Ruxolitinib in treatment-naive or corticosteroid-refractory paediatric patients with chronic graft-versus-host disease (REACH5): interim analysis of a single-arm, multicentre, phase 2 study.

BACKGROUND: Chronic graft-versus-host disease (GVHD) is a debilitating, and sometimes life threatening, complication of allogeneic haematopoietic stem-cell transplantation (HSCT). We aimed to investigate the activity, pharmacokinetics, and safety of ruxolitinib added to corticosteroids in paediatric patients (ie, <18 years) with moderate-to-severe chronic GVHD. METHODS: In this single-arm, phase 2 study, patients were recruited at 21 hospitals or clinics across 14 countries in Asia, Europe, and Canada. Eligible patients were aged 28 days to younger than 18 years, had undergone allogenic HSCT, and had been diagnosed with treatment-naive or corticosteroid-refractory moderate-to-severe chronic GVHD, per 2014 National Institutes of Health consensus criteria. Patients received oral ruxolitinib dosing on the basis of their age at the start of treatment: those aged 12 years to younger than 18 years received 10 mg twice daily (age ≥12 to <18 years group), those aged 6 years to younger than 12 years (age ≥6 to <12 years group) received 5 mg twice daily, and those aged 2 years to younger than 6 years received 4 mg/m2 twice daily (age ≥2 to <6 years group). Treatment was to be administered in 28-day cycles for approximately 36 months, alongside supportive treatment per institutional guidelines. The primary activity endpoint was overall response rate at cycle 7 day 1. Activity and safety analyses are reported in the full analysis set, which included all patients who received at least one dose of ruxolitinib. Here we report the prespecified interim analysis, scheduled to occur after all patients had completed 1 year of treatment or discontinued treatment, and the results for the primary endpoint evaluation reported here is to be considered final. This study is registered with ClinicalTrials.gov, NCT03774082, enrolment is complete, and the study is ongoing. FINDINGS: Between May 20, 2020, and Sept 17, 2021, 48 patients were screened, of whom 45 were enrolled and received at least one dose of study drug (median age was 11·0 years [IQR 7·2-14·3], 16 [36%] were female, 29 [64%] were male, 21 [47%] were White, one [2%] was Black or African American, 23 [51%] were Asian, 17 [38%] were treatment-naive, 28 [62%] were corticosteroid-refractory). As of data cutoff (Oct 19, 2022), after a median ruxolitinib exposure of 55·1 weeks (IQR 13·1-75·3), the overall response rate at cycle 7 day 1 was 40·0% (18 of 45; 90% CI 27·7-53·3), with responses seen in seven (41%) of 17 treatment-naive patients and 11 (39%) of 28 corticosteroid-refractory patients. The most common treatment-related adverse events of grade 3 or worse were neutropenia (eight [18%] of 45) and thrombocytopenia (six [13%]). Seven (16%) patients had grade 3 or worse serious treatment-related adverse events; the most common was hyponatraemia (two [4%] of 45). Three (7%) patients died while on-treatment (within 30 days of treatment discontinuation), one due to Aspergillus infection, one due to septic shock, and one due to acute respiratory distress syndrome; none were considered to be related to study drug. INTERPRETATION: Pending final analysis, this study suggests that ruxolitinib is active and well tolerated in both treatment-naive and corticosteroid-refractory patients aged 2 years to younger than 18 years with chronic GVHD, thereby supporting its use in this patient population. The safety profile of ruxolitinib in this patient population is consistent with that of adults. Final analysis of this study will provide further information on the long-term benefits of ruxolitinib in children with chronic GVHD. FUNDING: Novartis.

Functional Antagonism of Junctional Adhesion Molecule-A (JAM-A), Overexpressed in Breast Ductal Carcinoma In Situ (DCIS), Reduces HER2-Positive Tumor Progression.

