Family firm versus non-family firm: the role of resource orchestration in fast-growing high-tech SMEs

PurposeThis paper strives to understand the role of resource orchestration (RO) in the rapid growth of high-tech small and medium-sized enterprises (SMEs).Design/methodology/approachBased on a comparative case study, RO is compared between a high-tech family firm and a high-tech non-family firm. To capture the complexity of RO, this study applies a longitudinal approach using a large volume of archival and interview data gathered over ten years.FindingsThe configuration of family-firm paradoxical growth-oriented RO emphasizes RO based on collectivism and responsibility, although relying on large-scale conforming normative control. In contrast, the configuration of non-family-firm growth-oriented RO emphasizes administrative-based delegation and management-supported value creation.Originality/valueBy suggesting ownership-based RO configurations, this study provides insights into how ownership types, i.e. family firms and non-family firms, affect RO in firms operating in complex and dynamic environments. These configurations explain how and why RO is arranged in a growth context.

Supraphysiological testosterone induces ferroptosis and activates NF-kappaB mediated immune pathways in prostate cancer through nucleophagy

The discovery that androgens play an important role in the progression of prostate cancer (PCa) has led to the development of androgen deprivation therapy as a first line of treatment against PCa. However, paradoxical growth inhibition has been observed, both experimentally and clinically, in a subset of PCa upon administration of supraphysiological levels of testosterone (SupraT). Here we report that SupraT activates cytoplasmic nucleic acid sensors and induces growth inhibition of SupraT-sensitive PCa cells. This is initiated by induction of two parallel autophagy-mediated processes, namely, ferritinophagy and nucleophagy. Consequently, autophagosomal DNA activates nucleic acid sensors that converge on NF-kappaB to drive immune signaling pathways. Chemokines and cytokines secreted by the tumor cells in response to SupraT results in increased migration of cytotoxic immune cells to tumor beds of animal xenografts and patient tumors. Collectively, our findings indicate that SupraT may inhibit a subset of PCa by activating nucleic acid sensors and downstream immune signaling.

Relative Frequency of Paradoxical Growth and Trailing Effect with Caspofungin, Micafungin, Anidulafungin, and the Novel Echinocandin Rezafungin against Candida Species

Rezafungin is a next-generation echinocandin that has favorable pharmacokinetic properties. We compared the occurrence of paradoxical growth (PG) and trailing effect (TE) characteristics to echinocadins with rezafungin, caspofungin, micafungin and anidulafungin using 365 clinical Candida isolates belonging to 13 species. MICs were determined by BMD method according to CLSI (M27 Ed4). Disconnected growth (PG plus TE) was most frequent with caspofungin (49.6%), followed by anidulafungin (33.7%), micafungin (25.7%), while it was least frequent with rezafungin (16.9%). PG was relatively common in the case of caspofungin (30.1%) but was rare in the case of rezafungin (3.0%). C. tropicalis, C. albicans, C. orthopsilosis and C. inconspicua exhibited PG most frequently with caspofungin, micafungin or anidulafungin. PG never occurred in the case of C. krusei isolates. Against C. tropicalis and C. albicans, echinocandins frequently showed PG after 24 h followed by TE after 48 h. All four echinocandins exhibited TE for the majority of C. auris and C. dubliniensis isolates. Disconnected growth was common among Candida species and was echinocandin- and species-dependent. In contrast to earlier echinocandins, PG was infrequently found with rezafungin.

