State-of-the-art Nrf2 Inhibitors: Therapeutic Opportunities in Non-cancer Diseases.

Nrf2 is a cytoprotective transcription factor that induces the transcription of genes responsible for the cell's response to oxidative stress. While Nrf2 activation has led to the development of clinically relevant therapeutics, the oncogenic role of Nrf2 in the proliferation of cancer cells has underscored the complex nature of Nrf2 and the necessity for the development of Nrf2 inhibitors. Although the application of Nrf2 inhibitors appears limited as anticancer agents, recent studies have begun to pinpoint the impairment of autophagy in diseases as a cellular marker that shifts Nrf2 from a protective to a deleterious state. Therefore, the cytoplasmic accumulation of Nrf2 can lead to the accumulation of lipid hydroperoxides and, ultimately, to ferroptosis. However, some studies aimed at elucidating the role of Nrf2 in non-cancer diseases have yielded conflicting results, attributed to differences in approaches used to inhibit or activate Nrf2, as well as variations in disease models. Overall, these results highlight the necessity for a deeper evaluation of Nrf2's role in diseases, especially chronic diseases. In this review, we discuss diseases where Nrf2 inhibition holds potential for beneficial therapeutic effects and summarize recently reported Nrf2 inhibitors exploiting medicinal chemistry approaches suitable for targeting transcription factors like Nrf2.

WNT5B drives osteosarcoma stemness, chemoresistance and metastasis.

BACKGROUND: Treatment for osteosarcoma, a paediatric bone cancer with no therapeutic advances in over three decades, is limited by a lack of targeted therapies. Osteosarcoma frequently metastasises to the lungs, and only 20% of patients survive 5 years after the diagnosis of metastatic disease. We found that WNT5B is the most abundant WNT expressed in osteosarcoma tumours and its expression correlates with metastasis, histologic subtype and reduced survival. METHODS: Using tumor-spheroids to model cancer stem-like cells, we performed qPCR, immunoblotting, and immunofluorescence to monitor changes in gene and protein expression. Additionally, we measured sphere size, migration and forming efficiency to monitor phenotypic changes. Therefore, we characterised WNT5B's relevance to cancer stem-like cells, metastasis, and chemoresistance and evaluated its potential as a therapeutic target. RESULTS: In osteosarcoma cell lines and patient-derived spheres, WNT5B is enriched in stem cells and induces the expression of the stemness gene SOX2. WNT5B promotes sphere size, sphere-forming efficiency, and cell proliferation, migration, and chemoresistance to methotrexate (but not cisplatin or doxorubicin) in spheres formed from conventional cell lines and patient-derived xenografts. In vivo, WNT5B increased osteosarcoma lung and liver metastasis and inhibited the glycosaminoglycan hyaluronic acid via upregulation of hyaluronidase 1 (HYAL1), leading to changes in the tumour microenvironment. Further, we identified that WNT5B mRNA and protein correlate with the receptor ROR1 in primary tumours. Targeting WNT5B through inhibition of WNT/ROR1 signalling with an antibody to ROR1 reduced stemness properties, including chemoresistance, sphere size and SOX2 expression. CONCLUSIONS: Together, these data define WNT5B's role in driving osteosarcoma cancer stem cell expansion and methotrexate resistance and provide evidence that the WNT5B pathway is a promising candidate for treating osteosarcoma patients. KEY POINTS: WNT5B expression is high in osteosarcoma stem cells leading to increased stem cell proliferation and migration through SOX2. WNT5B expression in stem cells increases rates of osteosarcoma metastasis to the lungs and liver in vivo. The hyaluronic acid degradation enzyme HYAL1 is regulated by WNT5B in osteosarcoma contributing to metastasis. Inhibition of WNT5B with a ROR1 antibody decreases osteosarcoma stemness.

Leaders, Talent Management, and Allies: The Keys to Successful Integration in the Combat Arms.

