Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model.

Introduction: Chemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now. Methods: We used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses. Results: We identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors. Discussion: Conclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC.

Safe transport of children with disabilities and medical conditions: Caregiver experiences.

BACKGROUND: Road vehicle transportation is essential to support community access and participation for all children. However, little is known about the transport patterns of children with disabilities and medical conditions and their caregivers' experiences supporting them to be transported safely in road vehicles in Australia. AIM: To understand the transport needs of children with disabilities and medical conditions and the transport needs of their caregivers. MATERIALS AND METHODS: A large-scale national survey was undertaken online to explore the experiences and perspectives of 193 caregivers, identifying the challenges and needs associated with providing and supporting safe road transportation for their children. RESULTS: Caregivers believed their child was missing out on participating in everyday life due to their transportation needs, with caregivers experiencing multiple challenges and barriers to transporting their child safely. CONCLUSIONS AND SIGNIFICANCE: There is a need to provide knowledge and support to caregivers who are primarily responsible for the safe transportation of their children with disabilities and medical conditions.

Preventing suicide in post-secondary students: a scoping review of suicide prevention programs.

Suicide among students enrolled in post-secondary education, including university or college, is a major public health concern. Previous research has examined the effectiveness of suicide prevention programs for this population. However, the effective elements of these interventions remain unknown. This study reviewed the literature on suicide prevention programs for post-secondary students, exploring and identifying those elements likely contributing to their effectiveness. A scoping review process was undertaken exploring suicide prevention programs for post-secondary students. Methodological quality of the articles was assessed, and content analysis was used to explore the programs and their effective elements. Twenty seven articles were included in this review, covering a variety of approaches. Gatekeeper training programs were the most common type of suicide prevention program. Programs for post-secondary students may be effective in improving student rates of engagement with mental health services and were associated with greater knowledge, and help-seeking attitudes and behaviors, and gatekeeper-related outcomes. While evidence was found supporting the effectiveness of some interventions such as gatekeeper programs to influence suicide-related knowledge, attitudes and behaviour, further and more rigorous research surrounding suicide prevention programs for post-secondary students is required, with a particular emphasis on student outcomes.

The efficacy of the "Talk-to-Me" suicide prevention and mental health education program for tertiary students: a crossover randomised control trial.

Despite suicide ideation being one of the most frequently reported health issues impacting tertiary students, there is a paucity of research evaluating the efficacy of preventive interventions aimed at improving mental health outcomes for students studying at two tertiary institutes. The current study evaluated the efficacy of the "Talk-to-Me" Mass Open Online Course (MOOC) in improving tertiary students' abilities to support the mental health of themselves and their peers via a randomised controlled trial design, comparing them to a waitlist control group. Overall, 129 tertiary students (M = 25.22 years, SD = 7.43; 80% female) undertaking a health science or education course at two Western Australian universities were randomly allocated to either "Talk-to-Me" (n = 66) or waitlist control (n = 63) groups. The participants' responses to suicidal statements (primary outcome), knowledge of mental health, generalised self-efficacy, coping skills, and overall utility of the program (secondary outcomes) were collected at three timepoints (baseline 10-weeks and 24-weeks from baseline). Assessment time and group interaction were explored using a random-effects regression model, examining changes in the primary and secondary outcomes. Intention-to-treat analysis (N = 129) at 10-weeks demonstrated a significant improvement in generalised self-efficacy for "Talk-to-Me" compared to the control group (ES = 0.36, p = .04), with only the "Talk-to-Me" participants reporting increased knowledge in responding to suicidal ideation (primary outcome). This change was sustained for 24 weeks. Findings provide preliminary evidence suggesting that the "Talk-to-Me" MOOC can effectively improve tertiary students' mental health and knowledge of how to support themselves and others in distress. ACTRN12619000630112, registered 18-03-2019, anzctr.org.au.

Considerations of the built environment for autistic individuals: A review of the literature.