Analysis of crude mineral sample preparation schemes

Introduction. Sample preparation schemes are multi-stage. Sample reduction in the process of preparation introduces extra inaccuracy in the result of sampling, consequently, sample preparation schemes inaccuracy should be calculated with further selection of its rational parameters. Research methodology is based on calculation by the formula of sample reduction random inaccuracy. Inaccuracy calculation of a sample preparation scheme. Calculation has been carries out of the scheme recommended by GOST 14180-80. Paradoxical growth of inaccuracy of sample preparation has been shown with ore homogeneity growth. Determination of sample mass by the stages of preparation. Standards and techniques of ore and nonferrous metals concentrates sampling for the creation of sample preparation schemes recommend finding the coefficient in minimum mass formula depending on the mass fraction variation coefficient in the sampled product. Sample preparation is carried out in laboratory conditions, and sample mass cannot depend on this coefficient of variation. Sample inhomogeneity in the laboratory depends only on the inhomogeneity of separate lumps of a sample. Sample inhomogeneity in the preparation laboratory is defined by lump dispersion, and the coefficient is the function of this dispersion, admissible inaccuracy of sample reduction and the dimensions of grain impregnations of the mineral which contains the analyte. 78 "Izvestiya vysshikh uchebnykh zavedenii. Gornyi zhurnal". No. 1. 2020 ISSN 0536-1028 For each factory, individual coefficient can be found, and sample masses can be calculated by the stages of preparation. Analysis of sample preparation schemes. Sample preparation scheme inaccuracy formula is given. Calculation and analysis of the model scheme of sample preparation according to GOST 14180-80 have shown that at the third crushing stage the sample is advisable to be crushed not up to 3, but up to 2 mm, and the recommended sample size at the final stage 8.08 hardly improves the result of preparation, that is why the previous recommendation of 0.1 mm can be used.

Echinocandins for the Treatment of Invasive Aspergillosis: from Laboratory to Bedside

ABSTRACT Echinocandins (caspofungin, micafungin, anidulafungin), targeting β-1,3-glucan synthesis of the cell wall, represent one of the three currently available antifungal drug classes for the treatment of invasive fungal infections. Despite their limited antifungal activity against Aspergillus spp., echinocandins are considered an alternative option for the treatment of invasive aspergillosis (IA). This drug class exhibits several advantages, such as excellent tolerability and its potential for synergistic interactions with some other antifungals. The objective of this review is to discuss the in vitro and clinical efficacy of echinocandins against Aspergillus spp., considering the complex interactions between the drug, the mold, and the host. The antifungal effect of echinocandins is not limited to direct inhibition of hyphal growth but also induces an immunomodulatory effect on the host’s response. Moreover, Aspergillus spp. have developed important adaptive mechanisms of tolerance to survive and overcome the action of echinocandins, such as paradoxical growth at increased concentrations. This stress response can be abolished by several compounds that potentiate the activity of echinocandins, such as drugs targeting the heat shock protein 90 (Hsp90)-calcineurin axis, opening perspectives for adjuvant therapies. Finally, the present and future places of echinocandins as prophylaxis, monotherapy, or combination therapy of IA are discussed in view of the emergence of pan-azole resistance among Aspergillus fumigatus isolates, the occurrence of breakthrough IA, and the advent of new long-lasting echinocandins (rezafungin) or other β-1,3-glucan synthase inhibitors (ibrexafungerp).

Caspofungin-Mediated Growth Inhibition and Paradoxical Growth in Aspergillus fumigatus Involve Fungicidal Hyphal Tip Lysis Coupled with Regenerative Intrahyphal Growth and Dynamic Changes in β-1,3-Glucan Synthase Localization