Servicewomen enhance the U.S. Military fighting force by bringing diverse perspectives, collaborative and creative problem-solving skills for global peace and security, and innovative, adaptive talent as leaders. Despite servicewomen integrating into combat units over the past decade, a number of barriers remain related to inclusion, promotion, and quality of life, particularly for marginalized women. To eliminate inequities experienced by servicewomen, leaders across all levels of the military play a key role in supporting the successful integration of servicewomen, cultivating an environment of belonging, and guarding against toxicity, which will result in optimized performance and readiness for all servicemembers in defense of the Nation. Herein, we review the original gaps related to leadership and peer behaviors identified by the 2014 Women in Combat Symposium, provide updates in the literature, address the topics that arose at the 2021 Women in Combat Symposium, and finally, outline the remaining barriers and challenges to the successful integration of female servicemembers.

A Patient-Centred Approach to Early Pregnancy Loss: The First 18 Months of a Canadian Outpatient Program for Early Pregnancy Loss (OPEL).

OBJECTIVE: Manual vacuum aspiration is a safe surgical option for the management of early pregnancy loss. To provide rapid, patient-centred access to MVA, an Outpatient Program for Early pregnancy Loss ("OPEL") was established at our institution. Objectives were to (1) assess complete uterine evacuation rates; (2) assess complication rates, and (3) assess patient satisfaction with the program. METHODS: With REB approval, a retrospective study was performed. Patient records from the first 18 months of OPEL (November 2015 to April 2017) were reviewed. Anonymous patient satisfaction questionnaires were completed immediately post-procedure. RESULTS: A total of 162 patients received treatment. Missed abortions accounted for 94 cases (58%). Median delay from referral to clinic appointment was 4.0 (interquartile range [IQR] 2.0-6.0) days. Average length of stay was 3.0 (IQR 2.5-3.0) hours. Efficacy of the procedure was 95.1%. Complication rate (immediate and delayed) was 14.2% and included intraoperative hemorrhage (3.1%; 5/162), Asherman's syndrome (1.9%; 3/162), retained products of conception requiring further treatment (4.9%; 8/162), and postoperative infection requiring antibiotic therapy (1.9%; 3/162). A total of 151 post-procedure satisfaction surveys were completed (93%); 100% agreed/strongly agreed that the nursing staff and physicians provided professional and compassionate care; 99.3% were satisfied with their care overall. Qualitative feedback was positive. CONCLUSION: Pregnant patients experiencing early pregnancy loss benefit from safe, timely, accessible, patient-centred care in the outpatient OPEL program. Similar models should be adopted nationally to ensure women experiencing this common pregnancy complication receive safe and compassionate care.

Geometric determinants of local hemodynamics in severe carotid artery stenosis.

In cases of severe carotid artery stenosis (CAS), carotid endarterectomy (CEA) is performed to recover lumen patency and alleviate stroke risk. Under current guidelines, the decision to surgically intervene relies primarily on the percent loss of native arterial lumen diameter within the stenotic region (i.e. the degree of stenosis). An underlying premise is that the degree of stenosis modulates flow-induced wall shear stress elevations at the lesion site, and thus indicates plaque rupture potential and stroke risk. Here, we conduct a retrospective study on pre-CEA computed tomography angiography (CTA) images from 50 patients with severe internal CAS (>60% stenosis) to better understand the influence of plaque and local vessel geometry on local hemodynamics, with geometrical descriptors that extend beyond the degree of stenosis. We first processed CTA images to define a set of multipoint geometric metrics characterizing the stenosed region, and next performed computational fluid dynamics simulations to quantify local wall shear stress and associated hemodynamic metrics. Correlation and regression analyses were used to relate obtained geometric and hemodynamic metrics, with inclusion of patient sub-classification based on the degree of stenosis. Our results suggest that in the context of severe CAS, prediction of shear stress-based metrics can be enhanced by consideration of readily available, multipoint geometric metrics in addition to the degree of stenosis.