Breast ductal carcinoma in situ (DCIS) is clinically challenging, featuring high diagnosis rates and few targeted therapies. Expression/signaling from junctional adhesion molecule-A (JAM-A) has been linked to poor prognosis in invasive breast cancers, but its role in DCIS is unknown. Since progression from DCIS to invasive cancer has been linked with overexpression of the human epidermal growth factor receptor-2 (HER2), and JAM-A regulates HER2 expression, we evaluated JAM-A as a therapeutic target in DCIS. JAM-A expression was immunohistochemically assessed in patient DCIS tissues. A novel JAM-A antagonist (JBS2) was designed and tested alone/in combination with the HER2 kinase inhibitor lapatinib, using SUM-225 cells in vitro and in vivo as validated DCIS models. Murine tumors were proteomically analyzed. JAM-A expression was moderate/high in 96% of DCIS patient tissues, versus 23% of normal adjacent tissues. JBS2 bound to recombinant JAM-A, inhibiting cell viability in SUM-225 cells and a primary DCIS culture in vitro and in a chick embryo xenograft model. JBS2 reduced tumor progression in in vivo models of SUM-225 cells engrafted into mammary fat pads or directly injected into the mammary ducts of NOD-SCID mice. Preliminary proteomic analysis revealed alterations in angiogenic and apoptotic pathways. High JAM-A expression in aggressive DCIS lesions and their sensitivity to treatment by a novel JAM-A antagonist support the viability of testing JAM-A as a novel therapeutic target in DCIS.

Understanding online teaching effectiveness: Nursing student and faculty perspectives.

BACKGROUND: Online teaching has expanded over the past few decades, particularly during the COVID-19 pandemic. However, characteristics of online teaching effectiveness and quality remain understudied. PURPOSE: This study examined perceptions of online teaching effectiveness from nursing faculty and student perspectives. METHODS: The findings presented are from phase 1 of a three-phase, mixed methods research project. In this phase, a qualitative descriptive design was used to analyze data obtained from focus group interview sessions. A purposive sampling of faculty (N = 15) and students (N = 17) from one midwestern, public university participated in five focus groups. RESULTS: Seven themes emerged through qualitative data analysis of faculty focus group data. Student focus groups yielded six themes. Faculty and students identified challenges and strategies for effective online teaching. Student and faculty perceptions of online teaching effectiveness aligned for many themes. CONCLUSION: Study findings have distinct implications for nursing education. Identifying the characteristics of online teaching effectiveness provides the foundation for establishing tangible constructs and robust evaluation, broadening the impact on learning outcomes, faculty development, and educational practice.

Client Violence Against Youth Care Workers: Findings of an Exploratory Study of Workforce Issues in Residential Treatment.

Residential treatment centers (RTCs) for youth are plagued by high turnover of youth care workers who provide round-the-clock treatment and supervision to youth with severe affective and behavioral problems. This article presents findings from a 15-month ethnographic study of workforce issues in one RTC related to youth care workers' exposure to client violence (CV). Findings are based on 65 semistructured interviews and 490 hours of participant observation with consenting employees. Participants reported CV incidents, including punching, kicking, biting, hair pulling, choking, threats or assaults with a weapon, and other physical and sexualized violence. Workers viewed CV as an inevitable aspect of youth care work that could be reduced-though not eliminated-through proper use of de-escalation and behavior management techniques. Participants reported that exposure to CV sometimes resulted in serious physical injury and/or missed work, as well as substance abuse, anxiety, sleep disturbance, and memory loss. Participants reported that CV was the most difficult part of their jobs and cited it as a reason for leaving or wishing to leave youth care work. We conceptualize youth care workers in RTCs as a vulnerable class whose biopsychosocial well-being must be protected to better serve the vulnerable youth in their care. To that end, we suggest directions for future research on CV in residential treatment and propose measures RTCs can take immediately to better understand and prevent CV in their organizations.

Stall the Fall: Training Non-Clinical Caregivers to Prevent Falls in Community-Dwelling Older Adults.

Fall injuries are the leading cause of injury death in older adults, yet despite this, health-care providers do not routinely incorporate fall prevention into practice. A fall prevention training program was developed for non-clinical caregivers serving community-dwelling older adults using the CDC's STEADI tool. The project outcomes revealed statistically significant increases in items related to knowledge and confidence in fall risk and assessment. Findings could guide the development of fall prevention training programs targeted at non-clinical caregivers to community-dwelling older adults.

Exercise-based interventions for post-stroke social participation: A systematic review and network meta-analysis.

