Alternating Electric Fields (Tumor-Treating Fields Therapy) Can Improve Chemotherapy Treatment Efficacy in Non-Small Cell Lung Cancer Both In Vitro and In Vivo

Non-small cell lung cancer (NSCLC) is one of the leading causes of cancer-related deaths worldwide. Common treatment modalities for NSCLC include surgery, radiotherapy, chemotherapy, and, in recent years, the clinical management paradigm has evolved with the advent of targeted therapies. Despite such advances, the impact of systemic therapies for advanced disease remains modest, and as such, the prognosis for patients with NSCLC remains poor. Standard modalities are not without their respective toxicities and there is a clear need to improve both efficacy and safety for current management approaches. Tumor-treating fields (TTFields) are low-intensity, intermediate-frequency alternating electric fields that disrupt proper spindle microtubule arrangement, thereby leading to mitotic arrest and ultimately to cell death. We evaluated the effects of combining TTFields with standard chemotherapeutic agents on several NSCLC cell lines, both in vitro and in vivo. Frequency titration curves demonstrated that the inhibitory effects of TTFields were maximal at 150 kHz for all NSCLC cell lines tested, and that the addition of TTFields to chemotherapy resulted in enhanced treatment efficacy across all cell lines. We investigated the response of Lewis lung carcinoma and KLN205 squamous cell carcinoma in mice treated with TTFields in combination with pemetrexed, cisplatin, or paclitaxel and compared these to the efficacy observed in mice exposed only to the single agents. Combining TTFields with these therapeutic agents enhanced treatment efficacy in comparison with the respective single agents and control groups in all animal models. Together, these findings suggest that combining TTFields therapy with chemotherapy may provide an additive efficacy benefit in the management of NSCLC

Caring International Research Collaborative: A Five-Country Partnership to Measure Perception of Nursing Staffs’ Compassion Fatigue, Burnout, and Caring for Self

Partnering in research across disciplines and across countries can be challenging due to differing contexts of practice and culture. This study sought to demonstrate how central constructs that have application across disciplines and countries can be studied while concurrently considering context. Groups of nurses from Botswana, Ireland, Israel, New Zealand, and Spain partnered to identify how to measure the constructs of caring for self, burnout, and compassion fatigue, replicating a study by Johnson (2012), who found that caring for self had a moderately strong negative relationship with both compassion fatigue and burnout. While these constructs were of interest to all five groups, the conversation of contextual influences varied. All five groups used the same instruments to measure the central constructs. Levels of burnout and compassion fatigue varied by country but were moderated by caring for self. Partnering across countries made it possible to understand that caring for self moderates the negative impact of burnout and compassion fatigue in all five countries. This study gives insight into methods for partnering across disciplines and contexts

D-Sitter Space: Causal Structure, Thermodynamics, and Entropy

We study the entropy of concrete de Sitter flux compactifications and deformations of them containing D-brane domain walls. We determine the relevant causal and thermodynamic properties of these "D-Sitter" deformations of de Sitter spacetimes. We find a string scale correspondence point at which the entropy localized on the D-branes (and measured by probes sent from an observer in the middle of the bubble) scales the same with large flux quantum numbers as the entropy of the original de Sitter space, and at which Bousso's bound is saturated by the D-brane degrees of freedom (up to order one coefficients) for an infinite range of times. From the geometry of a static patch of D-Sitter space and from basic relations in flux compactifications, we find support for the possibility of a low energy open string description of the static patch of de Sitter space.Comment: 46 pages, harvmac big; 14 figure

Membrane anchored IL-18 linked to constitutively active TLR4 and CD40 improves human T cell antitumor capacities for adoptive cell therapy