LAY ABSTRACT: Factors related to the interiors of buildings, including the layout of rooms, colours, smells, noises, temperature, ventilation, colour and clutter, among other things, can change the way we interact with our environment and the people around us. Autistic individuals can have differences in processing sensory information and may find aspects of the built environment (BE) over-whelming and difficult to navigate. We reviewed the existing literature exploring the BE and autism. This study found that it is possible to make changes to the BE to create more inclusive and friendly environments for everyone, including autistic individuals. Findings from this study provide clear recommendations that can be used by interior designers, architects, builders, and clinical practitioners to make a positive difference. Key recommendations include using simple spatial layouts, compartmentalising and zoning spaces into specific activity sections and providing retreat spaces. The thoughtful placement of windows and blinds and the installation of dimmable lights, for example, will allow users to manage or reduce sensory over-stimulation caused by lights. Similarly, we recommend creating soundproofing and sound absorbent materials to reduce background noise and sound levels. We also recommend using neutral or simple colour palettes and restrained use of patterns. Finally, and most importantly, the BE needs to be flexible and adaptable to meet the unique needs of each person. This study provides a starting point for design guidelines and recommendations towards making a difference to the everyday experiences of the interiors of buildings.

At the Intersection of Cardiology and Oncology: TGFß as a Clinically Translatable Therapy for TNBC Treatment and as a Major Regulator of Post-Chemotherapy Cardiomyopathy.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. While there is immense focus on the development of novel therapies for TNBC treatment, a persistent and critical issue is the rate of heart failure and cardiomyopathy, which is a leading cause of mortality and morbidity amongst cancer survivors. In this review, we highlight mechanisms of post-chemotherapeutic cardiotoxicity exposure, evaluate how this is assessed clinically and highlight the transforming growth factor-beta family (TGF-ß) pathway and its significance as a mediator of cardiomyopathy. We also highlight recent findings demonstrating TGF-ß inhibition as a potent method to prevent cardiac remodeling, fibrosis and cardiomyopathy. We describe how dysregulation of the TGF-ß pathway is associated with negative patient outcomes across 32 types of cancer, including TNBC. We then highlight how TGF-ß modulation may be a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations in TNBC models. CSCs are associated with tumorigenesis, metastasis, relapse, resistance and diminished patient prognosis; however, due to plasticity and differential regulation, these populations remain difficult to target and continue to present a major barrier to successful therapy. TGF-ß inhibition represents an intersection of two fields: cardiology and oncology. Through the inhibition of cardiomyopathy, cardiac damage and heart failure may be prevented, and through CSC targeting, patient prognoses may be improved. Together, both approaches, if successfully implemented, would target the two greatest causes of cancer-related morbidity in patients and potentially lead to a breakthrough therapy.

The "Talk-to-Me" MOOC intervention for suicide prevention and mental health education among tertiary students: Protocol of a multi-site cross-over randomised controlled trial.

INTRODUCTION: Mental health problems are common among tertiary education students, with concerning levels of suicide ideation frequently observed in this population. There is a need for evidence-based mental health education and suicide prevention programs designed to meet the specific needs of these students. The "Talk-to-Me" Mass Open Online Course (MOOC) is a strengths-based mental health education program underpinned by a six-phase model for managing a suicidal crisis. METHODS: To evaluate the efficacy of the "Talk-to-Me" MOOC in improving student knowledge of appropriate responses to suicide crisis via a randomised control trial (RCT) comparing tertiary education health science and education students attending the program to a waitlist control group. Overall, 170 will be screened and randomly allocated to either the "Talk-to-Me" MOOC or a waitlist control group, with data collection occurring at three-time points (baseline, 10-weeks and 24-weeks from baseline) over one year. The primary outcome will be participants' knowledge and responses to suicidal statements as measured by the Suicide Intervention Response Inventory. Secondary outcomes will be knowledge of mental health and coping skills as well as the overall utility of the program. CONCLUSIONS: This pragmatic RCT will demonstrate the efficacy of the "Talk-to-Me" MOOC in improving the students' ability to respond to suicidal and mental health concerns compared to the waitlist group. This design will enable rigorous evaluation of the "Talk-to-Me" MOOC, contributing to a greater understanding of the online-delivered safe-paced suicide prevention programs for tertiary students. Australian New Zealand Clinical Trials Registry (ANZCTR): #12619000630112.