BACKGROUND: Resuming participation in society is an important goal of post-stroke rehabilitation. Exercise-based interventions have been shown to be effective non-pharmacological methods for improving social participation in post-stroke survivors, however it is unclear what the most effective types of exercise interventions are. OBJECTIVE: To assess the comparative effects and ranks of all exercise-based interventions in improving social participations in patients after a stroke. METHODS: A random-effects network meta-analysis was performed to identify evidence from relevant randomized control trials. We searched MEDLINE, CINAHL, EMBASE, PsycINFO, CINHAL, Cochrane Library, AMED, SPORTDiscus, Web of Science and Clinical Trials.gov from their earliest records to January 2020. Included trials must include at least one types of exercise for patients with stroke. The primary e was social participation. Bias will be assessed according to the revised Cochrane risk of bias tool. Data were analysed using Stata v14.0. Registration number of this study is CRD42020152523. RESULTS: A total of 16 randomized control trials involving 1704 patients and 12 intervention arms were included in our study. We performed three subgroup analyses divided based on follow up time (1 to <6 months post-treatment, and ≥6 months post-treatment), and intervention adherence. Based on the ranking probabilities, motor relearning programme was ranked as the most effective among all exercise interventions (surface under cumulative ranking curve values [SUCRCV]: 95.6%, standardized mean difference [SMD]: 2.72, 95% confidence interval [CI]: 1.76 to 3.69) in overall and short-term treatment efficacy. In the long-term subgroup, home-based combined exercise ranked the best for the efficacy of social participation improvements among stroke survivors (SUCRCV: 71.8%, SMD: -0.23, 95% CI: -0.61 to 0.15). In the analysis of all interventions with adherence of >90%, cognitive-based exercise ranked the best (SUCRCV: 100%, SMD: 2.64, 95% CI: 1.62 to 3.66). CONCLUSIONS: Interventions that emerged with the highest ranks in our analysis might be considered in practice when resources allow. More large, well-designed multicentre trials are needed to support the conclusion of this study.

Effectiveness of Social Cognitive Theory-Based Interventions for Glycemic Control in Adults With Type 2 Diabetes Mellitus: Protocol for a Systematic Review and Meta-Analysis.

BACKGROUND: For those living with type 2 diabetes mellitus (T2DM), failing to engage in self-management behaviors leads to poor glycemic control. Social cognitive theory (SCT) has been shown to improve health behaviors by altering cognitive processes and increasing an individual's belief in their ability to accomplish a task. OBJECTIVE: We aim to present a protocol for a systematic review and meta-analysis to systematically identify, evaluate, and analyze the effect of SCT-based interventions to improve glycemic control in adults with T2DM. METHODS: This protocol follows the 2009 Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines. Data sources will include PubMed, Cumulative Index to Nursing and Allied Health Literature (CINAHL), PsychINFO, Cochrane Library, and Web of Science, and data will be reviewed with the use of customized text mining software. Studies examining SCT-based behavioral interventions for adults diagnosed with T2DM in randomized controlled trials located in the outpatient setting will be included. Intervention effectiveness will be compared with routine care. Screening and data collection will be performed in multiple stages with three reviewers as follows: (1) an independent review of titles/abstracts, (2) a full review, and (3) data collection with alternating teams of two reviewers for disputes to be resolved by a third reviewer. Study quality and risk of bias will be assessed by three reviewers using the Cochrane risk of bias tool. Standardized mean differences will be used to describe the intervention effect sizes with regard to self-efficacy and diabetes knowledge. The raw mean difference of HbA1c will be provided in a random effects model and presented in a forest plot. The expected limitations of this study are incomplete data, the need to contact authors, and analysis of various types of glycemic control measures accurately within the same data set. RESULTS: This protocol was granted institutional review board exemption on October 7, 2019. PROSPERO registration (ID: CRD42020147105) was received on April 28, 2020. The review began on April 29, 2020. The results of the review will be disseminated through conference presentations, peer-reviewed journals, and meetings. CONCLUSIONS: This systematic review will appraise the effectiveness of SCT-based interventions for adults diagnosed with T2DM and provide the most effective interventions for improving health behaviors in these patients. TRIAL REGISTRATION: PROSPERO CRD42020147105; https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=147105. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): PRR1-10.2196/17148.

