Natural Killer Cells Control Tumor Growth by Sensing a Growth Factor.

Many tumors produce platelet-derived growth factor (PDGF)-DD, which promotes cellular proliferation, epithelial-mesenchymal transition, stromal reaction, and angiogenesis through autocrine and paracrine PDGFRß signaling. By screening a secretome library, we found that the human immunoreceptor NKp44, encoded by NCR2 and expressed on natural killer (NK) cells and innate lymphoid cells, recognizes PDGF-DD. PDGF-DD engagement of NKp44 triggered NK cell secretion of interferon gamma (IFN)-γ and tumor necrosis factor alpha (TNF-α) that induced tumor cell growth arrest. A distinctive transcriptional signature of PDGF-DD-induced cytokines and the downregulation of tumor cell-cycle genes correlated with NCR2 expression and greater survival in glioblastoma. NKp44 expression in mouse NK cells controlled the dissemination of tumors expressing PDGF-DD more effectively than control mice, an effect enhanced by blockade of the inhibitory receptor CD96 or CpG-oligonucleotide treatment. Thus, while cancer cell production of PDGF-DD supports tumor growth and stromal reaction, it concomitantly activates innate immune responses to tumor expansion.

Epigenetic regulation during cancer transitions across 11 tumour types.

Chromatin accessibility is essential in regulating gene expression and cellular identity, and alterations in accessibility have been implicated in driving cancer initiation, progression and metastasis1-4. Although the genetic contributions to oncogenic transitions have been investigated, epigenetic drivers remain less understood. Here we constructed a pan-cancer epigenetic and transcriptomic atlas using single-nucleus chromatin accessibility data (using single-nucleus assay for transposase-accessible chromatin) from 225 samples and matched single-cell or single-nucleus RNA-sequencing expression data from 206 samples. With over 1 million cells from each platform analysed through the enrichment of accessible chromatin regions, transcription factor motifs and regulons, we identified epigenetic drivers associated with cancer transitions. Some epigenetic drivers appeared in multiple cancers (for example, regulatory regions of ABCC1 and VEGFA; GATA6 and FOX-family motifs), whereas others were cancer specific (for example, regulatory regions of FGF19, ASAP2 and EN1, and the PBX3 motif). Among epigenetically altered pathways, TP53, hypoxia and TNF signalling were linked to cancer initiation, whereas oestrogen response, epithelial-mesenchymal transition and apical junction were tied to metastatic transition. Furthermore, we revealed a marked correlation between enhancer accessibility and gene expression and uncovered cooperation between epigenetic and genetic drivers. This atlas provides a foundation for further investigation of epigenetic dynamics in cancer transitions.

Multimodal neuro-nanotechnology: Challenging the existing paradigm in glioblastoma therapy.

Integrating multimodal neuro- and nanotechnology-enabled precision immunotherapies with extant systemic immunotherapies may finally provide a significant breakthrough for combatting glioblastoma (GBM). The potency of this approach lies in its ability to train the immune system to efficiently identify and eradicate cancer cells, thereby creating anti-tumor immune memory while minimizing multi-mechanistic immune suppression. A critical aspect of these therapies is the controlled, spatiotemporal delivery of structurally defined nanotherapeutics into the GBM tumor microenvironment (TME). Architectures such as spherical nucleic acids or poly(beta-amino ester)/dendrimer-based nanoparticles have shown promising results in preclinical models due to their multivalency and abilities to activate antigen-presenting cells and prime antigen-specific T cells. These nanostructures also permit systematic variation to optimize their distribution, TME accumulation, cellular uptake, and overall immunostimulatory effects. Delving deeper into the relationships between nanotherapeutic structures and their performance will accelerate nano-drug development and pave the way for the rapid clinical translation of advanced nanomedicines. In addition, the efficacy of nanotechnology-based immunotherapies may be enhanced when integrated with emerging precision surgical techniques, such as laser interstitial thermal therapy, and when combined with systemic immunotherapies, particularly inhibitors of immune-mediated checkpoints and immunosuppressive adenosine signaling. In this perspective, we highlight the potential of emerging treatment modalities, combining advances in biomedical engineering and neurotechnology development with existing immunotherapies to overcome treatment resistance and transform the management of GBM. We conclude with a call to action for researchers to leverage these technologies and accelerate their translation into the clinic.