BACKGROUND: Adoptive transfer of tumor-infiltrating lymphocytes (TILs) or blood T cells genetically redirected by an antitumor TCR or CAR induces a strong antitumor response in a proportion of patients with cancer; however, the therapeutic efficacy is often limited by rapid decline in T cell functions. Coadministering supportive cytokines frequently provokes systemic side effects preventing their broad clinical application. We recently showed that cytokines can be anchored to the cell membrane in a functional fashion and that cytokine receptor signaling can synergize with TLR4 and CD40 signaling. Here, we aimed at augmenting T cell activation by simultaneous signaling through the cytokine receptor, toll-like receptor and TNF-type receptor using IL-18, TLR4 and CD40 as prototypes. METHODS: Genes were expressed on electroporation of in vitro-transcribed mRNA in CD4(+) and CD8(+) T cells from healthy donors redirected against melanoma cells with an anti-melanotransferrin CAR and in TILs derived from melanoma patients. Functional assays included the activation of signaling pathways, expression of activation and differentiation markers, cytokine secretion and killing of melanoma target cells. RESULTS: To provide IL-18 costimulation to T cells in-cis while avoiding systemic effects, we genetically anchored IL-18 to the T cell membrane, either alone (memIL-18) or fused with constitutively active (ca)TLR4 and caCD40 signaling domains arranged in tandem, creating a synthetic ‘all-in-one’ memIL-18-TLR4-CD40 receptor. MemIL-18-TLR4-CD40, but not memIL-18, triggered strong NF-κB activation in cells lacking the IL-18 receptor, attesting to functionality of the TLR-CD40 moiety. While the membrane-anchored cytokine was found to act mainly in-cis, some T cell activation in-trans was also observed. The electroporated T cells exhibited spontaneous T-bet upregulation and IFN-γ and TNF-α secretion. Melanoma-induced activation of CAR-T cells and TILs as manifested by cytokine secretion and cytolytic activity was substantially augmented by both constructs, with memIL-18-TLR4-CD40 exerting stronger effects than memIL-18 alone. CONCLUSIONS: Linking membrane anchored IL-18 with caTLR4 and caCD40 signaling in one hybrid transmembrane protein provides simultaneous activation of three T cell costimulatory pathways through one genetically engineered membrane molecule, strongly amplifying T cell functions for adoptive T cell therapy of cancer

Epigenetic Profiling and Response to CD19 Chimeric Antigen Receptor T-Cell Therapy in B-Cell Malignancies

Background: Chimeric antigen receptor (CAR) T cells directed against CD19 (CART19) are effective in B-cell malignancies, but little is known about the molecular factors predicting clinical outcome of CART19 therapy. The increasingly recognized relevance of epigenetic changes in cancer immunology prompted us to determine the impact of the DNA methylation profiles of CART19 cells on the clinical course. Methods: We recruited 114 patients with B-cell malignancies, comprising 77 patients with acute lymphoblastic leukemia and 37 patients with non-Hodgkin lymphoma who were treated with CART19 cells. Using a comprehensive DNA methylation microarray, we determined the epigenomic changes that occur in the patient T cells upon transduction of the CAR vector. The effects of the identified DNA methylation sites on clinical response, cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, event-free survival, and overall survival were assessed. All statistical tests were 2-sided. Results: We identified 984 genomic sites with differential DNA methylation between CAR-untransduced and CAR-transduced T cells before infusion into the patient. Eighteen of these distinct epigenetic loci were associated with complete response (CR), adjusting by multiple testing. Using the sites linked to CR, an epigenetic signature, referred to hereafter as the EPICART signature, was established in the initial discovery cohort (n = 79), which was associated with CR (Fisher exact test, P < .001) and enhanced event-free survival (hazard ratio [HR] = 0.36; 95% confidence interval [CI] = 0.19 to 0.70; P = .002; log-rank P = .003) and overall survival (HR = 0.45; 95% CI = 0.20 to 0.99; P = .047; log-rank P = .04;). Most important, the EPICART profile maintained its clinical course predictive value in the validation cohort (n = 35), where it was associated with CR (Fisher exact test, P < .001) and enhanced overall survival (HR = 0.31; 95% CI = 0.11 to 0.84; P = .02; log-rank P = .02). Conclusions: We show that the DNA methylation landscape of patient CART19 cells influences the efficacy of the cellular immunotherapy treatment in patients with B-cell malignancy.Supported by CERCA Programme/Generalitat de Catalunya, Health Department PERIS #SLT/002/16/00374, AGAUR-project #2017SGR1080; MCI/AEI/ERDF project #RTI2018-094049-B-I00; ERC EPIPHARM; Cellex Foundation; “la Caixa” Foundation (LCF/PR/GN18/51140001 and LCF/PR/GN18/50310007), RF-2016–02364388, Accelerator Award—Cancer Research UK/AIRC—INCAR Associazione Italiana Ricerca per la Ricerca sul Cancro (AIRC) Project 5 × 1000 no. 9962, AIRC IG 2018 id. 21724, AIRC MFAG id. 21769 and id. 20450; MIUR (Grant PRIN 2017); and RCR-2019–23669115

