Dielectrophoretic capture and electrochemical enzyme-linked immunosorbent assay of single melanoma cells at an array of interlocked spiral bipolar electrodes.

Analysis of single cancer cells is critical to obtain accurate patient diagnosis and prognosis. In this work, we report the selective dielectrophoretic capture and electrochemical analysis of single melanoma cells at an array of interlocked spiral bipolar electrodes (iBPEs). Following dielectrophoretic capture, individual melanoma cells are hydrodynamically transferred into picoliter-scale chambers for subsequent analysis. The interlocked spiral end of the iBPE (the sensing pole) is utilized to read out an electrochemical enzyme-linked immunosorbent assay (eELISA), which quantifies the expression of a cell surface antigen, melanoma cell adhesion marker (MCAM). The opposite pole of each BPE is located in a fluidically isolated compartment containing reagents for electrogenerated chemiluminescence (ECL), such that luminescence reports iBPE current. In a preliminary device design, the ECL intensity was insufficient to detect MCAM expression on single cells. To achieve single-cell analysis, we decreased the gap size between the interlocked spirals tenfold (5.0 µm to 0.5 µm), thereby creating a more sensitive biosensor by enhanced redox cycling of the product of eELISA. This work is significant because it allows for the selective isolation and sensitive analysis of individual melanoma cells in a device amenable to point-of-care (POC) application by combining dielectrophoresis (DEP) with interdigitated bipolar electrodes (IDBPEs).

Planning and evaluating an integrated clinical exercise oncology service: an exploratory mixed-methods study.

BACKGROUND: This project aimed to design and evaluate the potential to integrate an exercise oncology service into clinical care in a local healthcare system. The goal was to inform the design of an implementation strategy to promote its sustainable use in standard care. METHODS: This two-phase, exploratory study used a mixed-methods approach. First, qualitative measures were used to understand the context for exercise integration into oncology care by clinicians and administrators in the healthcare system. Next, the Reach, Effectiveness, Adoption, Implementation, Maintenance (RE-AIM) framework guided a comprehensive evaluation of the exercise service. Reach and Adoption were measured via number of patients enrolled in the program relative to those treated. Adoption was measured via referrals from stakeholders. Implementation was described using the program structure and delivery. Maintenance was described using hospital funding decisions. Effectiveness was assessed using the Bellarmine Norton Assessment Tool (BNAT) and Functional Assessment of Cancer Therapy - Fatigue Scale. RESULTS: Phase 1 context analysis suggested critical elements to guide program delivery, including limiting participants to post-primary treatment (surgery, chemotherapy and radiation) and streamlining referral process. The Phase 2 evaluation demonstrated suboptimal program reach (2%); significant program effectiveness (improved physical function (BNAT; p = 0.05 ) and decreased fatigue (p < 0.05)); receptiveness to program adoption (75%); and strong potential for program maintenance. CONCLUSIONS: Traditional approaches to exercise oncology research trials are not easily integrated into healthcare systems. Designing an exercise program for meaningful integration and sustainment requires understanding the context where the program will be delivered, followed by intentional and continuous engagement with key stakeholders to ensure the program continues to meet the needs of the system. Initial exploration of the settings is critical to inform a comprehensive implementation strategy. TRIAL REGISTRATION: clinicaltrials.gov: NCT06039488. Prospectively Registered Sept 15th, 2023.

Interleukin-15 and high-intensity exercise: relationship with inflammation, body composition and fitness in cancer survivors.

Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth. These anti-oncogenic effects of exercise were associated with the exercise-mediated release of myokines such as interleukin (IL)-15. However, no study has quantified the acute IL-15 response in human cancer survivors, and whether physiological adaptations to exercise training (i.e. body composition and cardiorespiratory fitness) influence this response. In the present study breast, prostate and colorectal cancer survivors (n = 14) completed a single bout of high-intensity interval exercise (HIIE) [4×4 min at 85-95% heart rate (HR) peak, 3 min at 50-70% HR peak] before and after 7 months of three times weekly high-intensity interval training (HIIT) on a cycle ergometer. At each time point venous blood was sampled before and immediately after HIIE to assess the acute myokine (IL-15, IL-6, IL-10, IL-1ra) responses. Markers of inflammation, cardiorespiratory fitness and measures of body composition were obtained at baseline and 7 months. An acute bout of HIIE resulted in a significant increase in IL-15 concentrations (pre-intervention: 113%; P = 0.013, post-intervention: 102%; P = 0.005). Post-exercise IL-15 concentrations were associated with all other post-exercise myokine concentrations, lean mass (P = 0.031), visceral adipose tissue (P = 0.039) and absolute V ̇ O 2 ${{\dot{V}}_{{{{\mathrm{O}}}_{\mathrm{2}}}}}$ peak (P = 0.032). There was no significant effect of 7 months of HIIT on pre- or post-HIIE IL-15 concentrations (P > 0.05). This study demonstrates HIIE is a sufficient stimulus to increase circulating IL-15 and other myokines including IL-6, IL-10 and IL-1ra which may be clinically relevant in the anti-oncogenic effect of exercise and repetitive exposure to these effects may contribute to the positive relationship between exercise and cancer recurrence. KEY POINTS: Exercise has been demonstrated to reduce the risk of cancer recurrence. Pre-clinical murine and in vitro models have demonstrated that exercise suppresses tumour and cancer cell growth, mediated by exercise-induced myokines (IL-6 and IL-15). High-intensity interval exercise significantly increased myokines associated with the anti-oncogenic effect of exercise and the magnitude of response was associated with lean mass, but training did not appear to influence this response. Given IL-15 has been implicated in the anti-oncogenic effect of exercise and is being explored as an immunotherapy agent, high-intensity interval exercise may improve outcomes for people living beyond cancer through IL-15-mediated pathways. Interventions that increase lean mass may also enhance this response.

Comparing regularized Kelvinlet functions and the finite element method for registration of medical images to sparse organ data.

Image-guided surgery collocates patient-specific data with the physical environment to facilitate surgical decision making. Unfortunately, these guidance systems commonly become compromised by intraoperative soft-tissue deformations. Nonrigid image-to-physical registration methods have been proposed to compensate for deformations, but clinical utility requires compatibility of these techniques with data sparsity and temporal constraints in the operating room. While finite element models can be effective in sparse data scenarios, computation time remains a limitation to widespread deployment. This paper proposes a registration algorithm that uses regularized Kelvinlets, which are analytical solutions to linear elasticity in an infinite domain, to overcome these barriers. This algorithm is demonstrated and compared to finite element-based registration on two datasets: a phantom liver deformation dataset and an in vivo breast deformation dataset. The regularized Kelvinlets algorithm resulted in a significant reduction in computation time compared to the finite element method. Accuracy as evaluated by target registration error was comparable between methods. Average target registration errors were 4.6 ± 1.0 and 3.2 ± 0.8 mm on the liver dataset and 5.4 ± 1.4 and 6.4 ± 1.5 mm on the breast dataset for the regularized Kelvinlets and finite element method, respectively. Limitations of regularized Kelvinlets include the lack of organ-specific geometry and the assumptions of linear elasticity and infinitesimal strain. Despite limitations, this work demonstrates the generalizability of regularized Kelvinlets registration on two soft-tissue elastic organs. This method may improve and accelerate registration for image-guided surgery, and it shows the potential of using regularized Kelvinlets on medical imaging data.

The impact of COVID-19 and vaccination status on outcomes in veterans with head and neck squamous cell carcinoma.