Clinically Translatable Approaches of Inhibiting TGF-ß to Target Cancer Stem Cells in TNBC.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that disproportionally accounts for the majority of breast cancer-related deaths due to the lack of specific targets for effective treatments. In this review, we highlight the complexity of the transforming growth factor-beta family (TGF-ß) pathway and discuss how the dysregulation of the TGF-ß pathway promotes oncogenic attributes in TNBC, which negatively affects patient prognosis. Moreover, we discuss recent findings highlighting TGF-ß inhibition as a potent method to target mesenchymal (CD44+/CD24-) and epithelial (ALDHhigh) cancer stem cell (CSC) populations. CSCs are associated with tumorigenesis, metastasis, relapse, resistance, and diminished patient prognosis; however, due to differential signal pathway enrichment and plasticity, these populations remain difficult to target and persist as a major barrier barring successful therapy. This review highlights the importance of TGF-ß as a driver of chemoresistance, radioresistance and reduced patient prognosis in breast cancer and highlights novel treatment strategies which modulate TGF-ß, impede cancer progression and reduce the rate of resistance generation via targeting the CSC populations in TNBC and thus reducing tumorigenicity. Potential TGF-ß inhibitors targeting based on clinical trials are summarized for further investigation, which may lead to the development of novel therapies to improve TNBC patient prognosis.

A triple-drug nanotherapy to target breast cancer cells, cancer stem cells, and tumor vasculature.

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, accounting for the majority of breast cancer-related death. Due to the lack of specific therapeutic targets, chemotherapeutic agents (e.g., paclitaxel) remain the mainstay of systemic treatment, but enrich a subpopulation of cells with tumor-initiating capacity and stem-like characteristics called cancer stem cells (CSCs); thus development of a new and effective strategy for TNBC treatment is an unmet medical need. Cancer nanomedicine has transformed the landscape of cancer drug development, allowing for a high therapeutic index. In this study, we developed a new therapy by co-encapsulating clinically approved drugs, such as paclitaxel, verteporfin, and combretastatin (CA4) in polymer-lipid hybrid nanoparticles (NPs) made of FDA-approved biomaterials. Verteporfin is a drug used in the treatment of macular degeneration and has recently been found to inhibit the Hippo/YAP (Yes-associated protein) pathway, which is known to promote the progression of breast cancer and the development of CSCs. CA4 is a vascular disrupting agent and has been tested in phase II/III of clinical trials. We found that our new three drug-NP not only effectively inhibited TNBC cell viability and cell migration, but also significantly diminished paclitaxel-induced and/or CA4-induced CSC enrichment in TNBC cells, partially through inhibiting the upregulated Hippo/YAP signaling. Combination of verteporfin and CA4 was also more effective in suppressing angiogenesis in an in vivo zebrafish model than single drug alone. The efficacy and application potential of our triple drug-NPs were further assessed by using clinically relevant patient-derived xenograft (PDX) models. Triple drug-NP effectively inhibited the viability of PDX organotypic slide cultures ex vivo and stopped the growth of PDX tumors in vivo. This study developed an approach capable of simultaneously inhibiting bulk cancer cells, CSCs, and angiogenesis.

A randomized pilot study on self-management in head and neck lymphedema.