Determination of Viscoelastic Properties of human Carotid Atherosclerotic Plaque by Inverse Boundary Value Analysis.

In this study, we assessed the mechanical response of samples from human atherosclerotic diseased media and fibrous cap via uniaxial tensile testing. Results show a pronounced hysteresis phenomenon caused by viscoelasticity during the loading-unloading process. An inverse analysis method with finite element modeling was employed to identify the material parameter values for a viscoelastic anisotropic (VA) constitutive model through matching simulation predictions of load-displacement curves with experimental measurements. The identified material parameter values can be used in simulation studies of diseased human carotid arteries, including investigations of inflation processes associated with stenting or angioplasty.

Experimental and numerical studies of two arterial wall delamination modes.

Arterial wall dissection, which results from various pathophysiological processes, can lead to the occurrence of large area delamination in the aortic wall that can potentially block blood flow and lead to deleterious clinical conditions. Despite its critical clinical relevance, few studies have focused on investigating the failure mode of delamination in the arterial wall. In this study, we quantify the energy release rate of the medial layer of a porcine abdominal aorta via two delamination experiments: the mixed-mode delamination experiment and the "T"-shaped delamination experiment. A cohesive zone model (CZM) is applied to simulate the arterial wall delamination and Holzapfel-Gasser-Ogden (HGO) material model is used to capture the bulk arterial material behavior. A set of parameter values for the HGO and CZM models are identified through matching simulation predictions of the load vs. load-point displacement curve with experimental measurements. Then the parameter values and critical energy release rates obtained from experiments are used as input data for simulation predictions for two arterial wall delamination experiments. The simulation predictions show that the delamination front matches well with experimental measurements. Moreover, the mixed-mode delamination experiment reveals a shear mode-dominated failure event, whereas the "T"-shaped delamination experiment is an opening failure process. The integration of experimental data and numerical predictions of arterial delamination events provides a comprehensive description of distinct failure modes and aids in the prediction of aortic dissection.

The relation of protective factors to deliberate self-harm among African-American adults: moderating roles of gender and sexual orientation identity.

BACKGROUND: Few studies have examined correlates of deliberate self-harm (DSH) among African-Americans. Moreover, most research on the correlates of DSH in general has focused on risk factors rather than protective factors. AIMS: This study examined differences in perceived social support, religiosity (both spirituality and church attendance) and overall life satisfaction between African-Americans with and without a history of DSH, as well as the moderating roles of gender and sexual orientation in these relations. METHOD: Participants were 244 African-American university students who completed questionnaires. RESULTS: Participants with (vs. without) DSH reported significantly lower levels of social support. Additionally, rates of DSH were significantly higher among participants who attended church irregularly versus regularly or rarely/never. However, the association between DSH and church attendance was significant only for women (vs. men) and LGBQ (vs. heterosexual) women. Further, gender moderated the relation between DSH and social support from both significant others and friends, with self-harming women (but not men) reporting less support than their non-DSH counterparts. CONCLUSIONS: Findings add to the literature on DSH among African-Americans, highlighting both social support and church attendance (depending on regularity) as potential protective factors within this population.

Silver Alerts: A Notification System for Communities with Missing Adults.

As the U.S. population ages, the prevalence of dementia will grow and communities will face the problem of older adults wandering or becoming lost. Silver Alert systems are programs designed to locate missing older adults with dementia or other mental disabilities. Such programs have been initiated in all but five states. Data collection for these programs is often minimal or incomplete. Social workers should be involved in prevention, follow up and education with caregivers, community members and law enforcement officers. When reviewing Silver Alert policy, special attention must be given to ethical concerns and protection of older adults' civil rights.

The meaning of being an oncology nurse: Investing to make a difference.