Fractional Flow Reserve-Guided PCI as Compared with Coronary Bypass Surgery.

BACKGROUND: Patients with three-vessel coronary artery disease have been found to have better outcomes with coronary-artery bypass grafting (CABG) than with percutaneous coronary intervention (PCI), but studies in which PCI is guided by measurement of fractional flow reserve (FFR) have been lacking. METHODS: In this multicenter, international, noninferiority trial, patients with three-vessel coronary artery disease were randomly assigned to undergo CABG or FFR-guided PCI with current-generation zotarolimus-eluting stents. The primary end point was the occurrence within 1 year of a major adverse cardiac or cerebrovascular event, defined as death from any cause, myocardial infarction, stroke, or repeat revascularization. Noninferiority of FFR-guided PCI to CABG was prespecified as an upper boundary of less than 1.65 for the 95% confidence interval of the hazard ratio. Secondary end points included a composite of death, myocardial infarction, or stroke; safety was also assessed. RESULTS: A total of 1500 patients underwent randomization at 48 centers. Patients assigned to undergo PCI received a mean (±SD) of 3.7±1.9 stents, and those assigned to undergo CABG received 3.4±1.0 distal anastomoses. The 1-year incidence of the composite primary end point was 10.6% among patients randomly assigned to undergo FFR-guided PCI and 6.9% among those assigned to undergo CABG (hazard ratio, 1.5; 95% confidence interval [CI], 1.1 to 2.2), findings that were not consistent with noninferiority of FFR-guided PCI (P = 0.35 for noninferiority). The incidence of death, myocardial infarction, or stroke was 7.3% in the FFR-guided PCI group and 5.2% in the CABG group (hazard ratio, 1.4; 95% CI, 0.9 to 2.1). The incidences of major bleeding, arrhythmia, and acute kidney injury were higher in the CABG group than in the FFR-guided PCI group. CONCLUSIONS: In patients with three-vessel coronary artery disease, FFR-guided PCI was not found to be noninferior to CABG with respect to the incidence of a composite of death, myocardial infarction, stroke, or repeat revascularization at 1 year. (Funded by Medtronic and Abbott Vascular; FAME 3 ClinicalTrials.gov number, NCT02100722.).

EF1α-associated protein complexes affect dendritic spine plasticity by regulating microglial phagocytosis in Fmr1 knock-out mice.

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability. There is no specific treatment for FXS due to the lack of therapeutic targets. We report here that Elongation Factor 1α (EF1α) forms a complex with two other proteins: Tripartite motif-containing protein 3 (TRIM3) and Murine double minute (Mdm2). Both EF1α-Mdm2 and EF1α-TRIM3 protein complexes are increased in the brain of Fmr1 knockout mice as a result of FMRP deficiency, which releases the normal translational suppression of EF1α mRNA and increases EF1α protein levels. Increased EF1α-Mdm2 complex decreases PSD-95 ubiquitination (Ub-PSD-95) and Ub-PSD-95-C1q interaction. The elevated level of TRIM3-EF1α complex is associated with decreased TRIM3-Complement Component 3 (C3) complex that inhibits the activation of C3. Both protein complexes thereby contribute to a reduction in microglia-mediated phagocytosis and dendritic spine pruning. Finally, we created a peptide that disrupts both protein complexes and restores dendritic spine plasticity and behavioural deficits in Fmr1 knockout mice. The EF1α-Mdm2 and EF1α-TRIM3 complexes could thus be new therapeutic targets for FXS.

Astrocytes Transplanted during Early Postnatal Development Integrate, Mature, and Survive Long Term in Mouse Cortex.