BACKGROUND: The purpose of this pilot trial was to determine the feasibility of a self-managed lymphedema randomized control trial to test the effectiveness of a head and neck-specific exercise protocol. METHODS: Nine participants were randomized to receive usual treatment provided by an Australian metropolitan teaching hospital (n = 4) or usual treatment with an added head and neck exercise regime (n = 5). Feasibility was assessed through ease of recruitment, adherence, and safety. Lymphedema reduction and quality of life (QOL) data were assessed at baseline (0 week) and follow-up (6 weeks). RESULTS: The study was feasible in terms of safety and participant retention. However, a slow recruitment rate and low adherence may impact future trials. There were no significant differences in lymphedema reduction or QOL between groups. CONCLUSION: This pilot feasibility study demonstrated that a self-management trial can be implemented, however, modifications will be required due to the slow recruitment and poor adherence rates. LEVEL OF EVIDENCE: 1b: Individualized randomized control trial.

Targeting Hypoxia Sensitizes TNBC to Cisplatin and Promotes Inhibition of Both Bulk and Cancer Stem Cells.

Development of targeted therapies for triple-negative breast cancer (TNBC) is an unmet medical need. Cisplatin has demonstrated its promising potential for the treatment of TNBC in clinical trials; however, cisplatin treatment is associated with hypoxia that, in turn, promotes cancer stem cell (CSC) enrichment and drug resistance. Therapeutic approaches to attenuate this may lead to increased cisplatin efficacy in the clinic for the treatment of TNBC. In this report we analyzed clinical datasets of TNBC and found that TNBC patients possessed higher levels of EGFR and hypoxia gene expression. A similar expression pattern was also observed in cisplatin-resistant ovarian cancer cells. We, thus, developed a new therapeutic approach to inhibit EGFR and hypoxia by combination treatment with metformin and gefitinib that sensitized TNBC cells to cisplatin and led to the inhibition of both CD44+/CD24- and ALDH+ CSCs. We demonstrated a similar inhibition efficacy on organotypic cultures of TNBC patient samples ex vivo. Since these drugs have already been used frequently in the clinic; this study illustrates a novel, clinically translatable therapeutic approach to treat patients with TNBC.

The use of wearable technology to measure and support abilities, disabilities and functional skills in autistic youth: a scoping review.

BACKGROUND: Wearable technology (WT) to measure and support social and non-social functioning in Autism Spectrum Disorder (ASD) has been a growing interest of researchers over the past decade. There is however limited understanding of the WTs currently available for autistic individuals, and how they measure functioning in this population. OBJECTIVE: This scoping review explored the use of WTs for measuring and supporting abilities, disabilities and functional skills in autistic youth. METHOD: Four electronic databases were searched to identify literature investigating the use of WT in autistic youth, resulting in a total of 33 studies being reviewed. Descriptive and content analysis was conducted, with studies subsequently mapped to the ASD International Classification of Functioning, Disability and Health Core-sets and the ICF Child and Youth Version (ICF-CY). RESULTS: Studies were predominately pilot studies for novel devices. WTs measured a range of physiological and behavioural functions to objectively measure stereotypical motor movements, social function, communication, and emotion regulation in autistic youth in the context of a range of environments and activities. CONCLUSIONS: While this review raises promising prospects for the use of WTs for autistic youth, the current evidence is limited and requires further investigation.

CSCs in Breast Cancer-One Size Does Not Fit All: Therapeutic Advances in Targeting Heterogeneous Epithelial and Mesenchymal CSCs.

Unlike other breast cancer subtypes, triple-negative breast cancer (TNBC) has no specific targets and is characterized as one of the most aggressive subtypes of breast cancer that disproportionately accounts for the majority of breast cancer-related deaths. Current conventional chemotherapeutics target the bulk tumor population, but not the cancer stem cells (CSCs) that are capable of initiating new tumors to cause disease relapse. Recent studies have identified distinct epithelial-like (E) ALDH+ CSCs, mesenchymal-like (M) CD44+/CD24- CSCs, and hybrid E/M ALDH+/CD44+/CD24- CSCs. These subtypes of CSCs exhibit differential signal pathway regulations, possess plasticity, and respond differently to treatment. As such, co-inhibition of different subtypes of CSCs is key to viable therapy. This review serves to highlight different pathway regulations in E and M CSCs in TNBC, and to further describe their role in disease progression. Potential inhibitors targeting E and/or M CSCs based on clinical trials are summarized for further investigation. Since future research needs to adopt suitable tumor models and take into account the divergence of E and M CSCs for the development of effective treatments, TNBC models for clinically translatable studies are further discussed.

