3,478 research outputs found

    Metronomic Chemotherapy with Vinorelbine Produces Clinical Benefit and Low Toxicity in Frail Elderly Patients Affected by Advanced Non-Small Cell Lung Cancer

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    Lung cancer is the leading cause of death worldwide. The treatment choice for advanced stage of lung cancer may depend on histotype, performance status (PS), age, and comorbidities. In the present study, we focused on the effect of metronomic vinorelbine treatment in elderly patients with advanced unresectable non-small cell lung cancer (NSCLC). Methods. From January 2016 to December 2016, 44 patients affected by non-small cell lung cancer referred to our oncology day hospital were progressively analyzed. The patients were treated with oral vinorelbine 30 mg x 3/wk or 40 mg x 3/wk meaning one day on and one day off. The patients were older than 60, stage IIIB or IV, ECOG PS ≥ 1, and have at least one important comorbidity (renal, hepatic, or cardiovascular disease). The schedule was based on ECOG-PS and comorbidities. The primary endpoint was progression-free survival (PFS). PFS was used to compare patients based on different scheduled dosage (30 or 40 mg x3/weekly) and age (more or less than 75 years old) as exploratory analysis. We also evaluated as secondary endpoint toxicity according to Common Toxicity Criteria Version 2.0. Results. Vinorelbine showed a good safety profile at different doses taken orally and was effective in controlling cancer progression. The median overall survival (OS) was 12 months. The disease control rate (DCR) achieved 63%. The median PFS was 9 months. A significant difference in PFS was detected comparing patients aged below with those over 75, and the HR value was 0.72 (p<0.05). Not significant was the difference between groups with different schedules. Conclusions. This study confirmed the safety profile of metronomic vinorelbine and its applicability for patients unfit for standard chemotherapies and adds the possibility of considering this type of schedule not only for very elderly patients

    Business model innovation and digital transformation in global management consulting firms

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    Purpose: This paper contains an exploratory analysis of the business model innovations (BMIs) that management consulting firms (MCFs) undertake to remain competitive during digital transformation. Design/methodology/approach: This paper uses data from a longitudinal multiple case study of the European practices of major global MCFs to provide an overview of how they reconfigure their business model (BM) to gain competitive advantages. It maps BMIs in MCFs through value creation innovation, value proposition innovation and value capturing innovation. Findings: There is a shift in value proposition from solely giving advice or supporting information technology (IT) implementation to providing end-to-end digital solutions. To materialize value propositions, MCFs acquire new knowledge and digital assets through talent scouting, and mergers and acquisitions (M&amp;As). MCFs rely heavily on complementary knowledge and capabilities of actors within ecosystems; thus, they focus on expanding, creating their ecosystems and adopting platforms' configuration and characteristics. Research limitations/implications: Inductively, the authors reached an analytical generalization through six propositions and a theoretical frame that embeds propositions in the previous literature. Future research should test them across the overall management consulting industry. Practical implications: MCFs are recognized as drivers of innovation and BMIs in most client firms. However, MCFs are rarely analyzed with respect to their BMIs. Understanding how MCFs innovate their business models (BMs) to provide digital transformation (DT) consulting services is relevant for delivering management innovation across industries. Originality/value: This is the first exploratory study on BMI inside global MCFs during DT

    Compartmentalized control of Cdk1 drives mitotic spindle assembly

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    During cell division, dramatic microtubular rearrangements driven by cyclin B-cdk1 (Cdk1) kinase activity mark the onset of mitosis leading to dismantling of the interphase microtubular cytoskeleton and assembly of the mitotic spindle. During interphase, Cdk1 accumulates in an inactive state, phosphorylated at inhibitory sites by Wee1/Myt1 kinases. At mitosis onset, Cdc25 phosphatase dephosphorylates and activates Cdk1. Once activated, Cdk1 clears cytoplasmic microtubules by inhibiting microtubule-stabilizing and growth-promoting microtubule-associated proteins (MAPs). Nevertheless, some of these MAPs are required for spindle microtubule growth and spindle assembly, creating quite a conundrum. We show here that a Cdk1 fraction bound to spindle structures escapes Cdc25 action and remains inhibited by phosphorylation (i-Cdk1) in mitotic human cells. Loss or restoration of i-Cdk1 inhibits or promotes spindle assembly, respectively. Furthermore, polymerizing spindle microtubules foster i-Cdk1 aggregating with Wee1 and excluding Cdc25. Our data reveal that spindle assembly relies on compartmentalized control of Cdk1 activity

    Microbial Resources and Innovation in the Wine Production Sector

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    Microbial starter cultures represent a fundamental level of innovation in the wine sector. Selected yeast strains are routinely used to achieve the needed biomass preparation to accelerate and steer alcoholic fermentation in grape must. The use of starter cultures to induce malolactic fermentation in wine relies on the characterisation and propagation of suitable strains of lactic acid bacteria. Furthermore, the selection of new strains, the renewal of management of microbial resources and new technologies allow continuous improvements in oenology, which may increase the beneficial aspects of wine. In this review, with the aim to stimulate microbial-driven, consumer-oriented advances in the oenological sector, we propose an overview of recent trends in this field that are reported by following the classical separation into 'product innovation' and 'process innovation'. Hence, we shall highlight i) the possible positive innovative impacts of microbial resources on the safety and the sensorial and functional properties of wine (product innovation) and ii) the potential microbial-based improvements allowing the reduction of time/costs and the environmental impacts associated with winemaking (process innovation)