The use of faculty policy teams for advancing policy advocacy and colleagueship.

Policy changes that impact nursing occur at multiple levels. The scope and pace of policy changes make it impossible for one faculty member to fill the role of policy advocate. Faculty are frequently reticent to participate, yet, policy work can be very rewarding for faculty. When engaged in policy advocacy, nursing faculty can be a valuable resource to the university, to legislators, and to other stakeholders. This article discusses the team approach to policy advocacy activity and outlines key steps in the policy process. Strategies for overcoming barriers when merging academic and advocacy responsibilities are identified. An example of a college of nursing faculty policy team that utilized nursing presence and their combined intellectual, social, and political capital is provided. In this example, the policy team influences policy discussions on issues impacting both the university community and citizens throughout the state. The strategies provided and the policy process steps discussed are applicable to policy changes at the local, state, and federal levels. Nursing faculty are positioned to engage students, alumni, practice leaders, and community stakeholders in interdisciplinary and transdisciplinary efforts that influence policy initiatives.

Neoadjuvant neratinib promotes ferroptosis and inhibits brain metastasis in a novel syngeneic model of spontaneous HER2+ve breast cancer metastasis.

BACKGROUND: Human epidermal growth factor receptor-2 (HER2)-targeted therapies prolong survival in HER2-positive breast cancer patients. Benefit stems primarily from improved control of systemic disease, but up to 50% of patients progress to incurable brain metastases due to acquired resistance and/or limited permeability of inhibitors across the blood-brain barrier. Neratinib, a potent irreversible pan-tyrosine kinase inhibitor, prolongs disease-free survival in the extended adjuvant setting, and several trials evaluating its efficacy alone or combination with other inhibitors in early and advanced HER2-positive breast cancer patients are ongoing. However, its efficacy as a first-line therapy against HER2-positive breast cancer brain metastasis has not been fully explored, in part due to the lack of relevant pre-clinical models that faithfully recapitulate this disease. Here, we describe the development and characterisation of a novel syngeneic model of spontaneous HER2-positive breast cancer brain metastasis (TBCP-1) and its use to evaluate the efficacy and mechanism of action of neratinib. METHODS: TBCP-1 cells were derived from a spontaneous BALB/C mouse mammary tumour and characterised for hormone receptors and HER2 expression by flow cytometry, immunoblotting and immunohistochemistry. Neratinib was evaluated in vitro and in vivo in the metastatic and neoadjuvant setting. Its mechanism of action was examined by transcriptomic profiling, function inhibition assays and immunoblotting. RESULTS: TBCP-1 cells naturally express high levels of HER2 but lack expression of hormone receptors. TBCP-1 tumours maintain a HER2-positive phenotype in vivo and give rise to a high incidence of spontaneous and experimental metastases in the brain and other organs. Cell proliferation/viability in vitro is inhibited by neratinib and by other HER2 inhibitors, but not by anti-oestrogens, indicating phenotypic and functional similarities to human HER2-positive breast cancer. Mechanistically, neratinib promotes a non-apoptotic form of cell death termed ferroptosis. Importantly, metastasis assays demonstrate that neratinib potently inhibits tumour growth and metastasis, including to the brain, and prolongs survival, particularly when used as a neoadjuvant therapy. CONCLUSIONS: The TBCP-1 model recapitulates the spontaneous spread of HER2-positive breast cancer to the brain seen in patients and provides a unique tool to identify novel therapeutics and biomarkers. Neratinib-induced ferroptosis provides new opportunities for therapeutic intervention. Further evaluation of neratinib neoadjuvant therapy is warranted.

Antibiotic Tetrocarcin-A Down-regulates JAM-A, IAPs and Induces Apoptosis in Triple-negative Breast Cancer Models.