ABSTRACT Caspofungin targets cell wall β-1,3-glucan synthesis and is the international consensus guideline-recommended salvage therapy for invasive aspergillosis. Although caspofungin is inhibitory at low concentrations, it exhibits a paradoxical effect (reversal of growth inhibition) at high concentrations by an undetermined mechanism. Treatment with caspofungin at either the growth-inhibitory concentration (0.5 μg/ml) or paradoxical growth-inducing concentration (4 μg/ml) for 24 h caused similar abnormalities, including wider, hyperbranched hyphae, increased septation, and repeated hyphal tip lysis, followed by regenerative intrahyphal growth. By 48 h, only hyphae at the colony periphery treated with the high caspofungin concentration displayed paradoxical growth. A similar high concentration of caspofungin also induced the paradoxical growth of Aspergillus fumigatus during human A549 alveolar cell invasion. Localization of the β-1,3-glucan synthase complex (Fks1 and Rho1) revealed significant differences between cells exposed to the growth-inhibitory and paradoxical growth-inducing concentrations of caspofungin. At both concentrations, Fks1 initially mislocalized from the hyphal tips to vacuoles. However, only continuous exposure to 4 μg/ml of caspofungin for 48 h led to recovery of the normal hyphal morphology with renewed localization of Fks1 to hyphal tips. Rho1 remained at the hyphal tip after treatment with both caspofungin concentrations but was required for paradoxical growth. Farnesol blocked paradoxical growth and relocalized Fks1 and Rho1 to vacuoles. Our results highlight the importance of regenerative intrahyphal growth as a rapid adaptation to the fungicidal lytic effects of caspofungin on hyphal tips and the dynamic localization of Fks1 as part of the mechanism for the caspofungin-mediated paradoxical response in A. fumigatus.

Calcium-Mediated Induction of Paradoxical Growth following Caspofungin Treatment Is Associated with Calcineurin Activation and Phosphorylation in Aspergillus fumigatus

ABSTRACTThe echinocandin antifungal drug caspofungin at high concentrations reverses the growth inhibition ofAspergillus fumigatus, a phenomenon known as the “paradoxical effect,” which is not consistently observed with other echinocandins (micafungin and anidulafungin). Previous studies ofA. fumigatusrevealed the loss of the paradoxical effect following pharmacological or genetic inhibition of calcineurin, yet the underlying mechanism is poorly understood. Here, we utilized a codon-optimized bioluminescent Ca2+reporter aequorin expression system inA. fumigatusand showed that caspofungin elicits a transient increase in cytosolic free Ca2+([Ca2+]c) in the fungus that acts as the initial trigger of the paradoxical effect by activating calmodulin-calcineurin signaling. While the increase in [Ca2+]cwas also observed upon treatment with micafungin, another echinocandin without the paradoxical effect, a higher [Ca2+]cincrease was noted with the paradoxical-growth concentration of caspofungin. Treatments with a Ca2+-selective chelator, BAPTA [1,2-bis(o-aminophenoxy)ethane-N,N,N′,N′-tetraacetic acid], or the L-type Ca2+channel blocker verapamil abolished caspofungin-mediated paradoxical growth in both the wild-type and the echinocandin-resistant (EMFR-S678P) strains. Concomitant with increased [Ca2+]clevels at higher concentrations of caspofungin, calmodulin and calcineurin gene expression was enhanced. Phosphoproteomic analysis revealed that calcineurin is activated through phosphorylation at its serine-proline-rich region (SPRR), a domain previously shown to be essential for regulation of hyphal growth, only at a paradoxical-growth concentration of caspofungin. Our results indicate that as opposed to micafungin, the increased [Ca2+]cat high concentrations of caspofungin activates calmodulin-calcineurin signaling at both a transcriptional and a posttranslational level and ultimately leads to paradoxical fungal growth.

Identification and Susceptibility of Aspergillus Section Nigri in China: Prevalence of Species and Paradoxical Growth in Response to Echinocandins

Molecular identification andin vitroantifungal susceptibility tests of 43AspergillussectionNigriisolates from China were performed.Aspergillus nigerandAspergillus tubingensiswere present in almost equal numbers. All of the isolates had low MIC/MECs (minimum effective concentrations) for the 7 common antifungals, and a paradoxical effect was observed for the first time in response to caspofungin and micafungin.