BACKGROUND: The impact of both COVID-19 infection and vaccination status on patients with head and neck squamous cell carcinoma (HNSCC) remains unknown. OBJECTIVE: To determine the impact of COVID-19 infection and vaccination status on 60-day mortality, cardiovascular, and respiratory complications in patients with a prior diagnosis of HNSCC. METHODS: This was a retrospective cohort study through the Veterans Affairs (VA) Corporate Data Warehouse of Veterans with HNSCC who were tested for COVID-19 during any inpatient VA medical center admission. A cohort of patients was created of Veterans with a diagnosis of HNSCC of the oral cavity,oropharynx, hypopharynx, larynx, and nasopharynx based on International Classification of Disease (ICD) codes. Data collected included clinical/demographic data, vaccination status, and incidence of 60-day mortality, 60-day cardiovascular complication (including myocardial infarction, venous thromboembolism, cerebrovascular accident), and 60-day respiratory complication (including acute respiratory failure, acute respiratory distress syndrome, and pneumonia). The interactions between COVID-19 infection, vaccination status, morbidity and mortality were investigated. RESULTS: Of the 14 262 patients with HNSCC who were tested for COVID-19 during inpatient admission, 4754 tested positive (33.3%), and 9508 (67.7%) tested negative. Patients who tested positive demonstrated increased 60-day mortality (4.7% vs. 2.0%, respectively; p < 0.001), acute respiratory failure (ARF; 15.4% vs. 7.1%, p < 0.001), acute respiratory distress syndrome (ARDS; 0.9% vs. 0.2%, p < 0.001), and pneumonia (PNA; 20.0% vs. 6.4%, p < 0.001) compared to those who never tested positive, respectively. Patients who received COVID-19 vaccination between 2 weeks and 6 months prior to a positive test demonstrated decreased rates of ARF (13.2% vs. 16.0%, p = 0.034) and PNA (16.7% vs. 20.9%, p = 0.003) compared to the unvaccinated group. A logistic regression of patients with COVID-19 infections who died within 60 days was performed, with no significant survival advantage among patients vaccinated between 2 weeks and 6 months prior to the positive test. CONCLUSION: COVID-19 infection may significantly increase rates of 60-day mortality and respiratory complications in patients with HNSCC. COVID-19 vaccination between 2 weeks and 6 months prior to infection may decrease severity of respiratory complications but did not show significant mortality benefits in this study. These data highlight the need for surveillance of respiratory infection and vaccination in this vulnerable population.

Regulatory T cells: Supporting lung homeostasis and promoting resolution and repair after lung injury.

Regulatory T cells, characterized by their expression of the transcription factor Forkhead box P3, are indispensable in maintaining immune homeostasis. The respiratory system is constantly exposed to many environmental challenges, making it susceptible to various insults and infections. Regulatory T cells play essential roles in maintaining homeostasis in the lung and promoting repair after injury. Regulatory T cell function dysregulation can lead to inflammation, tissue damage, or aberrant repair. Research on regulatory T cell mechanisms in the lung has unveiled their influence on lung inflammation and repair mechanisms. In this review, our goal is to highlight the advances in regulatory T cell biology with respect to lung injury and resolution. We further provide a perspective that a deeper understanding of regulatory T cell interactions in the lung microenvironment in health and disease states offers opportunities for therapeutic interventions as treatments to promote lung health.

Serine/arginine-rich splicing factor 7 promotes the type I interferon response by activating Irf7 transcription.

Tight regulation of macrophage immune gene expression is required to fight infection without risking harmful inflammation. The contribution of RNA-binding proteins (RBPs) to shaping the macrophage response to pathogens remains poorly understood. Transcriptomic analysis reveals that a member of the serine/arginine-rich (SR) family of mRNA processing factors, SRSF7, is required for optimal expression of a cohort of interferon-stimulated genes in macrophages. Using genetic and biochemical assays, we discover that in addition to its canonical role in regulating alternative splicing, SRSF7 drives transcription of interferon regulatory transcription factor 7 (IRF7) to promote antiviral immunity. At the Irf7 promoter, SRSF7 maximizes STAT1 transcription factor binding and RNA polymerase II elongation via cooperation with the H4K20me1 histone methyltransferase KMT5a (SET8). These studies define a role for an SR protein in activating transcription and reveal an RBP-chromatin network that orchestrates macrophage antiviral gene expression.

The early macrophage response to pathogens requires dynamic regulation of the nuclear paraspeckle.