BACKGROUND/AIM: Triple-negative breast cancers (TNBC) lack expression of three important receptors, and have limited treatment options. High expression of junctional adhesion molecule-A (JAM-A) has been linked with aggressive tumor phenotypes including TNBC. This study aimed to evaluate the bioactivity of a JAM-A-down-regulating compound, Tetrocarcin-A, in TNBC. MATERIALS AND METHODS: TNBC cell viability, colony formation and xenograft growth were examined in Tetrocarcin-A-treated HCC38 human cells, 4T1 mouse cells or patient-derived primary cells. Protein expression of cell fate signaling effectors was examined by immunoblotting (versus transient JAM-A gene silencing). Apoptotic pathways were investigated in parallel. RESULTS: Tetrocarcin-A reduced TNBC cell viability in vitro and in an in ovo/semi-in vivo xenograft model. Tetrocarcin-A-induced JAM-A down-regulation and reduced ERK phosphorylation, followed by c-FOS phosphorylation on its transcription-regulating residue, which down-regulated several inhibitor of apoptosis (IAP) proteins and induced caspase-dependent intrinsic pathway of apoptosis. CONCLUSION: Tetrocarcin-A merits further investigation as a novel anti-tumor agent in TNBC.

Intensive oversight of youth residential treatment: Staff perspectives on the New York State Justice Center for the Protection of People with Special Needs.

Youth care workers in U.S. residential treatment centers (RTCs) provide 24-h care to youth whose significant psychosocial needs cannot be managed in a less restrictive setting. They have sometimes abused or neglected youth in their care. This study investigates staff perspectives on a new form of intensive oversight developed in New York State to prevent maltreatment of youth in care facilities. It asks: How does intensive oversight and investigation mandated by a state-run agency for the protection of people in care affect residential youth care workers in RTCs? Derived from a 15-month ethnographic study of an RTC serving a child welfare population conducted in 2015 and 2016, these results suggest that intensive oversight may have unanticipated consequences for RTCs, the youth care workforce, and youth in care. Consistent with other studies of regulation and surveillance in risk societies, participants reported that fear of prolonged and intimidating investigations, false allegations, and unavoidable violations of policy negatively affected their practice and contributed to staff turnover. Organizational consequences included serious staffing challenges and increased costs of overtime and administrative management of compliance. Some participants suggested that the form of intensive oversight studied here may have reduced the quality of care received by youth by disrupting therapeutic relationships, causing youth to be cared for by unfamiliar workers, and compelling workers to act defensively to prevent allegations rather than in the best interest of youth. We suggest that, under conditions of intensive oversight, youth care workers, like their clients, should be considered an at risk population whose well being is essential for the provision of high quality care. We conclude with modest recommendations to organizations and jurisdictions using or considering intensive oversight practices to protect the rights and safety of youth in RTCs.

Moral People or Moral Projects? Worker Altruism in Youth Residential Treatment.

Paraprofessional youth care workers in residential treatment centers (RTCs) are responsible for the everyday care, supervision, and treatment of youth with serious behavioral and mental health challenges. Turnover rates among this poorly paid workforce are high, and it is not known why individuals seek and maintain youth care work despite its significant challenges. Following anthropologists who study morality as situated practice, we investigate the role of altruism in recruiting and retaining workers in RTCs. We ask: How do managers and youth care workers understand altruism and its role in youth care work and what are the consequences of those understandings? Through organizational ethnography of an RTC, we show that workers and management understood altruism differently. Managers viewed altruism as an inherent trait of some and attributed turnover to its lack. Although workers sometimes enacted this script, they understood themselves as engaged in far more complex situated moral projects in which altruism was only one part. We demonstrate political effects of these differing understandings of altruism, namely, that management deflected institutional critique by viewing it as a sign of workers' immorality. We offer modest recommendations for RTCs seeking to recruit and retain competent youth care workers and address potential new directions for moral anthropology of organizations.

Cleavage of the extracellular domain of junctional adhesion molecule-A is associated with resistance to anti-HER2 therapies in breast cancer settings.