Astrocytes have complex structural, molecular, and physiological properties and form specialized microenvironments that support circuit-specific functions in the CNS. To better understand how astrocytes acquire their unique features, we transplanted immature mouse cortical astrocytes into the developing cortex of male and female mice and assessed their integration, maturation, and survival. Within days, transplanted astrocytes developed morphologies and acquired territories and tiling behavior typical of cortical astrocytes. At 35-47 d post-transplantation, astrocytes appeared morphologically mature and expressed levels of EAAT2/GLT1 similar to nontransplanted astrocytes. Transplanted astrocytes also supported excitatory/inhibitory (E/I) presynaptic terminals within their territories, and displayed normal Ca2+ events. Transplanted astrocytes showed initially reduced expression of aquaporin 4 (AQP4) at endfeet and elevated expression of EAAT1/GLAST, with both proteins showing normalized expression by 110 d and one year post-transplantation, respectively. To understand how specific brain regions support astrocytic integration and maturation, we transplanted cortical astrocytes into the developing cerebellum. Cortical astrocytes interlaced with Bergmann glia (BG) in the cerebellar molecular layer to establish discrete territories. However, transplanted astrocytes retained many cortical astrocytic features including higher levels of EAAT2/GLT1, lower levels of EAAT1/GLAST, and the absence of expression of the AMPAR subunit GluA1. Collectively, our findings demonstrate that immature cortical astrocytes integrate, mature, and survive (more than one year) following transplantation and retain cortical astrocytic properties. Astrocytic transplantation can be useful for investigating cell-autonomous (intrinsic) and non-cell-autonomous (environmental) mechanisms contributing to astrocytic development/diversity, and for determining the optimal timing for transplanting astrocytes for cellular delivery or replacement in regenerative medicine.SIGNIFICANCE STATEMENT The mechanisms that enable astrocytes to acquire diverse molecular and structural properties remain to be better understood. In this study, we systematically analyzed the properties of cortical astrocytes following their transplantation to the early postnatal brain. We found that immature cortical astrocytes transplanted into cerebral cortex during early postnatal mouse development integrate and establish normal astrocytic properties, and show long-term survival in vivo (more than one year). In contrast, transplanted cortical astrocytes display reduced or altered ability to integrate into the more mature cerebral cortex or developing cerebellum, respectively. This study demonstrates the developmental potential of transplanted cortical astrocytes and provides an approach to tease apart cell-autonomous (intrinsic) and non-cell-autonomous (environmental) mechanisms that determine the structural, molecular, and physiological phenotype of astrocytes.

Fractional Flow Reserve-Guided PCI or Coronary Bypass Surgery for 3-Vessel Coronary Artery Disease: 3-Year Follow-Up of the FAME 3 Trial.

BACKGROUND: Previous studies comparing percutaneous coronary intervention (PCI) with coronary artery bypass grafting (CABG) in patients with multivessel coronary disease not involving the left main have shown significantly lower rates of death, myocardial infarction (MI), or stroke after CABG. These studies did not routinely use current-generation drug-eluting stents or fractional flow reserve (FFR) to guide PCI. METHODS: FAME 3 (Fractional Flow Reserve versus Angiography for Multivessel Evaluation) is an investigator-initiated, multicenter, international, randomized trial involving patients with 3-vessel coronary artery disease (not involving the left main coronary artery) in 48 centers worldwide. Patients were randomly assigned to receive FFR-guided PCI using zotarolimus drug-eluting stents or CABG. The prespecified key secondary end point of the trial reported here is the 3-year incidence of the composite of death, MI, or stroke. RESULTS: A total of 1500 patients were randomized to FFR-guided PCI or CABG. Follow-up was achieved in >96% of patients in both groups. There was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI compared with CABG (12.0% versus 9.2%; hazard ratio [HR], 1.3 [95% CI, 0.98-1.83]; P=0.07). The rates of death (4.1% versus 3.9%; HR, 1.0 [95% CI, 0.6-1.7]; P=0.88) and stroke (1.6% versus 2.0%; HR, 0.8 [95% CI, 0.4-1.7]; P=0.56) were not different. MI occurred more frequently after PCI (7.0% versus 4.2%; HR, 1.7 [95% CI, 1.1-2.7]; P=0.02). CONCLUSIONS: At 3-year follow-up, there was no difference in the incidence of the composite of death, MI, or stroke after FFR-guided PCI with current-generation drug-eluting stents compared with CABG. There was a higher incidence of MI after PCI compared with CABG, with no difference in death or stroke. These results provide contemporary data to allow improved shared decision-making between physicians and patients with 3-vessel coronary artery disease. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02100722.