To ensure a robust immune response to pathogens without risking immunopathology, the kinetics and amplitude of inflammatory gene expression in macrophages need to be exquisitely well controlled. There is a growing appreciation for stress-responsive membraneless organelles (MLOs) regulating various steps of eukaryotic gene expression in response to extrinsic cues. Here, we implicate the nuclear paraspeckle, a highly ordered biomolecular condensate that nucleates on the Neat1 lncRNA, in tuning innate immune gene expression in murine macrophages. In response to a variety of innate agonists, macrophage paraspeckles rapidly aggregate (0.5 h poststimulation) and disaggregate (2 h poststimulation). Paraspeckle maintenance and aggregation require active transcription and MAPK signaling, whereas paraspeckle disaggregation requires degradation of Neat1 via the nuclear RNA exosome. In response to lipopolysaccharide treatment, Neat1 KO macrophages fail to properly express a large cohort of proinflammatory cytokines, chemokines, and antimicrobial mediators. Consequently, Neat1 KO macrophages cannot control replication of Salmonella enterica serovar Typhimurium or vesicular stomatitis virus. These findings highlight a prominent role for MLOs in orchestrating the macrophage response to pathogens and support a model whereby dynamic assembly and disassembly of paraspeckles reorganizes the nuclear landscape to enable inflammatory gene expression following innate stimuli.

Nonoperative versus operative management of type II odontoid fracture in older adults: a systematic review and meta-analysis.

OBJECTIVE: Odontoid fractures are the most common fracture of the cervical spine in adults older than 65 years of age. Fracture management remains controversial, given the inherently increased surgical risks in older patients. The objective of this study was to compare fusion rates and outcomes between operative and nonoperative treatments of type II odontoid fractures in the older population. METHODS: A systematic literature review was performed to identify studies reporting the management of type II odontoid fractures in patients older than 65 years from database inception to September 2022. A meta-analysis was performed to compare rates of fusion, stable and unstable nonunion, mortality, and complication. RESULTS: Forty-six articles were included in the final review. There were 2822 patients included in the different studies (48.9% female, 51.1% male), with a mean ± SD age of 81.5 ± 3.6 years. Patients in the operative group were significantly younger than patients in the nonoperative group (81.5 ± 3.5 vs 83.4 ± 2.5 years, p < 0.001). The overall (operative and nonoperative patients) fusion rate was 52.9% (720/1361). The fusion rate was higher in patients who underwent surgery (74.3%) than in those who underwent nonoperative management (40.3%) (OR 4.27, 95% CI 3.36-5.44). The likelihood of stable or unstable nonunion was lower in patients who underwent surgery (OR 0.37, 95% CI 0.28-0.49 vs OR 0.32, 95% CI 0.22-0.47). Overall, 4.8% (46/964) of nonoperatively managed patients subsequently required surgery due to treatment failure. Patient mortality across all studies was 16.6% (452/2721), lower in the operative cohort (13.2%) than the nonoperative cohort (19.0%) (OR 0.64, 95% CI 0.52-0.80). Complications were more likely in patients who underwent surgery (26.0% vs 18.5%) (OR 1.55, 95% CI 1.23-1.95). Length of stay was also higher with surgery (13.6 ± 3.8 vs 8.1 ± 1.9 days, p < 0.001). CONCLUSIONS: Patients older than 65 years of age with type II odontoid fractures had higher fusion rates when treated with surgery and higher stable nonunion rates when managed nonoperatively. Complications and length of stay were higher in the surgical cohort. Mortality rates were lower in patients managed with surgery, but this phenomenon could be related to surgical selection bias. Fewer than 5% of patients who underwent nonoperative treatment required revision surgery due to treatment failure, suggesting that stable nonunion is an acceptable treatment goal.

Psychosocial outcomes after varying risk management strategies in women at increased familial breast cancer risk: a mixed methods study of patient and partner outcomes.