BACKGROUND: Junctional adhesion molecule-A (JAM-A) is an adhesion molecule whose overexpression on breast tumor tissue has been associated with aggressive cancer phenotypes, including human epidermal growth factor receptor-2 (HER2)-positive disease. Since JAM-A has been described to regulate HER2 expression in breast cancer cells, we hypothesized that JAM-dependent stabilization of HER2 could participate in resistance to HER2-targeted therapies. METHODS: Using breast cancer cell line models resistant to anti-HER2 drugs, we investigated JAM-A expression and the effect of JAM-A silencing on biochemical/functional parameters. We also tested whether altered JAM-A expression/processing underpinned differences between drug-sensitive and -resistant cells and acted as a biomarker of patients who developed resistance to HER2-targeted therapies. RESULTS: Silencing JAM-A enhanced the anti-proliferative effects of anti-HER2 treatments in trastuzumab- and lapatinib-resistant breast cancer cells and further reduced HER2 protein expression and Akt phosphorylation in drug-treated cells. Increased epidermal growth factor receptor expression observed in drug-resistant models was normalized upon JAM-A silencing. JAM-A was highly expressed in all of a small cohort of HER2-positive patients whose disease recurred following anti-HER2 therapy. High JAM-A expression also correlated with metastatic disease at the time of diagnosis in another patient cohort resistant to trastuzumab therapy. Importantly, cleavage of JAM-A was increased in drug-resistant cell lines in conjunction with increased expression of ADAM-10 and -17 metalloproteases. Pharmacological inhibition or genetic silencing studies suggested a particular role for ADAM-10 in reducing JAM-A cleavage and partially re-sensitizing drug-resistant cells to the anti-proliferative effects of HER2-targeted drugs. Functionally, recombinant cleaved JAM-A enhanced breast cancer cell invasion in vitro and both invasion and proliferation in a semi-in vivo model. Finally, cleaved JAM-A was detectable in the serum of a small cohort of HER2-positive patients and correlated significantly with resistance to HER2-targeted therapy. CONCLUSIONS: Collectively, our data suggest a novel model whereby increased expression and cleavage of JAM-A drive tumorigenic behavior and act as a biomarker and potential therapeutic target for resistance to HER2-targeted therapies.

Dog Ownership and Training Reduces Post-Traumatic Stress Symptoms and Increases Self-Compassion Among Veterans: Results of a Longitudinal Control Study.

Objectives: The aims of this study were to measure the potential impact of a therapeutic dog ownership and training program for Veterans with symptoms of post-traumatic stress. Design: The study used a quasi-experimental design with two cohorts of Veterans-a dog owner-trainer intervention and a wait list control group. Participants completed baseline and 12-month follow-up assessments. Setting: Clear Path for Veterans, a nonclinical, open recreation facility whose mission is to support Veterans and their families in the reintegration process after military service. Subjects: Participants (n = 48) were either enrolled in the veterans therapeutic dog owner-trainer program (Dogs2Vets) or were placed in the wait list control group. Intervention: Veterans were enrolled in the Dogs2Vets program, a 12-month structured dog owner-trainer program that engages veterans in the training and care of a dog that they ultimately adopt. The Dogs2Vets Program focuses on the healing aspects of the human-animal bond. Outcome measures: PTSD Checklist, Military Version (PCL-M), perceived stress scale, self-compassion scale (SCS) composite, and SCS subscales for isolation and self-judgment. Results: Veterans participating in the Dogs2Vets owner-trainer program experienced significant reductions in symptoms of post-traumatic stress, perceived stress, isolation, and self-judgment accompanied by significant increases in self-compassion. In contrast there were no significant improvements in these measures among veterans in the wait list control group. Qualitative data reinforced the statistical findings with themes of decreased isolation, unconditional acceptance and companionship, and a renewed sense of safety and purpose from their relationships with their dogs. Conclusion: Veterans benefit significantly from dog ownership in combination with a structured dog training program. Not only do they experience significant decreases in stress and post-traumatic stress symptoms but also they experience less isolation and self-judgment while also experiencing significant improvements in self-compassion.

Diterpenoid natural compound C4 (Crassin) exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species.