The landscape of cancer care is evolving. Oncology nursing continues to develop and respond to the changing needs of patients with cancer and their families. There is limited understanding of what it means to be an oncology nurse, as well as the factors that facilitate or hinder being an oncology nurse. This study used an interpretive phenomenological approach. Six nurses from two in-patient units in a tertiary care teaching facility were interviewed. The overarching theme, Investing to Make a Difference, reflected how oncology nurses invested in building relationships with patients and their family members and invested in themselves by developing their knowledge and skills and, eventually, their identities as oncology nurses. In turn, these investments enhanced their role, and were seen to make a difference in the lives of patients and their family members by supporting them through the cancer journey. Implications of these findings for oncology nursing are highlighted as they relate to nursing practice, education, research, and leadership.

Atherosclerotic plaque delamination: Experiments and 2D finite element model to simulate plaque peeling in two strains of transgenic mice.

Finite element analyses using cohesive zone models (CZM) can be used to predict the fracture of atherosclerotic plaques but this requires setting appropriate values of the model parameters. In this study, material parameters of a CZM were identified for the first time on two groups of mice (ApoE-/- and ApoE-/- Col8-/-) using the measured force-displacement curves acquired during delamination tests. To this end, a 2D finite-element model of each plaque was solved using an explicit integration scheme. Each constituent of the plaque was modeled with a neo-Hookean strain energy density function and a CZM was used for the interface. The model parameters were calibrated by minimizing the quadratic deviation between the experimental force displacement curves and the model predictions. The elastic parameter of the plaque and the CZM interfacial parameter were successfully identified for a cohort of 11 mice. The results revealed that only the elastic parameter was significantly different between the two groups, ApoE-/- Col8-/- plaques being less stiff than ApoE-/- plaques. Finally, this study demonstrated that a simple 2D finite element model with cohesive elements can reproduce fairly well the plaque peeling global response. Future work will focus on understanding the main biological determinants of regional and inter-individual variations of the material parameters used in the model.

Recent Advances in Organocatalyzed Domino C-C Bond-Forming Reactions.

Reactions that form a C-C bond make up a foundational pillar of synthetic organic chemistry. In addition, organocatalysis has emerged as an easy, environmentally-friendly way to promote this type of bond formation. Since around 2000, organocatalysts have been used in a variety of C-C bond-forming reactions including Michael and aldol additions, Mannich-type reactions, and Diels-Alder reactions, to name a few. Many of these methodologies have been refined and further developed to include cascade and domino processes. This review will focus on recent advances in this area with an emphasis on methodologies having applications in the synthesis of biologically-significant compounds.

Characterization of fracture behavior of human atherosclerotic fibrous caps using a miniature single edge notched tensile test.

UNLABELLED: One well-established cause of ischemic stroke is atherosclerotic plaque rupture in the carotid artery. Rupture occurs when a tear in the fibrous cap exposes highly thrombogenic material in the lipid core. Though some fibrous cap material properties have been measured, such as ultimate tensile strength and stress-strain responses, there has been very little, if any, data published regarding the fracture behavior of atherosclerotic fibrous caps. This study aims to characterize the qualitative and quantitative fracture behavior of human atherosclerotic plaque tissue obtained from carotid endarterectomy samples using two different metrics. Uniaxial tensile experiments along with miniature single edge notched tensile (MSENT) experiments were performed on strips of isolated fibrous cap. Crack tip opening displacement (CTOD) and stress in the un-cracked segment (UCS) were measured at failure in fibrous cap MSENT specimens subjected to uniaxial tensile loading. Both CTOD and the degree of crack blunting, measured as the radius of curvature of the crack tip, increased as tearing propagated through the tissue. Higher initial stress in the UCS is significantly correlated with higher collagen content and lower macrophage content in the fibrous cap (ρ=0.77, P=0.009; ρ=-0.64, P=0.047; respectively). Trends in the data show that higher CTOD is inversely related to collagen content, though the sample size in this study is insufficient to statistically substantiate this relationship. To the authors' knowledge, this is the pioneering study examining the fracture behavior of fibrous caps and the first use of the CTOD metric in vascular tissue. STATEMENT OF SIGNIFICANCE: A tear in the fibrous cap of atherosclerotic plaque can lead to ischemic stroke or myocardial infarction. While there is some information in the literature regarding quantitative measures of fibrous cap failure, there is little information regarding the behavior of the tissue during failure. This study examines the failure behavior of fibrous caps both qualitatively, by examining how and where the tissue fails, and quantitatively, by measuring (a) crack tip opening displacement (CTOD) in vascular tissue for the first time and (b) uniaxial stress in the un-cracked segment (UCS). This study shows that both metrics should be evaluated when assessing plaque vulnerability.

