Proliferation to Apoptosis Tumor Cell Ratio as a Biomarker to Improve Clinical Management of Pre-Malignant and Symptomatic Plasma Cell Neoplasms

Proliferation and apoptosis of neoplastic cells are prognostic biomarkers in plasma cell neoplasms (PCNs). The prognostic capacity of proliferation to apoptosis ratio (Ratio-PA) in the era of immunomodulatory treatments is re-evaluated in 316 gammopathy of undetermined significance (MGUS), 57 smoldering multiple myeloma (SMM), and 266 multiple myeloma (MM) patients. Ratio-PA of 0.77 ± 0.12, 1.94 ± 0.52, and 11.2 ± 0.7 (p < 0.0001) were observed in MGUS, SMM, and MM patients. Ten-year overall survival (10y-OS) rates for patients with low/high Ratio-PA were 93.5%/77.3% p < 0.0001) for MGUS, 82.5%/64.7% (p < 0.05) for SMM, and 62.3%/47.0% (p < 0.05) for MM. For patients with low, intermediate, and high risk, 10y-OS for low/high Ratio-PA were 95.5%/72.9% (p < 0.0001), 74.2%/50.4% (p < 0.0001), and 35.3%/20.0% (p = 0.836), respectively. Ratio-PA was an independent prognostic factor for OS (HR = 2.119, p < 0.0001, Harrell-C-statistic = 0.7440 ± 0.0194) when co-analyzed with sex, age, and standard risk. In patients with Ratio-PA^high, only first-line therapy with VRd/VTd, but not PAD/VCD, coupled with ASCT was associated with high 10y-OS (82.7%). Tumor cell Ratio-PA estimated at diagnosis offers a prognostic biomarker that complements standard risk stratification and helps to guide the clinical management of pre-malignant and symptomatic PCNs. Every effort should be made to provide first-line therapies including VTd or VRd associated with ASCT to patients with Ratio-PA^high at higher risk of progression and death.     

Te concentration dependent photoemission and inverse-photoemission study of FeSe1?xTex

We have characterized the electronic structure of FeSe_1−xTe_x for various x values using soft x-ray photoemission spectroscopy (SXPES), high-resolution photoemission spectroscopy (HRPES) and inverse photoemission spectroscopy (IPES). The SXPES valence band spectral shape shows that the 2 eV feature in FeSe, which was ascribed to the lower Hubbard band in previous theoretical studies, becomes less prominent with increasing x. HRPES exhibits systematic x dependence of the structure near the Fermi level (E_F): its splitting near E_F and filling of the pseudogap in FeSe. IPES shows two features, near E_F and approximately 6 eV above E_F; the former may be related to the Fe 3d states hybridized with chalcogenide p states, while the latter may consist of plane-wave-like and Se d components. In the incident electron energy dependence of IPES, the density of states near E_F for FeSe and FeTe has the Fano lineshape characteristic of resonant behavior. These compounds exhibit different resonance profiles, which may reflect the differences in their electronic structures. By combining the PES and IPES data the on-site Coulomb energy was estimated at 3.5 eV for FeSe.     

Ambidextrous strategy and execution in entrepreneurial project-oriented organizations: The case of Pagani supercars

This research explores the dynamics underpinning entrepreneurial project-oriented organizations. Specifically, it focuses on how strategy and execution by projects are managed and how ambidexterity – a firm's ability to exploit old certainties while exploring new possibilities – operates as a logic. The empirical findings from an explorative longitudinal research of supercar maker Pagani Automobili in the period 2007–2019, offer an insight of a complex entrepreneurially led project-oriented organization and suggest three integrative mechanisms that describe the ambidextrous management of the interplay within and between strategy and project levels. Additionally, this research recognizes the critical role of projects also in entrepreneurial environments and suggests that the accomplishment of ambidexterity is unique in nature as it is aimed at reconciling the uniqueness of competitive propositions and that of projects within a unique entrepreneurial environment, opening avenues for more theoretical and empirical studies at the intersection of project management and entrepreneurship.     