PURPOSE: Triple-negative breast cancers (TNBC) lack expression of three common cell surface receptors, i.e., estrogen receptor (ER), progesterone receptor (PR) and human epidermal growth factor receptor-2 (HER2). Accordingly, TNBCs are associated with fewer treatment options and a relatively poor prognosis. Having screened a National Cancer Institute natural compound library, the purpose of this study was to investigate the bioactivity of compound C4 (Crassin) in TNBC cells. METHODS: Cell viability assays were performed in two TNBC cell lines, MDA-MB-231 and 4T1, following C4 treatment in the presence or absence of the antioxidant N-acetyl-L-cysteine (NAC). Phosphorylation of Akt and ERK was assessed by Western blotting. Apoptosis, necrosis, autophagy, necroptosis, ferroptosis and cytostasis assays were performed to explain viability deficits resulting from C4 exposure. RESULTS: We found that the viability of the TNBC cells tested decreased in a concentration- and time-dependent fashion following C4 treatment. This decrease coincided with an unexpected increase in the expression of the cell survival effectors pAkt and pERK. In addition, we found that both the decreased cell viability and the increased pAkt/pERK levels could be rescued by the antioxidant NAC, suggesting a central role for reactive oxygen species (ROS) in the mechanism of action of C4. Necrosis, apoptosis, necroptosis and ferroptosis could be ruled out as cell death mechanisms. Instead, we found that C4 induced cytostasis downstream of ROS activation. Finally, we observed a synergistic effect between C4 and the chemotherapeutic drug doxorubicin in TNBC cells. CONCLUSIONS: From our in vitro data we conclude that C4 exerts cytostatic effects on triple-negative breast cancer cells via a pathway involving reactive oxygen species. Its potential value in combination with cytotoxic therapies merits deeper investigation in pre-clinical models.

Nurse Educator Perceptions of the Importance of Relationship in Online Teaching and Learning.

The purpose of this study was to understand the perceptions of teaching nursing students in online environments as experienced by nursing educators who have been teaching online for a minimum of 2 years. The study used an interview-based qualitative descriptive design. Semistructured interviews with 10 full-time nurse educators were conducted. The participants represented a range of ranks and teaching experience. Analysis involved a constant comparative process of initial and focused coding. Relationships were important to these nurse educators, and there was an interconnected nature among (a) student engagement and learning, (b) "knowing students," and (c) helping students meet their needs. Although different in how they experienced these elements, they seemed to share a sense that you have to know your students to help them meet their needs, and that you have to help them meet their needs so that they can learn, and building relationships within the online environment is key to all if this. Relationships are the heart of nursing and, for these nurse educators, a key aspect of nursing education. Having a strong relationship between nurse educators and nursing students supports student engagement in learning online. With continually increasing online nurse education, understanding these relationships is important to improve nursing education and consequently improve nursing practice.

The three-dimensional kinematics and spatiotemporal parameters of gait in 6-10 year old typically developed children in the Cape Metropole of South Africa - a pilot study.

BACKGROUND: Functional gait is an integral part of life, allowing individuals to function within their environment and participate in activities of daily living. Gait assessment forms an essential part of a physical examination and can help screen for physical impairments. No three-dimensional (3D) gait analysis studies of children have been conducted in South Africa. South African gait analysis laboratory protocols and procedures may differ from laboratories in other countries, therefore a South African data base of normative values is required to make a valid assessment of South African children's gait. The primary aim of this study is to describe joint kinematics and spatiotemporal parameters of gait in South African children to constitute a normative database and secondly to assess if there are age related differences in aforementioned gait parameters. METHODS: A descriptive study was conducted. Twenty-eight typically developing children were conveniently sampled from the Cape Metropole in the Western Cape, South Africa. The 3D lower limb kinematics and spatiotemporal parameters of gait were analyzed. The lower limb Plug-in-Gait (PIG) marker placement was used. Participants walked bare foot at self-selected speed. Means and standard deviations (SD) were calculated for all spatiotemporal and kinematic outcomes. Children were sub-divided into two groups (Group A: 6-8 years and Group B: 9-10 years) for comparison. RESULTS: A significant difference between the two sub-groups for the normalized mean hip rotation minimum values (p = 0.036) was found. There was no significant difference between the sub-groups for any other kinematic parameter or when comparing the normalized spatiotemporal parameters. CONCLUSION: The study's findings concluded that normalized spatiotemporal parameters are similar between the two age groups and are consistent with the values of children from other countries. The joint kinematic values showed significant differences for hip rotation, indicating that older children had more external rotation than younger children.

Worker Perspectives on Contemporary Milieu Therapy: A Cross-Site Ethnographic Study.