Immune checkpoint inhibitor-mediated polymyalgia rheumatica versus primary polymyalgia rheumatica: comparison of disease characteristics and treatment requirement.

OBJECTIVES: To compare clinical characteristics, imaging findings and treatment requirements of patients with immune checkpoint inhibitor-mediated polymyalgia rheumatica (ICI-PMR) and primary PMR. METHODS: This single centre, retrospective cohort study compared ICI-PMR in patients with cancer (n = 15) to patients with primary PMR (n = 37). A comparison was made between clinical symptoms, laboratory markers, ultrasonography,18F-FDG-PET/CT findings and treatment requirements related to PMR. RESULTS: Patients with ICI-PMR less frequently fulfilled the EULAR/ACR classification criteria for PMR (66.7%) than patients with primary PMR (97.3%). Morning stiffness, weight loss and elevation of the ESR were less frequently seen in patients with ICI-PMR. No differences were observed regarding the presence of inflammatory lesions on ultrasound of the shoulders and hips between the two groups. The Leuven and the Leuven/Groningen 18F-FDG-PET/CT scores were significantly lower in the ICI-PMR group. Finally, the ICI-PMR group could be managed with less glucocorticoids than the primary PMR group. CONCLUSION: Our findings indicate that ICI-PMR may have a milder course with less inflammation than primary PMR on 18F-FDG-PET/CT. ICI-mediated PMR patients can be managed with a relatively low glucocorticoid dose. Our study underscores that ICI-PMR should be regarded as PMR-like syndrome.

A centrosomal Cdc20-APC pathway controls dendrite morphogenesis in postmitotic neurons.

The ubiquitin ligase anaphase-promoting complex (APC) recruits the coactivator Cdc20 to drive mitosis in cycling cells. However, the nonmitotic functions of Cdc20-APC have remained unexplored. We report that Cdc20-APC plays an essential role in dendrite morphogenesis in postmitotic neurons. Knockdown of Cdc20 in cerebellar slices and in postnatal rats in vivo profoundly impairs the formation of granule neuron dendrite arbors in the cerebellar cortex. Remarkably, Cdc20 is enriched at the centrosome in neurons, and the centrosomal localization is critical for Cdc20-dependent dendrite development. We also find that the centrosome-associated protein histone deacetylase 6 (HDAC6) promotes the polyubiquitination of Cdc20, stimulates the activity of centrosomal Cdc20-APC, and drives the differentiation of dendrites. These findings define a postmitotic function for Cdc20-APC in the morphogenesis of dendrites in the mammalian brain. The identification of a centrosomal Cdc20-APC ubiquitin signaling pathway holds important implications for diverse biological processes, including neuronal connectivity and plasticity.

Tympanomastoidectomy versus parenteral antibiotic therapy for pediatric otorrhea.