Caring international research collaborative: A five-country partnership to measure perception of nursing staffs' compassion fatigue, burnout, and caring for self

Partnering in research across disciplines and across countries can be challenging due to differing contexts of practice and culture. This study sought to demonstrate how central constructs that have application across disciplines and countries can be studied while concurrently considering context. Groups of nurses from Botswana, Ireland, Israel, New Zealand, and Spain partnered to identify how to measure the constructs of caring for self, burnout, and compassion fatigue, replicating a study by Johnson (2012), who found that caring for self had a moderately strong negative relationship with both compassion fatigue and burnout. While these constructs were of interest to all five groups, the conversation of contextual influences varied. All five groups used the same instruments to measure the central constructs. Levels of burnout and compassion fatigue varied by country but were moderated by caring for self. Partnering across countries made it possible to understand that caring for self moderates the negative impact of burnout and compassion fatigue in all five countries. This study gives insight into methods for partnering across disciplines and contexts

Regulation of Cancer Aggressive Features in Melanoma Cells by MicroRNAs

MicroRNAs (miRNAs) are small non-coding RNAs with regulatory roles, which are involved in a broad spectrum of physiological and pathological processes, including cancer. A common strategy for identification of miRNAs involved in cell transformation is to compare malignant cells to normal cells. Here we focus on identification of miRNAs that regulate the aggressive phenotype of melanoma cells. To avoid differences due to genetic background, a comparative high-throughput miRNA profiling was performed on two isogenic human melanoma cell lines that display major differences in their net proliferation, invasion and tube formation activities. This screening revealed two major cohorts of differentially expressed miRNAs. We speculated that miRNAs up-regulated in the more-aggressive cell line contribute oncogenic features, while the down-regulated miRNAs are tumor suppressive. This assumption was further tested experimentally on five candidate tumor suppressive miRNAs (miR-31, -34a, -184, -185 and -204) and on one candidate oncogenic miRNA (miR-17-5p), all of which have never been reported before in cutaneous melanoma. Remarkably, all candidate Suppressive-miRNAs inhibited net proliferation, invasion or tube formation, while miR-17-5p enhanced cell proliferation. miR-34a and miR-185 were further shown to inhibit the growth of melanoma xenografts when implanted in SCID-NOD mice. Finally, all six candidate miRNAs were detected in 15 different metastatic melanoma specimens, attesting for the physiological relevance of our findings. Collectively, these findings may prove instrumental for understanding mechanisms of disease and for development of novel therapeutic and staging technologies for melanoma

A Universal System for Highly Efficient Cardiac Differentiation of Human Induced Pluripotent Stem Cells That Eliminates Interline Variability

