The impact of the global crisis on the growth of SMEs: A resource system perspective

In this commentary, we examine both the positive and negative potential impact of the COVID-19 pandemic on the growth of small- and medium-sized enterprises (SMEs). We conceptualise the firm as a system of various resource components (strategic, physical, financial, human and organisational resources) and firm growth as the expansion of this resource system. Based on qualitative data drawn from Canadian high-growth SMEs, we discuss the potential impact of the crisis on these resource system components. We demonstrate how virtuous growth spirals of these resources co-evolve through various feedback and feed-forward loops. Furthermore, we discuss how a temporary growth setback, due to the crisis, can in fact provide an opportunity for entrepreneurs to realign, and regain the balance and fit within their firm’s resource system. This realignment enables the firm to take on the next phase of growth.

The Spiroindolone KAE609 Does Not Induce Dormant Ring Stages in Plasmodium falciparum Parasites

ABSTRACTIn vitrodrug treatment with artemisinin derivatives, such as dihydroartemisinin (DHA), results in a temporary growth arrest (i.e., dormancy) at an early ring stage inPlasmodium falciparum. This response has been proposed to play a role in the recrudescence ofP. falciparuminfections following monotherapy with artesunate and may contribute to the development of artemisinin resistance inP. falciparummalaria. We demonstrate here that artemether does induce dormant rings, a finding which further supports the class effect of artemisinin derivatives in inducing the temporary growth arrest ofP. falciparumparasites. In contrast and similarly to lumefantrine, the novel and fast-acting spiroindolone compound KAE609 does not induce growth arrest at the early ring stage ofP. falciparumand prevents the recrudescence of DHA-arrested rings at a low concentration (50 nM). Our findings, together with previous clinical data showing that KAE609 is active against artemisinin-resistant K13 mutant parasites, suggest that KAE609 could be an effective partner drug with a broad range of antimalarials, including artemisinin derivatives, in the treatment of multidrug-resistantP. falciparummalaria.

Differential activity of afatinib (AFAT), cetuximab (CET), and erlotinib (E) in a patient-derived xenograft (PDX) model of acquired E resistance.

8110 Background: The UC Davis - Jackson Labs Consortium has established a PDX resource of over 50 NSCLC models (12 EGFR mutant) for experimental therapeutics and personalized medicine, using the NSG mouse. Here we report on a unique PDX model, LG703, derived from a patient at time of acquired E resistance. This tumor harbors EGFR L858R with no T790M mutation, high MET and very high EGFR protein expression. The patient is in remission following treatment with AFAT-CET. In this model, we investigated the respective contribution of CET and AFAT relative to E on tumor growth and signal transduction. Methods: Individual mice implanted with LG703 tumor fragments were randomized to E (50 mg/kg qd po), AFAT (20 mg/kg qd po), CET (10 mg/kg twice weekly iv), AFAT-CET, or vehicle control (n per arm = 12) for 3 weeks followed by a 75-day monitoring period. Changes in signal transduction mediators and RTKs were assessed after 6 and 24h treatment exposures using kinase arrays (R&D systems) and immunoblotting. Results: AFAT, CET and AFAT-CET resulted in complete tumor response (CR) during the 21-day treatment period; whereas E resulted in temporary growth delay. After cessation of treatment, E-treated mice progressed rapidly and AFAT-treated mice progressed within 2 weeks. Mice treated with CET or AFAT-CET remained in complete remission. At 6h, E and AFAT significantly (>70%) reduced EGFR phosphorylation as well as that of AKT1, AKT2, ERK1, p38a, RSK1 and p70S6K. At 24h, E-treated tumors had returned to baseline-like states for all factors, AFAT showed an intermediate response, and CET, alone or with AFAT, achieved the greatest inhibition of pEGFR with sustained inhibition of all downstream effectors. Conclusions: In the LG703 PDX model, CET and AFAT+CET resulted in CRs, mirroring the patient's response to similar therapy, associated with sustained inhibition of pEGFR and multiple downstream signaling factors. In contrast, E exhibited only temporary growth delay associated with transient inhibition of EGFR pathway factors. These experiments demonstrate the potential of this PDX resource to assess new therapeutic strategies in models representing individual patients. Supported by BJALCF.

Phenotypic Changes in Artemisinin-Resistant Plasmodium falciparum LinesIn Vitro: Evidence for Decreased Sensitivity to Dormancy and Growth Inhibition

ABSTRACTThe appearance ofPlasmodium falciparumparasites with decreasedin vivosensitivity but no measurablein vitroresistance to artemisinin has raised the urgent need to characterize the artemisinin resistance phenotype. Changes in the temporary growth arrest (dormancy) profile of parasites may be one aspect of this phenotype. In this study, we investigated the link between dormancy and resistance, using artelinic acid (AL)-resistant parasites. Our results demonstrate that the AL resistance phenotype has (i) decreased sensitivity of mature-stage parasites, (ii) decreased sensitivity of the ring stage to the induction of dormancy, and (iii) a faster recovery from dormancy.