Co-targeting Bulk Tumor and CSCs in Clinically Translatable TNBC Patient-Derived Xenografts via Combination Nanotherapy.

Triple-negative breast cancer (TNBC) accounts disproportionally for the majority of breast cancer-related deaths throughout the world. This is largely attributed to lack of a specific therapy capable of targeting both bulk tumor mass and cancer stem cells (CSC), as well as appropriate animal models to accurately evaluate treatment efficacy for clinical translation. Thus, development of effective and clinically translatable targeted therapies for TNBC is an unmet medical need. We developed a hybrid nanoparticles-based co-delivery platform containing both paclitaxel and verteporfin (PV-NP) to target TNBC patient-derived xenograft (PDX) tumor and CSCs. MRI and IVIS imaging were performed on mice containing PDX tumors to assess tumor vascularity and accumulation of NPs. NF-κB, Wnt, and YAP activities were measured by reporter assays. Mice bearing TNBC PDX tumor were treated with PV-NPs and controls, and tumors progression and CSC subpopulations were analyzed. MRI imaging indicated high vascularization of PDX tumors. IVIS imaging showed accumulation of NPs in PDX tumors. In comparison with control-NPs and free-drug combination, PV-NPs significantly retarded tumor growth of TNBC PDX. PV-NPs simultaneously repressed NF-κB, Wnt, and YAP that have been shown to be crucial for cancer growth, CSC development, and tumorigenesis. In conclusion, NPs containing two clinically used drugs concurrently inhibited NF-κB, Wnt, and YAP pathways and exhibited synergic effects on killing TNBC bulk tumor and CSCs. This combination nanotherapy evaluated with a PDX model may lead to an effective treatment of patients with TNBC.

Carbon dioxide laser treatment in burn-related scarring: A prospective randomised controlled trial.

AIM: To investigate the effect of ablative fractional CO2 laser (AFCO2L) on burns scar appearance and dermal architecture at 6 weeks and up to 3-years post-treatment. METHODS: Twenty adult patients with a burn-related scar were recruited. Inclusion criteria were a minimum scar area of 10 × 10 cm and Vancouver scar scale (VSS) score of >5 and ≥6 months since the time of injury. The region of scar was randomised to treatment/control zones. Treatment zones received 3 standardised laser treatments at 4- to 6-week intervals. All areas of scar received standard scar care. Outcome measures were recorded at baseline, 6-weeks post final treatment and up to 3 years post-treatment. Measures included blinded assessor VSS, Patient Scar Assessment Scale and histological tissue analysis. RESULTS: Nineteen and nine patients completed the short- and long-term studies, respectively. Clinical results revealed improvement in all scar areas over time. There was a statistically significant improvement in pain and itch in the treatment zone compared to the control zone at 6 weeks. Histological data revealed a significant increase in medium-sized collagen fibres at 6 weeks relative to the control site. Sub-group analysis according to scar age revealed greater histological improvement following laser treatment in immature scars relative to more mature scar. CONCLUSIONS: Results demonstrate that 3 treatments of AFCO2L significantly improve scar pain, itch and dermal architecture at 6 weeks post-treatment. Histological results suggest greater potential in treating immature scar. Further investigation into the timing of laser treatment could help assist treatment protocols.

Long-term mental health outcomes after unintentional burns sustained during childhood: a retrospective cohort study.