The Contribution of Toll-like Receptor (TLR) Pathway Hyper-Reactivity to Clonal Selection in Secondary MDS and AML

Background: Stem cell (HSC) hypersensitivity to inflammatory cytokines and exaggerated TLR-dependent production of such cytokines contribute to bone marrow failure and clonal selection in Fanconi anemia (FA). Clonal neoplasms in FA patients and FA-deficient mice exhibit either resistance or paradoxical proliferative responses to tumor necrosis factor-alpha (TNF) and interferon-gamma (IFN). Because FA MDS/AML shares cytogenetic and clinical features in common with secondary MDS/AML developing after prior MDS or exposure to cytotoxic chemotherapy (sMDS/sAML), we tested the idea that an FA-like TLR/cytokine hypersensitive phenotype might underlie clonal selection in sMDS/sAML. A pilot study of 4 hematologically normal individuals with histories of prior cytotoxic chemotherapy (including alkylating agents) revealed 2 whose committed progenitor cells were hypersensitive to TNF and IFN. Three patients with sMDS/sAML exhibited resistance to IFN and paradoxical growth responses to TNF. To determine the true prevalence of these FA-like phenotypes, we conducted a larger study of patients with sMDS/sAML, quantifying a) progenitor cell growth in response to inflammatory cytokines and b) TLR7/8 or TLR4-dependent cytokine production in peripheral blood monocytes. Methods: Patients with newly diagnosed sMDS or sAML were eligible. All potential subjects with active infections were excluded. Research bone marrow aspirates and peripheral blood (PB) were obtained at the same time. TNF was quantified (ELISA) in the supernatants of PB CD14+ cells cultured in the presence of 1 ng/ml lipopolysaccharide (LPS, a TLR-4 agonist) or 3-5 μM R848 (TLR-7/8 agonist) for 24-hours. BFU-E and CFU-GM were quantified in methylcellulose cultures of low density bone marrow mononuclear cells (LDBMCs) (SCF, IL-3, EPO +/- TNF or IFN). Progenitor responses were classified as resistant/paradoxical if either CFU-GM or BFU-E colonies were >120% of control (normal volunteer bone marrow cells) at TNF 1 ng/ml, or >100% at IFN 0.1 ng/ml; all other responses were categorized as sensitive. TNF production was classified as exaggerated if levels exceeded normal mean values by more than two standard deviations. Results: A total of 22 patients with sMDS/sAML had bone marrow and PB analysis, including 13 patients with complex karyotypes and 9 patients with non-complex karyotypes. An additional 18 patients had PB samples drawn without providing bone marrow samples. Progenitor responses: In colony assays, 18/22 patients demonstrated resistant/paradoxical growth responses to TNF/IFN, a phenomenon seen in patients with both complex and non-complex karyotypes. Interestingly, TNF resistance was observed only in samples that were also IFN resistant. Among patients with a complex karyotype, only 3 demonstrated normal progenitor sensitivity. None of these 3 had received prior chemotherapy (2 with radiation only). Macrophage responses: CD14+ cells from 63% of patients with resistant/paradoxical colony assay responses overproduced TNF in response to either R848 or LPS. Mean TNF levels from CD14+ cells of these patients were higher compared to patients with sensitive colony responses [1756 pg/ml (R848) and 1699 pg/ml (LPS), versus 783 pg/ml (R848) and 959 pg/ml (LPS), for resistant/paradoxical versus sensitive patients respectively]. Among all patients with PB samples (including those with/without marrow results), CD14+ cells from 68% of these patients overproduced TNF. Mean TNF levels in response to R848 or LPS stimulation of patient cells were elevated compared to normal donor controls [1730 pg/ml (R848) and 1795 pg/ml (LPS), versus 719 pg/ml (R848) and 555 pg/ml (LPS), from patient and normal donor CD14+ cells, respectively]. Conclusions: In patients with sMDS/sAML there is a high prevalence of TNF resistance in committed progenitors and TLR-hyper-reactivity in CD14+ cells. In FA the MDS/AML clonal resistance phenotype is selected because it possesses a selective advantage over the unfit pool of non-clonal FA HSC. We suggest that prior chemotherapy can create a fixed phenotype of HSC unfitness (e.g. hypersensitivity to inflammatory cytokines) and that the desultory fitness landscape in that pool permits the selection of cytokine resistant clones. Mechanistic studies should provide opportunities to identify patients at risk of sMDS/sAML and to develop pharmacological approaches to leukemia prevention. Disclosures No relevant conflicts of interest to declare.