Initiation and propagation of surface cracks in rolling fatigue of high hardness steel

Surface cracks initiating flaking failure observed by Sugino in rolling fatigue were further studied.Surface crack initiation was influenced by either running or material conditions, affecting the residual tensile stress just below the rolling contact surface. The fatigue crack is thought to initiate very near the surface by the stress cycle of small tensile residual stress and large compressive contact stress. The amount and direction of the tensile residual stress due to rolling contact varies with the contact geometry, which probably determines the direction of the surface crack and the appearance of flaking. The transition from the surface crack to flaking failure or complete section fracture is material and running condition dependent and is explained by a fracture mechanics concept.     

Failure analysis of rolling bearings by X-ray measurement of residual stress

Residual stress measurements were carried out for the failure analyses of rolling bearings. According to the survey of more than one hundred examples, some change in residual stress was observed in most cases.Compressive residual stresses peak below the surface and if present, represent the position of maximum shearing stress due to normal contact pressure. Unexpected overloading is confirmed by this method.However, bearings often fail without such overloading. Early failures were observed to be associated with the residual stress changes near the surface. The influences of sliding, vibration and surface roughness on residual stress changes are discussed.     

Present status of beryllides for fusion and industrial applications in Japan

Beryllides have remarkable characteristics besides their low density, such as high radiation resistance, high chemical stability, low hydrogen isotope retention and good high temperature mechanical strength especially for fusion applications. In order to have a practical usage for industrial applications, it is important to compile a set of quantitative data on such properties. It is also important to develop fabrication and processing paths to assure the processing of inherently brittle beryllides.The characterization and manufacturing technologies development have been carried out mainly on the Be₁₂Ti interemetallic compounds at the Be-rich side of the Be-Ti binary system. In the present paper, up-dated results on several properties are described for the compound fabricated by hot isostatic pressing (HIP) and ingot metallurgy. Mechanical properties of the compounds having a duplex microstructure with neighboring phases are evaluated by compressive tests from room temperature to 1273 K. Radiation damage of the compound is preliminary studied by charged particle irradiation. Oxidation in air and the interaction with water vapor are evaluated. Thermal desorption of the deuterium is examined by using transmission electron microscopy (TEM) and thermal desorption spectrometry (TDS). Through these evaluations it seems that Be₁₂Ti is superior as neutron multiplier with respect to pure Be metal.     

Liquidus and solidus temperatures of Ni-solid solution in Ni-Al-X (X: V, Nb and Ta) ternary systems

A systematic investigation was carried out to determine both liquidus and solidus surfaces of the Ni-solid solution (γ) in the Ni-Al-X ternary phase diagrams successively by differential thermal analysis (DTA) technique. Each of the Group V elements of the periodic table, V, Nb, and Ta, was chosen as a ternary additive X in the present study. The γ-solvus was also taken into account in determining a temperature range for a solid solution treatment above the γ-solvus, i.e., “the window,” as well as the maximum solubility limit of γ-Ni solid solution.     

Metabolomics reveals target and off-target toxicities of a model organophosphate pesticide to roach (Rutilus rutilus): implications for biomonitoring

The ability of targeted and nontargeted metabolomics to discover chronic ecotoxicological effects is largely unexplored. Fenitrothion, an organophosphate pesticide, is categorized as a "red list" pollutant, being particularly hazardous to aquatic life. It acts primarily as a cholinesterase inhibitor, but evidence suggests it can also act as an androgen receptor antagonist. Whole-organism fenitrothion-induced toxicity is well-established, but information regarding target and off-target molecular toxicities is limited. Here we study the molecular responses of male roach ( Rutilus rutilus ) exposed to fenitrothion, including environmentally realistic concentrations, for 28 days. Acetylcholine was assessed in brain; steroid metabolism was measured in testes and plasma; and NMR and mass spectrometry-based metabolomics were conducted on testes and liver to discover off-target toxicity. O-demethylation was confirmed as a major route of pesticide degradation. Fenitrothion significantly depleted acetylcholine, confirming its primary mode of action, and 11-ketotestosterone in plasma and cortisone in testes, showing disruption of steroid metabolism. Metabolomics revealed significant perturbations to the hepatic phosphagen system and previously undocumented effects on phenylalanine metabolism in liver and testes. On the basis of several unexpected molecular responses that were opposite to the anticipated acute toxicity, we propose that chronic pesticide exposure induces an adapting phenotype in roach, which may have considerable implications for interpreting molecular biomarker responses in field-sampled fish.