OBJECTIVE: To evaluate the efficacy of tympanomastoidectomy versus parenteral antibiotic therapy for otorrhea as a result of chronic suppurative otitis media (CSOM) without cholesteatoma in the pediatric population. METHODS: A retrospective review of 221 patients treated for otorrhea at a tertiary academic pediatric hospital was performed to evaluate the impact of tympanomastoidectomy versus parenteral antibiotic therapy on resolution of otorrhea. Inclusion criteria were age 0-18 years, prior treatment with otic and/or oral antibiotic, prior history of tympanostomy tube placement for recurrent otitis media, history of otorrhea, treatment with tympanomastoidectomy or parenteral antibiotic therapy, and follow-up of at least 1 month after intervention. Time to resolution was compared between the two modalities adjusting for age, bilateral ear disease status, and comorbidities using a Cox proportional hazard model. RESULTS: Eighty-three ears from 58 children met the inclusion criteria. Ears that initially underwent tympanomastoidectomy had a significantly shorter time to resolution of symptoms (median time to resolution) 9 months (95 % confidence interval CI: 6.2-14.8) vs. 48.5 months (95 % lower CI 9.4, p = 0.006). On multivariate analysis, however, only bilateral ear disease status was independently associated with time to resolution of symptoms (hazard ratio 0.4, 95 % CI 0.2-0.9, p = 0.03). There was no statistically significant difference in the rate of treatment-related complications when comparing tympanomastoidectomy to parenteral antibiotic therapy (p = 0.37). CONCLUSION: When adjusting for age, bilateral ear disease status, and comorbidities, there does not appear to be a significant difference in time to resolution of symptoms when comparing parenteral antibiotic therapy to tympanomastoidectomy. An informed discussion regarding risks and benefits of each approach should be employed when deciding on the next step in management for patients with CSOM who have failed more conservative therapies.

The multifaceted mechanisms of malignant glioblastoma progression and clinical implications.

With the application of high throughput sequencing technologies at single-cell resolution, studies of the tumor microenvironment in glioblastoma, one of the most aggressive and invasive of all cancers, have revealed immense cellular and tissue heterogeneity. A unique extracellular scaffold system adapts to and supports progressive infiltration and migration of tumor cells, which is characterized by altered composition, effector delivery, and mechanical properties. The spatiotemporal interactions between malignant and immune cells generate an immunosuppressive microenvironment, contributing to the failure of effective anti-tumor immune attack. Among the heterogeneous tumor cell subpopulations of glioblastoma, glioma stem cells (GSCs), which exhibit tumorigenic properties and strong invasive capacity, are critical for tumor growth and are believed to contribute to therapeutic resistance and tumor recurrence. Here we discuss the role of extracellular matrix and immune cell populations, major components of the tumor ecosystem in glioblastoma, as well as signaling pathways that regulate GSC maintenance and invasion. We also highlight emerging advances in therapeutic targeting of these components.

Optimizing the Timeliness of Surgical Therapy in Patients with Breast Cancer Undergoing Immediate Breast Reconstruction.

BACKGROUND: In breast cancer, coordination of surgical therapy with immediate breast reconstruction (IBR) has been found to significantly delay surgical therapy, which in turn can have an adverse effect on patient survival. The objective of this study was to investigate factors that impact the timeliness of surgical therapy in this setting, which may help to optimize the care of patients with breast cancer. PATIENTS AND METHODS: Patients with breast cancer undergoing surgical therapy for breast cancer and immediate reconstruction were reviewed. Patients were divided into two groups: those who underwent surgery ≤ 30 days (group A) and > 30 days (group B) after diagnosis. Multivariate statistical analysis of demographic, disease, surgical, and process of care factors was performed. RESULTS: A total of 348 cases met inclusion criteria, of which 255 (73.2%) were in group A and 93 (26.7%) were in group B. No significant differences were identified in clinical stage, oncologic procedure, or type of reconstruction. On multivariate analysis, an increased likelihood of undergoing surgery ≤ 30 days of diagnosis was observed, with shorter time intervals between surgical oncologist and plastic surgeon consultations [odds ratio (OR) 1.3; 95% confidence interval (CI) 1.1-1.6, p = 0.011]. The number of operating days in common between the surgical oncologist and plastic surgeon nor having the same clinic day impacted timeliness. CONCLUSIONS: Patients may undergo both breast conservation surgery and mastectomy with all major types of immediate reconstruction in a timely manner. Early initiation of plastic surgery referrals and surgeon flexibility to work outside the parameters of institutional schedules may help facilitate the timeliness of surgery.

Predicting survival in glioblastoma with multimodal neuroimaging and machine learning.

