The lived experience of novice senior nurse leaders during organizational role transitions

The qualitative interpretive phenomenological study investigates the lived experiences of novice senior nurse leaders, who have transitioned to new organizational roles within a single healthcare organization in the Southeast United States. Senior nurse leaders have complex responsibilities but may not have training adequate to lead masterfully at new organizational levels. This phenomenon is poorly understood. Senior nurse leaders who do not develop the appropriate interpersonal skills and systems thinking may experience a sense of role insufficiency. Yet, strong leadership among senior nurses is vital to the successful performance of healthcare organizations, given the current landscape of change and the rapidity with which change occurs. Given the above, one central research question is posed in this study: What are the lived experiences of novice senior nurse leaders who have transitioned into new roles as they professionally develop at a new organizational level? Based on a relativist ontology and a constructivist worldview, this study posits that novice senior nurse leaders create individual constructions of their lived experiences. Heidegger’s phenomenology, as a research tradition, offers a way to interpret the meaning of novice senior nurse leader’s role transition as it is experienced, grounded in the tenets of transitions theory (TT). Novice senior nurse leaders were purposively selected based on their familiarity with the two hospitals of one healthcare organization. Semi-structured interviews were conducted until data saturation was reached, and data was transcribed verbatim and analyzed with methods of hermeneutic analytics that encompassed intensive discourse, shared inquiry, and thematic analysis

Selinexor, a novel selective inhibitor of nuclear export, reduces SARS-CoV-2 infection and protects the respiratory system in vivo

The novel coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is responsible for the recent global pandemic. The nuclear export protein (XPO1) has a direct role in the export of SARS-CoV proteins including ORF3b, ORF9b, and nucleocapsid. Inhibition of XPO1 induces anti-inflammatory, anti-viral, and antioxidant pathways. Selinexor is an FDA-approved XPO1 inhibitor. Through bioinformatics analysis, we predicted nuclear export sequences in the ACE-2 protein and confirmed by in vitro testing that inhibition of XPO1 with selinexor induces nuclear localization of ACE-2. Administration of selinexor inhibited viral infection prophylactically as well as therapeutically in vitro. In a ferret model of COVID-19, selinexor treatment reduced viral load in the lungs and protected against tissue damage in the nasal turbinates and lungs in vivo. Our studies demonstrated that selinexor downregulated the pro-inflammatory cytokines IL-1β, IL-6, IL-10, IFN-γ, TNF-α, and GMCSF, commonly associated with the cytokine storm observed in COVID-19 patients. Our findings indicate that nuclear export is critical for SARS-CoV-2 infection and for COVID-19 pathology and suggest that inhibition of XPO1 by selinexor could be a viable anti-viral treatment option

Pharmacological treatment with inhibitors of nuclear export enhances the antitumor activity of docetaxel in human prostate cancer

Background and aims: Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon. Material and methods: Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their. DTX resistant derivatives. Results and conclusions: We show that DTX resistance may involve overexpression of β-III tubulin (TUBB3) and P-glycoprotein as well as increased cytoplasmic accumulation of Foxo3a. Increased levels of XPO-1 were also observed in DTX resistant cells suggesting that SINE compounds may modulate DTX effectiveness in sensitive cells as well as restore the sensitivity to DTX in resistant ones. Pretreatment with SINE compounds, indeed, sensitized to DTX through increased tumor shrinkage and apoptosis by preventing DTX-induced cell cycle arrest. Basally SINE compounds induce FOXO3a activation and nuclear accumulation increasing the expression of FOXO-responsive genes including p21, p27 and Bim causing cell cycle arrest. SINE compounds-catenin and survivin supporting apoptosis. βdown-regulated Cyclin D1, c-myc, Nuclear sequestration of p-Foxo3a was able to reduce ABCB1 and TUBB3 H2AX levels, prolonged γ expression. Selinexor treatment increased DTX-mediated double strand breaks (DSB), and reduced the levels of DNA repairing proteins including DNA PKc and Topo2A. Our results provide supportive evidence for the therapeutic use of SINE compounds in combination with DTX suggesting their clinical use in mCRPC patients

A Phase II Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma

PURPOSE: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma. PATIENTS AND METHODS: Seventy-six adults with Karnofsky Performance Status≥60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m(2) (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6). RESULTS: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88). CONCLUSION: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma. TRIAL REGISTRATION: ClinicalTrials.gov, NCT0198634

Health-related quality of life and pain with selinexor in patients with advanced dedifferentiated liposarcoma