BACKGROUND: Burns are a devastating injury that can cause physical and psychological issues. Limited data exist on long-term mental health (MH) after unintentional burns sustained during childhood. This study assessed long-term MH admissions after paediatric burns. METHODS: This retrospective cohort study included all children (< 18 years) hospitalised for a first burn (n = 11,967) in Western Australia, 1980-2012, and a frequency matched uninjured comparison cohort (n = 46,548). Linked hospital, MH and death data were examined. Multivariable negative binomial regression modelling was used to generate incidence rate ratios (IRR) and 95% confidence intervals (CI). RESULTS: The burn cohort had a significantly higher adjusted rate of post-burn MH admissions compared to the uninjured cohort (IRR, 95% CI: 2.55, 2.07-3.15). Post-burn MH admission rates were twice as high for those younger than 5 years at index burn (IRR, 95% CI 2.06, 1.54-2.74), three times higher for those 5-9 years and 15-18 years (IRR, 95% CI: 3.21, 1.92-5.37 and 3.37, 2.13-5.33, respectively) and almost five times higher for those aged 10-14 (IRR, 95% CI: 4.90, 3.10-7.76), when compared with respective ages of uninjured children. The burn cohort had higher admission rates for mood and anxiety disorders (IRR, 95% CI: 2.79, 2.20-3.53), psychotic disorders (IRR, 95% CI: 2.82, 1.97-4.03) and mental and behavioural conditions relating to drug and alcohol abuse (IRR, 95% CI: 4.25, 3.39-5.32). CONCLUSIONS: Ongoing MH support is indicated for paediatric burn patients for a prolonged period after discharge to potentially prevent psychiatric morbidity and associated academic, social and psychological issues.

Co-inhibition of mTORC1, HDAC and ESR1α retards the growth of triple-negative breast cancer and suppresses cancer stem cells.

Triple-negative breast cancer (TNBC) is the most refractory subtype of breast cancer. It causes the majority of breast cancer-related deaths, which has been largely associated with the plasticity of tumor cells and persistence of cancer stem cells (CSCs). Conventional chemotherapeutics enrich CSCs and lead to drug resistance and disease relapse. Development of a strategy capable of inhibiting both bulk and CSC populations is an unmet medical need. Inhibitors against estrogen receptor 1, HDACs, or mTOR have been studied in the treatment of TNBC; however, the results are inconsistent. In this work, we found that patient TNBC samples expressed high levels of mTORC1 and HDAC genes in comparison to luminal breast cancer samples. Furthermore, co-inhibition of mTORC1 and HDAC with rapamycin and valproic acid, but neither alone, reproducibly promoted ESR1 expression in TNBC cells. In combination with tamoxifen (inhibiting ESR1), both S6RP phosphorylation and rapamycin-induced 4E-BP1 upregulation in TNBC bulk cells was inhibited. We further showed that fractionated CSCs expressed higher levels of mTORC1 and HDAC than non-CSCs. As a result, co-inhibition of mTORC1, HDAC, and ESR1 was capable of reducing both bulk and CSC subpopulations as well as the conversion of fractionated non-CSC to CSCs in TNBC cells. These observations were partially recapitulated with the cultured tumor fragments from TNBC patients. Furthermore, co-administration of rapamycin, valproic acid, and tamoxifen retarded tumor growth and reduced CD44high/+/CD24low/- CSCs in a human TNBC xenograft model and hampered tumorigenesis after secondary transplantation. Since the drugs tested are commonly used in clinic, this study provides a new therapeutic strategy and a strong rationale for clinical evaluation of these combinations for the treatment of patients with TNBC.

Dual inhibition of Wnt and Yes-associated protein signaling retards the growth of triple-negative breast cancer in both mesenchymal and epithelial states.