The term "milieu therapy" (MT) is commonly used in mental health literatures. However, because MT has historically encompassed a wide range of practices, it has invited the criticism that it is simply an attractive theoretical packaging of the time clients spend between other specified interventions, such as individual and group therapies. Some have suggested that, because of its conceptual ambiguity, MT should be abandoned altogether. Despite these challenges, MT endures as a common approach to social work practice in a range of clinical settings. This article describes a study that used ethnography to investigate the perspectives of workers from two mental health organizations that claim to provide MT. By analyzing four themes common to both sites, this article brings exploratory empirical findings to bear on the question of what constitutes MT in contemporary mental health organizations. Participants reported that (a) everything in the physical and social milieu has the potential to affect therapeutic change; (b) the milieu itself functions as a therapeutic agent; (c) the milieu provides a context for modeling and practicing desired behaviors; and (d) MT is a principle-based ethos, rather than a set of specific interventions. Implications of these findings for social work research, practice, and funding are discussed.

Dynamic interplay between adhesion surfaces in carcinomas: Cell-cell and cell-matrix crosstalk.

Cell-cell and cell-matrix signaling and communication between adhesion sites involve mechanisms which are required for cellular functions during normal development and homeostasis; however these cellular functions and mechanisms are often deregulated in cancer. Aberrant signaling at cell-cell and cell-matrix adhesion sites often involves downstream mediators including Rho GTPases and tyrosine kinases. This review discusses these molecules as putative mediators of cellular crosstalk between cell-cell and cell-matrix adhesion sites, in addition to their attractiveness as therapeutic targets in cancer. Interestingly, inter-junctional crosstalk mechanisms are frequently typified by the way in which bacterial and viral pathogens opportunistically infect or intoxicate mammalian cells. This review therefore also discusses the concept of learning from pathogen-host interaction studies to better understand coordinated communication between cell-cell and cell-matrix adhesion sites, in addition to highlighting the potential therapeutic usefulness of exploiting pathogens or their products to tap into inter-junctional crosstalk. Taken together, we feel that increased knowledge around mechanisms of cell-cell and cell-matrix adhesion site crosstalk and consequently a greater understanding of their therapeutic targeting offers a unique opportunity to contribute to the emerging molecular revolution in cancer biology.

Functional and molecular characterisation of EO771.LMB tumours, a new C57BL/6-mouse-derived model of spontaneously metastatic mammary cancer.

The translation of basic research into improved therapies for breast cancer patients requires relevant preclinical models that incorporate spontaneous metastasis. We have completed a functional and molecular characterisation of a new isogenic C57BL/6 mouse model of breast cancer metastasis, comparing and contrasting it with the established BALB/c 4T1 model. Metastatic EO771.LMB tumours were derived from poorly metastatic parental EO771 mammary tumours. Functional differences were evaluated using both in vitro assays and spontaneous metastasis assays in mice. Results were compared to non-metastatic 67NR and metastatic 4T1.2 tumours of the 4T1 model. Protein and transcript levels of markers of human breast cancer molecular subtypes were measured in the four tumour lines, as well as p53 (Tp53) tumour-suppressor gene status and responses to tamoxifen in vivo and in vitro. Array-based expression profiling of whole tumours identified genes and pathways that were deregulated in metastatic tumours. EO771.LMB cells metastasised spontaneously to lung in C57BL/6 mice and displayed increased invasive capacity compared with parental EO771. By immunohistochemical assessment, EO771 and EO771.LMB were basal-like, as was the 4T1.2 tumour, whereas 67NR had a luminal phenotype. Primary tumours from all lines were negative for progesterone receptor, Erb-b2/Neu and cytokeratin 5/6, but positive for epidermal growth factor receptor (EGFR). Only 67NR displayed nuclear estrogen receptor alpha (ERα) positivity. EO771 and EO771.LMB expressed mutant p53, whereas 67NR and 4T1.2 were p53-null. Integrated molecular analysis of both the EO771/EO771.LMB and 67NR/4T1.2 pairs indicated that upregulation of matrix metalloproteinase-3 (MMP-3), parathyroid hormone-like hormone (Pthlh) and S100 calcium binding protein A8 (S100a8) and downregulation of the thrombospondin receptor (Cd36) might be causally involved in metastatic dissemination of breast cancer.