INTRODUCTION: Female carriers of BRCA1/2 genes have an increased lifetime risk of breast cancer. Options for managing risk include imaging surveillance or risk-reducing surgery (RRS). This mixed methods study aimed to identify factors affecting risk-management decisions and the psychosocial outcomes of these decisions for high-risk women and their partners. METHODS: Semi-structured qualitative interviews were performed with women at high breast cancer risk who had faced these choices. Partners were also interviewed. Analysis used a framework approach. A bespoke questionnaire was developed to quantify and explore associations. RESULTS: A total of 32 women were interviewed. Of these, 27 had partners of whom 7 (26%) agreed to be interviewed. Four main themes arose: perception of risk and impact of increased risk; risk-management strategy decision-making; impact of risk-management strategy; support needs and partner relationship issues. The questionnaire response rate was 36/157 (23%). Decision satisfaction was high in both surveillance and RRS groups. Relationship changes were common but not universal. Common causes of distress following RRS included adverse body image changes. Both groups experienced generalised and cancer-specific anxiety. Drivers for surgery included having children, deaths of close family from breast cancer and higher levels of cancer anxiety. CONCLUSIONS: Levels of psychosocial and decision satisfaction were high for women choosing both RRS and surveillance but, for a minority, risk-reducing measures result in long-term psychosocial morbidity. Efforts to recognise women at increased risk of psychological morbidity may allow targeted support.

Examining the variation in consent in general surgery.

INTRODUCTION: Consent is a fundamental aspect of surgery and expectations around the consent process have changed following the Montgomery vs Lanarkshire Health Board (2015) court ruling. This study aimed to identify trends in litigation pertaining to consent, explore variation in how consent is practised among general surgeons and identify potential causes of this variation. METHODS: This mixed-methods study examined temporal variation in litigation rates relating to consent (between 2011 and 2020), using data obtained from National Health Service (NHS) Resolutions. Semi-structured clinician interviews were then conducted to gain qualitative data regarding how general surgeons take consent, their ideologies and their outlook on the recent legal changes. The quantitative component included a questionnaire survey aiming to explore these issues with a larger population to improve the generalisability of the findings. RESULTS: NHS Resolutions litigation data showed a significant increase in litigation pertaining to consent following the 2015 health board ruling. The interviews demonstrated considerable variation in how surgeons approach consent. This was corroborated by the survey, which illustrated considerable variation in how consent is documented when different surgeons are presented with the same case vignette. CONCLUSION: A clear increase in litigation relating to consent was seen in the post-Montgomery era, which may be due to legal precedent being established and increased awareness of these issues. Findings from this study demonstrate variability in the information patients receive. In some cases, consent practices did not adequately meet current regulations and therefore are susceptible to potential litigation. This study identifies areas for improvement in the practice of consent.

Exercise and the gut microbiome: implications for supportive care in cancer.

PURPOSE: Growing recognition of the gut microbiome as an influential modulator of cancer treatment efficacy and toxicity has led to the emergence of clinical interventions targeting the microbiome to enhance cancer and health outcomes. The highly modifiable nature of microbiota to endogenous, exogenous, and environmental inputs enables interventions to promote resilience of the gut microbiome that have rapid effects on host health, or response to cancer treatment. While diet, probiotics, and faecal microbiota transplant are primary avenues of therapy focused on restoring or protecting gut function in people undergoing cancer treatment, the role of physical activity and exercise has scarcely been examined in this population. METHODS: A narrative review was conducted to explore the nexus between cancer care and the gut microbiome in the context of physical activity and exercise as a widely available and clinically effective supportive care strategy used by cancer survivors. RESULTS: Exercise can facilitate a more diverse gut microbiome and functional metabolome in humans; however, most physical activity and exercise studies have been conducted in healthy or athletic populations, primarily using aerobic exercise modalities. A scarcity of exercise and microbiome studies in cancer exists. CONCLUSIONS: Exercise remains an attractive avenue to promote microbiome health in cancer survivors. Future research should elucidate the various influences of exercise modalities, intensities, frequencies, durations, and volumes to explore dose-response relationships between exercise and the gut microbiome among cancer survivors, as well as multifaceted approaches (such as diet and probiotics), and examine the influences of exercise on the gut microbiome and associated symptom burden prior to, during, and following cancer treatment.

Synergism of Carbamoylated Erythropoietin and Insulin-like Growth Factor-1 in Immediate Early Gene Expression.