PURPOSE: Glioblastoma (GBM) is the most common and aggressive malignant glioma, with an overall median survival of less than two years. The ability to predict survival before treatment in GBM patients would lead to improved disease management, clinical trial enrollment, and patient care. METHODS: GBM patients (N = 133, mean age 60.8 years, median survival 14.1 months, 57.9% male) were retrospectively recruited from the neurosurgery brain tumor service at Washington University Medical Center. All patients completed structural neuroimaging and resting state functional MRI (RS-fMRI) before surgery. Demographics, measures of cortical thickness (CT), and resting state functional network connectivity (FC) were used to train a deep neural network to classify patients based on survival (< 1y, 1-2y, >2y). Permutation feature importance identified the strongest predictors of survival based on the trained models. RESULTS: The models achieved a combined cross-validation and hold out accuracy of 90.6% in classifying survival (< 1y, 1-2y, >2y). The strongest demographic predictors were age at diagnosis and sex. The strongest CT predictors of survival included the superior temporal sulcus, parahippocampal gyrus, pericalcarine, pars triangularis, and middle temporal regions. The strongest FC features primarily involved dorsal and inferior somatomotor, visual, and cingulo-opercular networks. CONCLUSION: We demonstrate that machine learning can accurately classify survival in GBM patients based on multimodal neuroimaging before any surgical or medical intervention. These results were achieved without information regarding presentation symptoms, treatments, postsurgical outcomes, or tumor genomic information. Our results suggest GBMs have a global effect on the brain's structural and functional organization, which is predictive of survival.

Review of Mechanisms and Research Methods for Blunt Ballistic Head Injury.

Head injuries account for 15%-20% of all military injuries and pose a high risk of causing functional disability and fatality. Blunt ballistic impacts are one of the threats that can lead to severe head injuries. This review aims to examine the mechanisms and injury risk assessment associated with blunt ballistic head injury (BBHI). The review further discusses research methods and instrumentation used in BBHI studies, focusing on their limitations and challenges. Studies on the mechanisms of focal and diffuse brain injuries remain largely inconclusive and require further effort. Some studies have attempted to associate BBHIs with head mechanics, but more research is required to establish correlations between head mechanics and injury severity. Limited access to experimental models and a lack of instrumentation capable of measuring the mechanics of brain tissue in situ are potential reasons for the lack of understanding of injury mechanisms, injury correlations, and injury tolerance levels specific to this loading regime. Targeted research for understanding and assessing head injuries in blunt ballistic impacts is a necessary step in improving our ability to design protection systems to mitigate these injuries.

Predictors and Outcomes of Stroke After Isolated Coronary Artery Bypass Grafting. A Single-Center Experience in 20,582 Patients.

OBJECTIVE: Stroke remains a devastating complication after cardiac surgical procedures despite perioperative monitoring and management advances. This study aimed to determine the predictors of stroke in a large, contemporary coronary artery surgery population. DESIGN: Patient data were analyzed retrospectively. SETTING: This single-center study was performed in the Catharina Hospital (Eindhoven). PARTICIPANTS: All patients who underwent isolated coronary artery bypass grafting (CABG) between January 1998 and February 2019 were included. INTERVENTIONS: Isolated CABG. MEASUREMENTS AND MAIN RESULTS: The primary endpoint was a postoperative stroke, defined according to the international updated definition for stroke. Logistic regression was performed to retrieve variables associated with postoperative stroke. A total of 20,582 patients underwent CABG during the period of the study. Stroke was observed in 142 patients (0.7%), of which 75 (52.8%) occurred during the first 72 hours. The incidence of postoperative stroke declined over the years. A significantly higher 30-day mortality rate was seen in patients with stroke (20.4%) compared with 1.8% in the rest of the population; p < 0.001. Multivariate logistic regression analysis showed age, peripheral arterial disease, reexploration for bleeding, perioperative myocardial infarction, and year of surgery as independent predictors for stroke. Patients with postoperative stroke had worse long-term survival (log-rank p < 0.001). Cox regression analysis revealed postoperative stroke (odds ratio 2.13 [1.73-2.64)) as an independent predictor of late mortality. CONCLUSIONS: Stroke after CABG is associated with high early and late mortality. Age, peripheral vascular disease, and the year of surgery were associated with postoperative stroke.