[Objective] Compare health-related quality of life (HRQoL) of selinexor versus placebo in patients with dedifferentiated liposarcoma.[Materials & methods] HRQoL was assessed at baseline and day 1 of each cycle using the European Organization for Research and Treatment of Cancer 30-item core quality of life questionnaire. Results were reported from baseline to day 169 (where exposure to treatment was maximized while maintaining adequate sample size).[Results] Pain scores worsened for placebo versus selinexor across all postbaseline visits, although differences in HRQoL at some visits were not significant. Other domains did not exhibit significant differences between arms; however, scores in both arms deteriorated over time.[Conclusion] Patients treated with selinexor reported lower rates and slower worsening of pain compared with patients who received placebo.This study was funded by Karyopharm Therapeutics, Inc. M Gounder: reports an institutional research grant from Karyopharm, personal fees from Karyopharm, Epizyme, Springworks, Daiichi, Bayer, Amgen, Tracon, Flatiron, Medscape, Physicians Education Resource, Guidepoint, GLG and UpToDate; and grants from the National Cancer Institute, National Institutes of Health (P30CA008748) – core grant (CCSG shared resources and core facility). ARA Razak: consulting/Ad board: Merck & Adaptimmune Research support: Karyopharm Therapeutics, Deciphera, Blueprint Medicines, Pfizer, Adaptimmune, Merck, Roche/Genentech, Bristol-Myers Squibb, Medimmune, Amgen, GSK, AbbVie, Iterion Therapeutics. AM Gilligan: employee of Karyopharm Therapeutics, Inc. H Leong: employee of Karyopharm Therapeutics, Inc. X Ma: employee of Karyopharm Therapeutics, Inc. N Somaiah: consultant for Deciphera, Blueprint, Bayer Research Support from Ascentage, Astra-Zeneca, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and GSK. SP Chawla: consultant for Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, NKMax, InhibRx. Grants or contracts from Amgen, Roche, GlaxoSmithKline, Threshold Pharmaceuticals, CytRx Corporation, Ignyta, Immune Design, TRACON Pharma, Karyopharm Therapeutics, SARC: Sarcoma Alliance for Research though Collaboration, Janssen, Advenchen Laboratories, Bayer, InhibRx, NKMax. G Grignani: consultant for Eli Lilly, Novartis, Glaxo, Pharmamar, EISAI, Bayer, Merck. SM Schuetze: consultant – NanoCarrier, UpToDate. Research funding to institution – Adaptimmune, Amgen, Blueprint, Glaxo-SmithKline, Karyopharm. B Vincenzi: Consultant for Pharmamar Eisai, Lilly, Abbott, Novartis, Accord AJ Wagner: consultant for Daiichi-Sankyo, Deciphera, Eli Lilly, Epizyme, NovoCarrier, Mundipharma, and Research Support to My Institution from Aadi Bioscience, Daiichi-Sankyo, Deciphera, Eli Lilly, Karyopharm and Plexxikon. RL Jones: consultant for Adaptimmune, Athenex, Bayer, Boehringer Ingelheim, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Immunedesign, Lilly, Merck, Pharmamar, Springworks, Tracon, Upto Date. J Shah: employee of Karyopharm Therapeutics, Inc. S Shacham: employee of Karyopharm Therapeutics, Inc. M Kauffman: employee of Karyopharm Therapeutics, Inc. RF Riedel: ownership - Limbguard, LLC (Spouse); Institutional Clinical Research Support - AADi, AROG, Blueprint, Daiichi-Sankyo, Deciphera, Glaxo-SmithKline, Karyopharm, Ignyta, Immune Design, NanoCarrier, Oncternal, Philogen, Plexxikon, Roche, Springworks, Tracon; Consultant/Advisor - Bayer, Blueprint, Daiichi-Sankyo, Deciphera, Ignyta, NanoCarrier. S Attia: reports research funding from Desmoid Tumor Research Foundation and research funding to their institution from: AB Science, TRACON Pharma, Bayer, Novartis, Lilly, Immune Design, Karyopharm Therapeutics, Epizyme, Blueprint Medicines, Genmab, CBA Pharma, Merck, Philogen, Gradalis, Deciphera, Takeda, Incyte, Springworks, Adaptimmune, Advenchen Laboratories, Bavarian Nordic, BTG, PTC Therapeutics, GlaxoSmithKline, FORMA Therapeutics. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.Peer reviewe