Trophic factors are secreted proteins that can modulate neuronal integrity, structure, and function. Previous preclinical studies have shown synergistic effects on decreasing apoptosis and improving behavioral performance after stroke when combining two such trophic factors, erythropoietin (EPO) and insulin-like growth factor-1 (IGF-1). However, EPO can elevate the hematocrit level, which can be life-threatening for non-anemic individuals. A chemically engineered derivative of EPO, carbamoylated EPO (CEPO), does not impact hematological parameters but retains neurotrophic effects similar to EPO. To obtain insight into CEPO and IGF-1 combination signaling, we examined immediate early gene (IEG) expression after treatment with CEPO, IGF-1, or CEPO + IGF-1 in rat pheochromocytoma (PC-12) cells and found that combining CEPO and IGF-1 produced a synergistic increase in IEG expression. An in vivo increase in the protein expression of Npas4 and Nptx2 was also observed in the rat hippocampus. We also examined which kinase signaling pathways might be mediating these effects and found that while AKT inhibition did not alter the pattern of IEG expression, both ERK and JAK2 inhibition significantly decreased IEG expression. These results begin to define the molecular effects of combining CEPO and IGF-1 and indicate the potential for these trophic factors to produce positive, synergistic effects.

The integrated stress response in cancer progression: a force for plasticity and resistance.

During their quest for growth, adaptation, and survival, cancer cells create a favorable environment through the manipulation of normal cellular mechanisms. They increase anabolic processes, including protein synthesis, to facilitate uncontrolled proliferation and deplete the tumor microenvironment of resources. As a dynamic adaptation to the self-imposed oncogenic stress, cancer cells promptly hijack translational control to alter gene expression. Rewiring the cellular proteome shifts the phenotypic balance between growth and adaptation to promote therapeutic resistance and cancer cell survival. The integrated stress response (ISR) is a key translational program activated by oncogenic stress that is utilized to fine-tune protein synthesis and adjust to environmental barriers. Here, we focus on the role of ISR signaling for driving cancer progression. We highlight mechanisms of regulation for distinct mRNA translation downstream of the ISR, expand on oncogenic signaling utilizing the ISR in response to environmental stresses, and pinpoint the impact this has for cancer cell plasticity during resistance to therapy. There is an ongoing need for innovative drug targets in cancer treatment, and modulating ISR activity may provide a unique avenue for clinical benefit.

A long-period radio transient active for three decades.

Several long-period radio transients have recently been discovered, with strongly polarized coherent radio pulses appearing on timescales between tens to thousands of seconds1,2. In some cases, the radio pulses have been interpreted as coming from rotating neutron stars with extremely strong magnetic fields, known as magnetars; the origin of other, occasionally periodic and less-well-sampled radio transients is still debated3. Coherent periodic radio emission is usually explained by rotating dipolar magnetic fields and pair-production mechanisms, but such models do not easily predict radio emission from such slowly rotating neutron stars and maintain it for extended times. On the other hand, highly magnetic isolated white dwarfs would be expected to have long spin periodicities, but periodic coherent radio emission has not yet been directly detected from these sources. Here we report observations of a long-period (21 min) radio transient, which we have labelled GPM J1839-10. The pulses vary in brightness by two orders of magnitude, last between 30 and 300 s and have quasiperiodic substructure. The observations prompted a search of radio archives and we found that the source has been repeating since at least 1988. The archival data enabled constraint of the period derivative to <3.6 × 10-13 s s-1, which is at the very limit of any classical theoretical model that predicts dipolar radio emission from an isolated neutron star.

Soft Tissue Monitoring of the Surgical Field: Detection and Tracking of Breast Surface Deformations.