Organocatalyzed Intramolecular Carbonyl-Ene Reactions.

An organocatalyzed intramolecular carbonyl-ene reaction was developed to produce carbocyclic and heterocyclic 5- and 6-membered rings from a citronellal-derived trifluoroketone and a variety of aldehydes. A phosphoramide derivative was found to promote the cyclization of the trifluoroketone, whereas a less acidic phosphoric acid proved to be a superior catalyst for the aldehyde substrates.

Microaggressions Toward Lesbian, Gay, Bisexual, Transgender, Queer, and Genderqueer People: A Review of the Literature.

Microaggressions are subtle forms of discrimination, often unconscious or unintentional, that communicate hostile or derogatory messages, particularly to and about members of historically marginalized social groups. While Sue's (2010a, 2010b) microaggression theory formed its foundation in studies based on racial microaggressions, the following review summarizes microaggression literature to date, as it pertains to the lesbian, gay, bisexual, transgender, queer, and genderqueer (LGBTQ) people. Searching PsycINFO and other databases between 2010 and 2015, we found 35 peer-reviewed papers or dissertations that concentrate on the negative impact microaggressions have on LGBTQ people. A comprehensive overview of the experiences of individual LGBTQ subgroups (e.g., lesbian women, gay men, bisexual people, transgender people, and genderqueer people) is included, as well as microaggressions based on intersectional identities (e.g., experiences of LGBTQ people of color). The significance of this review is that it is the only known article to comprehensively analyze the literature on LGBTQ people and microaggressions, examining the strengths and weaknesses of past literature while encouraging future areas of theory, research, and practice.

Numerical modeling of experimental human fibrous cap delamination.

Fibrous cap delamination is a critical process during the rupture of atherosclerotic plaque, which often leads to severe life-threatening clinical consequences such as myocardial infarction or stroke. In this study a finite element modeling and simulation approach is presented that enables the study of fibrous cap delamination experiments for the purpose of understanding the fibrous cap delamination process. A cohesive zone model (CZM) approach is applied to simulate delamination of the fibrous cap from the underlying plaque tissue. A viscoelastic anisotropic (VA) model for the bulk arterial material behavior is extended from existing studies so that the hysteresis phenomenon observed in the fibrous cap delamination experiments can be captured. A finite element model is developed for the fibrous cap delamination experiments, in which arterial layers (including the fibrous cap and the underlying plaque tissue) are represented by solid elements based on the VA model and the fibrous cap-underlying plaque tissue interface is characterized by interfacial CZM elements. In the CZM, the delamination process is governed by an exponential traction-separation law which utilizes critical energy release rates obtained directly from the fibrous cap delamination experiments. A set of VA model parameter values and CZM parameter values is determined based on values suggested in the literature and through matching simulation predictions of the load vs. load-point displacement curve with one set of experimental measurements. Using this set of parameter values, simulation predictions for other sets of experimental measurements are obtained and good agreement between simulation predictions and experimental measurements is observed. Results of this study demonstrate the applicability of the viscoelastic anisotropic model and the CZM approach for the simulation of diseased arterial tissue failure processes.