Clinical Static Balance Assessment: A Narrative Review of Traditional and IMU-Based Posturography in Older Adults and Individuals with Incomplete Spinal Cord Injury.

Maintaining a stable upright posture is essential for performing activities of daily living, and impaired standing balance may impact an individual's quality of life. Therefore, accurate and sensitive methods for assessing static balance are crucial for identifying balance impairments, understanding the underlying mechanisms of the balance deficiencies, and developing targeted interventions to improve standing balance and prevent falls. This review paper first explores the methods to quantify standing balance. Then, it reviews traditional posturography and recent advancements in using wearable inertial measurement units (IMUs) to assess static balance in two populations: older adults and those with incomplete spinal cord injury (iSCI). The inclusion of these two groups is supported by their large representation among individuals with balance impairments. Also, each group exhibits distinct aspects in balance assessment due to diverse underlying causes associated with aging and neurological impairment. Given the high vulnerability of both demographics to balance impairments and falls, the significance of targeted interventions to improve standing balance and mitigate fall risk becomes apparent. Overall, this review highlights the importance of static balance assessment and the potential of emerging methods and technologies to improve our understanding of postural control in different populations.

Barriers and facilitators to multidimensional symptom management in palliative care: A focus group study among patient representatives and clinicians.

OBJECTIVES: It is widely acknowledged that co-occurring symptoms in patients with a psychosocial and spiritual aspects should also be considered. However, this multidimensional approach is difficult to integrate into daily practice, especially for generalist clinicians not specialized in palliative care. We aimed to identify the barriers and facilitators to multidimensional symptom management. METHODS: Focus group meetings were conducted with the following stakeholders: (1) patient representatives, (2) generalist community nurses, (3) generalist hospital nurses, (4) general practitioners, (5) generalist hospital physicians, and (6) palliative care specialists. Audiotapes were transcribed verbatim and thematically analyzed. RESULTS: Fifty-one participants (6-12 per group) reported barriers and facilitators with 3 main themes: multidimensional symptom assessment, initiating management of nonphysical problems, and multidisciplinary collaboration. As barriers, generalist clinicians and palliative care specialists reported that generalist clinicians often lack the communication skills to address nonphysical problems and are unaware of available resources for multidimensional symptom management. Palliative care specialists felt that generalist clinicians may be unaware that assessing nonphysical problems is important and focus on pharmacological interventions. Generalist nurses and palliative care specialists indicated that hierarchical difficulties between them and generalist physicians are barriers to multidisciplinary collaboration. Reported facilitators included using symptom assessment scales and standardized questions on nonphysical problems. SIGNIFICANCE OF RESULTS: Generalist clinicians can be supported by improving their communication skills, increasing their awareness of available resources for multidimensional symptom management, and by using a standardized approach to assess all 4 dimensions of palliative care.

Exploring CRD mobility during RAS/RAF engagement at the membrane.

During the activation of mitogen-activated protein kinase (MAPK) signaling, the RAS-binding domain (RBD) and cysteine-rich domain (CRD) of RAF bind to active RAS at the plasma membrane. The orientation of RAS at the membrane may be critical for formation of the RAS-RBDCRD complex and subsequent signaling. To explore how RAS membrane orientation relates to the protein dynamics within the RAS-RBDCRD complex, we perform multiscale coarse-grained and all-atom molecular dynamics (MD) simulations of KRAS4b bound to the RBD and CRD domains of RAF-1, both in solution and anchored to a model plasma membrane. Solution MD simulations describe dynamic KRAS4b-CRD conformations, suggesting that the CRD has sufficient flexibility in this environment to substantially change its binding interface with KRAS4b. In contrast, when the ternary complex is anchored to the membrane, the mobility of the CRD relative to KRAS4b is restricted, resulting in fewer distinct KRAS4b-CRD conformations. These simulations implicate membrane orientations of the ternary complex that are consistent with NMR measurements. While a crystal structure-like conformation is observed in both solution and membrane simulations, a particular intermolecular rearrangement of the ternary complex is observed only when it is anchored to the membrane. This configuration emerges when the CRD hydrophobic loops are inserted into the membrane and helices α3-5 of KRAS4b are solvent exposed. This membrane-specific configuration is stabilized by KRAS4b-CRD contacts that are not observed in the crystal structure. These results suggest modulatory interplay between the CRD and plasma membrane that correlate with RAS/RAF complex structure and dynamics, and potentially influence subsequent steps in the activation of MAPK signaling.