Triple-negative breast cancer (TNBC), the most refractory subtype of breast cancer to current treatments, accounts disproportionately for the majority of breast cancer-related deaths. This is largely due to cancer plasticity and the development of cancer stem cells (CSCs). Recently, distinct yet interconvertible mesenchymal-like and epithelial-like states have been revealed in breast CSCs. Thus, strategies capable of simultaneously inhibiting bulk and CSC populations in both mesenchymal and epithelial states have yet to be developed. Wnt/ß-catenin and Hippo/YAP pathways are crucial in tumorigenesis, but importantly also possess tumor suppressor functions in certain contexts. One possibility is that TNBC cells in epithelial or mesenchymal state may differently affect Wnt/ß-catenin and Hippo/YAP signaling and CSC phenotypes. In this report, we found that YAP signaling and CD44high /CD24-/low CSCs were upregulated while Wnt/ß-catenin signaling and ALDH+ CSCs were downregulated in mesenchymal-like TNBC cells, and vice versa in their epithelial-like counterparts. Dual knockdown of YAP and Wnt/ß-catenin, but neither alone, was required for effective suppression of both CD44high /CD24-/low and ALDH+ CSC populations in mesenchymal and epithelial TNBC cells. These observations were confirmed with cultured tumor fragments prepared from patients with TNBC after treatment with Wnt inhibitor ICG-001 and YAP inhibitor simvastatin. In addition, a clinical database showed that decreased gene expression of Wnt and YAP was positively correlated with decreased ALDH and CD44 expression in patients' samples while increased patient survival. Furthermore, tumor growth of TNBC cells in either epithelial or mesenchymal state was retarded, and both CD44high /CD24-/low and ALDH+ CSC subpopulations were diminished in a human xenograft model after dual administration of ICG-001 and simvastatin. Tumorigenicity was also hampered after secondary transplantation. These data suggest a new therapeutic strategy for TNBC via dual Wnt and YAP inhibition.

Biomedical device innovation methodology: applications in biophotonics.

The process of medical device innovation involves an iterative method that focuses on designing innovative, device-oriented solutions that address unmet clinical needs. This process has been applied to the field of biophotonics with many notable successes. Device innovation begins with identifying an unmet clinical need and evaluating this need through a variety of lenses, including currently existing solutions for the need, stakeholders who are interested in the need, and the market that will support an innovative solution. Only once the clinical need is understood in detail can the invention process begin. The ideation phase often involves multiple levels of brainstorming and prototyping with the aim of addressing technical and clinical questions early and in a cost-efficient manner. Once potential solutions are found, they are tested against a number of known translational factors, including intellectual property, regulatory, and reimbursement landscapes. Only when the solution matches the clinical need, the next phase of building a "to market" strategy should begin. Most aspects of the innovation process can be conducted relatively quickly and without significant capital expense. This white paper focuses on key points of the medical device innovation method and how the field of biophotonics has been applied within this framework to generate clinical and commercial success.

Quality of life and posttraumatic growth after adult burn: A prospective, longitudinal study.

Posttraumatic growth is positive psychological change that occurs beyond pre-trauma levels. Understanding the relationship between growth, stress and quality of life after burn improves understanding about the nature of postburn psychological growth and associated quality of life factors. This study aimed to determine the nature of these relationships, and whether posttraumatic growth changed over time in individuals. Two hundred and seventeen surveys were collected from 73 adult burn patients. The Posttraumatic Growth Inventory, Depression, Anxiety and Stress Score, SF-36 quality of life and Burns Specific Health Score - Brief surveys, together with demographic and clinical information was collected over a six month period. Acute and non-acute burns were equally represented. Growth and stress were positively correlated (p=0.004), but depression and growth had a curved relationship (p=0.050). Growth scores reduced as affect (p=0.008) and mental health improved (p<0.0001), and were highest at mid-levels of physical recovery (p=0.001). This supports the concept that PTG is linked to coping as higher growth is reported with more stress, and that depression is a barrier to growth. As patients recover both physically and mentally from burn, less growth is reported. Early identification and management of depression is important to optimise growth outcomes.