coatings by coupling electroforming with higher output additive processes such as SLM - that furthermore allows the introduction of cooling channels in close contact with the mould surface. [ABSTRACT FROM AUTHOR]