Acute heat exposure improves microvascular function in skeletal muscle of aged adults.

Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. We hypothesized that acute hot water immersion would improve endothelial-dependent, but not endothelial-independent vasodilation in the microcirculation of the vastus lateralis muscle in healthy aged adults. Participants (70 ± 5 yr) were immersed for 60 min in thermoneutral (36°C) or hot (40°C) water. Ninety minutes following immersion, skeletal muscle microdialysis was used to bypass the cutaneous circulation and directly assess endothelial-dependent and endothelial-independent vasodilation by measuring the local hyperemic response to graded infusions of acetylcholine (ACh, 27.5 and 55.0 mM) and sodium nitroprusside (SNP, 21 and 42 mM), respectively. The hyperemic response to 27.5 mM ACh did not differ between thermal conditions (P = 0.9). However, the hyperemic response to 55.0 mM ACh was increased with prior hot water immersion (thermoneutral immersion, 43.9 ± 23.2 mL/min/100 g vs. hot water immersion, 66.5 ± 25.5 mL/min/100 g; P < 0.01). Similarly, the hyperemic response to 21 mM SNP did not differ between thermal conditions (P = 0.3) but was increased following hot water immersion with the infusion of 42 mM SNP (thermoneutral immersion, 48.8 ± 25.6 mL/min/100 g vs. hot water immersion, 90.7 ± 53.5 mL/min/100 g; P < 0.01). These data suggest that acute heat exposure improves microvascular function in skeletal muscle of aged humans.NEW & NOTEWORTHY Acute heat exposure improves microvascular function in aged adults as assessed using reactive hyperemia. The cutaneous and skeletal muscle microcirculations are thought to contribute to this response, but this has never been confirmed due to the methodological challenges associated with differentiating blood flow between these vascular beds. Using the microdialysis technique to bypass the cutaneous circulation, we demonstrated that heat exposure improves endothelial-dependent and endothelial-independent vasodilation in the microcirculation of skeletal muscle in aged humans.

Acute heat exposure protects against endothelial ischemia-reperfusion injury in aged humans.

Nonpharmacological therapies that protect against endothelial ischemia-reperfusion injury (I/R) remain limited in aged adults. Acute heat exposure protects against endothelial I/R injury in young adults, but its efficacy has never been explored in aged adults. Therefore, we tested the hypothesis that acute heat exposure would prevent the attenuation of endothelium-dependent vasodilation after I/R injury in aged adults. Nine (2 men, 69 ± 8 yr) aged adults were exposed to a thermoneutral control condition or whole body passive heating (water-perfused suit) sufficient to increase body core temperature by 1.2°C. Experiments were separated by at least 7 days. Heat exposure was always performed first to time match the thermoneutral control condition. Endothelium-dependent vasodilation was assessed via flow-mediated dilation of the brachial artery before (pre-I/R) and after I/R injury (post-I/R), which was induced by 20 min of arm ischemia followed by 20 min of reperfusion. Flow-mediated dilation was reduced following I/R injury for the thermoneutral control condition (pre-I/R, 4.5 ± 2.9% vs. post-I/R, 0.9 ± 2.8%, P < 0.01), but was well maintained with prior heat exposure (pre-I/R, 4.4 ± 2.8% vs. post-I/R, 3.5 ± 2.8%, P = 0.5). Taken together, acute heat exposure protects against endothelial I/R injury in aged adults. These results highlight the therapeutic potential of heat therapy to prevent endothelial dysfunction associated with I/R injury in aged adults who are most at risk for an ischemic event.