OBJECTIVE: Deformable object tracking is common in the computer vision field, with applications typically focusing on nonrigid shape detection and usually not requiring specific three-dimensional point localization. In surgical guidance however, accurate navigation is intrinsically linked to precise correspondence of tissue structure. This work presents a contactless, automated fiducial acquisition method using stereo video of the operating field to provide reliable three-dimensional fiducial localization for an image guidance framework in breast conserving surgery. METHODS: On n = 8 breasts from healthy volunteers, the breast surface was measured throughout the full range of arm motion in a supine mock-surgical position. Using hand-drawn inked fiducials, adaptive thresholding, and KAZE feature matching, precise three-dimensional fiducial locations were detected and tracked through tool interference, partial and complete marker occlusions, significant displacements and nonrigid shape distortions. RESULTS: Compared to digitization with a conventional optically tracked stylus, fiducials were automatically localized with 1.6 ± 0.5 mm accuracy and the two measurement methods did not significantly differ. The algorithm provided an average false discovery rate <0.1% with all cases' rates below 0.2%. On average, 85.6 ± 5.9% of visible fiducials were automatically detected and tracked, and 99.1 ± 1.1% of frames provided only true positive fiducial measurements, which indicates the algorithm achieves a data stream that can be used for reliable on-line registration. CONCLUSIONS: Tracking is robust to occlusions, displacements, and most shape distortions. SIGNIFICANCE: This work-flow friendly data collection method provides highly accurate and precise three-dimensional surface data to drive an image guidance system for breast conserving surgery.

Incorporating heterogeneity and anisotropy for surgical applications in breast deformation modeling.

BACKGROUND: Simulating soft-tissue breast deformations is of interest for many applications including image fusion, longitudinal registration, and image-guided surgery. For the surgical use case, positional changes cause breast deformations that compromise the use of preoperative imaging to inform tumor excision. Even when acquiring imaging in the supine position, which better reflects surgical presentation, deformations still occur due to arm motion and orientation changes. A biomechanical modeling approach to simulate supine breast deformations for surgical applications must be both accurate and compatible with the clinical workflow. METHODS: A supine MR breast imaging dataset from n = 11 healthy volunteers was used to simulate surgical deformations by acquiring images in arm-down and arm-up positions. Three linear-elastic modeling approaches with varying levels of complexity were used to predict deformations caused by this arm motion: a homogeneous isotropic model, a heterogeneous isotropic model, and a heterogeneous anisotropic model using a transverse-isotropic constitutive model. FINDINGS: The average target registration errors for subsurface anatomical features were 5.4 ± 1.5 mm for the homogeneous isotropic model, 5.3 ± 1.5 mm for the heterogeneous isotropic model, and 4.7 ± 1.4 mm for the heterogeneous anisotropic model. A statistically significant improvement in target registration error was observed between the heterogeneous anisotropic model and both the homogeneous and the heterogeneous isotropic models (P < 0.01). INTERPRETATION: While a model that fully incorporates all constitutive complexities of anatomical structure likely achieves the best accuracy, a computationally tractable heterogeneous anisotropic model provided significant improvement and may be applicable for image-guided breast surgeries.

Immunomodulatory Function of Interleukin-15 and Its Role in Exercise, Immunotherapy, and Cancer Outcomes.

Exercise has been shown to improve physical and psychosocial outcomes for people across the cancer care continuum. A proposed mechanism underpinning the relationship between exercise and cancer outcomes is exercise-induced immunomodulation via secretion of anti-inflammatory myokines from skeletal muscle tissue. Myokines have the potential to impair cancer growth through modulation of natural killer (NK) cells and CD8+ T cells while improving the effectiveness of cancer therapies. Interleukin-15 (IL-15), one of the most abundant myokines found in skeletal muscle, has a key immunoregulatory role in supporting the proliferation and maturation of T cells and NK cells, which have a key role in the host's immune response to cancer. Furthermore, IL-15 is being explored clinically as an immunotherapy agent with doses similar to the IL-15 concentrations released by skeletal muscle during exercise. Here we review the role of IL-15 within the immune system, examine how IL-15 is produced as a myokine during exercise, and how it may improve outcomes for people with cancer, specifically as an adjuvant or neoadjuvant to immunotherapy. We summarize the available evidence showing changes in IL-15 in response to both acute exercise and training, and the results are inconsistent; higher quality research is needed to advance the understanding of how exercise-mediated increases in IL-15 potentially benefit those who are being treated for, or who have had, cancer.