    Monitoring and ming bio-physical parameters for hypoxia hazard in a coastal sand pit

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    Management of coastal areas requires monitoring and modeling of the anthropogenic drivers and the bio-physical processes affecting water quality. To assess the range of hydrographic conditions controlling oxygen distribution in the bottom layers of sand pits, a multi-year oceanographic survey has been conducted in a coastal area with several extraction pits. Hydrographic data including profiles of temperature, salinity and oxygen were collected and related to local wind conditions and circulation. Moreover, 1D and 3D high-resolution non-hydrostatic ocean models were used to describe turbulent mixing regimes and to obtain the range of wind speeds for which the critical anoxic conditions may occur. It is shown that wind speed appears to control the dynamics of oxygen concentrations, with oxygen depleted zones developing in a short time in low wind speed conditions. Moreover, the depth and the shape of the extraction pit contribute to decrease the mixing of the bottom layers and increase the water retention in the hole increasing the output and the persistence of oxygen depleted zones in the excavated area. The results of the numerical simulations show that the risk of hypoxia at the bottom of the sand pits is associated with higher temperatures and wind speed lower than 5 m/s, which is not infrequent during the summer season. However, the number of consecutive days of oxygen depletion can be considered lower than the danger threshold level assumed in the literature

    Volcanic spreading forcing and feedback in geothermal reservoir development, Amiata Volcano, Italia

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    We made a stratigraphic, structural and morphologic study of Amiata Volcano in Italy. We find that the edifice is dissected by intersecting grabens that accommodate the collapse of the higher sectors of the volcano. In turn, a number of compressive structures and diapirs exist all around the margin of the volcano. These structures create an angular drainage pattern, with stream damming and captures, and a set of lakes within and around the volcano. We interpret these structures as the result of volcanic spreading of the edifice of Amiata onto its weak substratum, formed by the late Triassic evaporites (Anidriti of Burano) and the Middle-Jurassic to Early-Cretaceous clayey chaotic complexes (Ligurian Complex). Regional doming created a slope in the basement forcing the outward flow and spreading of the ductile layers below the volcano. We model the dynamics of spreading with a scaled lubrication approximation of the Navier Stokes equations, and numerically study a solution. In the model we include simple functions for volcanic deposition and surface erosion that change the topography over time. Scaling indicates that spreading at Amiata could still be active. The numerical solution shows that, as the central part of the edifice sinks into the weak basement, diapiric structures of the underlying formations form around the base of the volcano. Deposition of volcanic rocks within the volcano and surface erosion away from it both enhance spreading. In addition, a sloping basement may constitute a trigger for the formation of trains of adjacent diapirs. Finally, we observe that volcanic spreading has created ideal heat traps that constitute todays’ exploited geothermal fields at Amiata. Normal faults generated by volcanic spreading, volcanic conduits, and direct contact between volcanic rocks (which host an extensive fresh-water aquifer) and the rocks of the geothermal field, constitute ideal pathways for water recharge during vapour extraction for geothermal energy production. We think that volcanic spreading could maintain faults in a critically stressed state, facilitating the occurrence of triggered seismicity

    Ataxia with oculomotor apraxia type 2: a clinical, pathologic, and genetic study

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    BACKGROUND: Ataxia with oculomotor apraxia type 2 (AOA2) is characterized by onset between age 10 and 22 years, cerebellar atrophy, peripheral neuropathy, oculomotor apraxia (OMA), and elevated serum alpha-fetoprotein (AFP) levels. Recessive mutations in SETX have been described in AOA2 patients. OBJECTIVE: To describe the clinical features of AOA2 and to identify the SETX mutations in 10 patients from four Italian families. METHODS: The patients underwent clinical examination, routine laboratory tests, nerve conduction studies, sural nerve biopsy, and brain MRI. All were screened for SETX mutations. RESULTS: All the patients had cerebellar features, including limb and truncal ataxia, and slurred speech. OMA was observed in two patients, extrapyramidal symptoms in two, and mental impairment in three. High serum AFP levels, motor and sensory axonal neuropathy, and marked cerebellar atrophy on MRI were detected in all the patients who underwent these examinations. Sural nerve biopsy revealed a severe depletion of large myelinated fibers in one patient, and both large and small myelinated fibers in another. Postmortem findings are also reported in one of the patients. Four different homozygous SETX mutations were found (a large-scale deletion, a missense change, a single-base deletion, and a splice-site mutation). CONCLUSIONS: The clinical phenotype of oculomotor apraxia type 2 is fairly homogeneous, showing only subtle intrafamilial variability. OMA is an inconstant finding. The identification of new mutations expands the array of SETX variants, and the finding of a missense change outside the helicase domain suggests the existence of at least one more functional region in the N-terminus of senataxin
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