The production of cardiomyocytes from human induced pluripotent stem cells (hiPSC) holds great promise for patient-specific cardiotoxicity drug testing, disease modeling, and cardiac regeneration. However, existing protocols for the differentiation of hiPSC to the cardiac lineage are inefficient and highly variable. We describe a highly efficient system for differentiation of human embryonic stem cells (hESC) and hiPSC to the cardiac lineage. This system eliminated the variability in cardiac differentiation capacity of a variety of human pluripotent stem cells (hPSC), including hiPSC generated from CD34(+) cord blood using non-viral, non-integrating methods.We systematically and rigorously optimized >45 experimental variables to develop a universal cardiac differentiation system that produced contracting human embryoid bodies (hEB) with an improved efficiency of 94.7±2.4% in an accelerated nine days from four hESC and seven hiPSC lines tested, including hiPSC derived from neonatal CD34(+) cord blood and adult fibroblasts using non-integrating episomal plasmids. This cost-effective differentiation method employed forced aggregation hEB formation in a chemically defined medium, along with staged exposure to physiological (5%) oxygen, and optimized concentrations of mesodermal morphogens BMP4 and FGF2, polyvinyl alcohol, serum, and insulin. The contracting hEB derived using these methods were composed of high percentages (64-89%) of cardiac troponin I(+) cells that displayed ultrastructural properties of functional cardiomyocytes and uniform electrophysiological profiles responsive to cardioactive drugs.This efficient and cost-effective universal system for cardiac differentiation of hiPSC allows a potentially unlimited production of functional cardiomyocytes suitable for application to hPSC-based drug development, cardiac disease modeling, and the future generation of clinically-safe nonviral human cardiac cells for regenerative medicine

Coping with fibromyalgia - a focus group study

Purpose Fibromyalgia affects patients’ quality of life. Therefore, an essential part of patients’ medical management is to develop appropriate coping strategies. This study aimed to obtain a comprehensive picture of patients’ cognitive and behavioural strategies to cope with fibromyalgia. Methods A qualitative design was conducted based on the grounded theory method. Two focus group discussion sessions were held with 15 Israeli women diagnosed with fibromyalgia. A constant comparative analysis method was utilized. Results The findings of themes related to women’s coping with fibromyalgia included: Emotional coping, with two categories: (a) from repression and despair to acceptance and completion, and (b) a range of negative and positive emotions; Practical coping, with three categories: (a) the agonizing process of receiving/internalizing the diagnosis, (b) living with the symptoms, and (c) changing lifestyle; Coping with the social environment, with three categories: (a) sharing vs. concealing, (b) social connection—disconnection, and (c) environmental resources. In addition, we identified a theme on the patients’ perceptions of the causes of their fibromyalgia that effect their coping, with three categories: (a) demanding lifestyle; (b) traumatic life events; and (c) personality trait—perfectionism. Conclusion It would be desirable for rheumatology units to have an interdisciplinary professional team to work together with patients to consider how best to manage and effectively cope with their condition

Choosing a nursing specialty: connection to nursing students’ personality traits, clinical self-efficacy, adoption of technology changes, and specialty prestige; a cross-sectional study

Abstract Background Choosing a field of specialization within the nursing profession is affected by nurses’ personality traits, self-confidence in performing clinical skills, and the field’s prestige. A successful choice of area of expertise may improve nurses’ job satisfaction and reduce job mobility. This study aims to examine the relationship between personality traits, clinical self-efficacy, perceived prestige, adoption of technological changes, and choice of specialty field among nursing students. Methods A cross-sectional study was conducted. One-hundred-twenty-seven undergraduate nursing students in their fourth year of studies at a large university in Israel participated in the study. The questionnaire administered was comprised of six parts: demographic data, personality traits, adoption of technological changes, clinical self-efficacy, perceived prestige, and intention to select a field of specialization. Results Acute disciplines were rated more prestigious than chronic disciplines, with intensive care and emergency medicine considered the most prestigious, while mental health and geriatrics were the least prestigious. Students’ mean perceived confidence in performing nursing clinical skills was high and more than half considered themselves open to technology changes. Positive correlations were found between prestige and intention to choose a field of expertise (r = 0.41, p < 0.001) and the personality trait of openness and the intention to choose an acute care area (r = 0.26, p < 0.01). Conclusions Despite the gradual aging of the population and the increase in chronic morbidity, which demand a greater nursing focus on older adults, and notwithstanding the mental health reforms, nursing students perceive geriatrics and mental health as less prestigious fields. A career development path can be applied by developing a tool for occupational guidance designed to rank students’ suitability for specialty fields and thus help them choose the area that best suits them