IL-27 Gene Therapy Induces Stat3-Mediated Expansion of CD11b+Gr1+ Myeloid Cells and Promotes Accumulation of M1 Macrophages in the Tumor Microenvironment.

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells and has a potential to be used as a therapeutic for cancer. We have recently demonstrated that administration of IL-27 producing adeno-associated virus (AAV-IL-27) exhibits potent inhibition of tumor growth in mouse models. In this study, we demonstrate that AAV-IL-27 treatment leads to significant expansion of CD11b+Gr1+ myeloid cells. AAV-IL-27-induced expansion of CD11b+Gr1+ cells is IL-27R-dependent and requires Stat3 signaling, but it is inhibited by Stat1 signaling. AAV-IL-27 treatment does not increase the self-renewal capacity of CD11b+Gr1+ cells but induces significant expansion of Lin-Sca1+c-Kit+ (LSK) and granulocyte-monocyte progenitor cells. Despite exhibiting significant suppression of T cells in vitro, IL-27-induced CD11b+Gr1+ cells lost the tumor-promoting activity in vivo and overall play an antitumor role. In tumors from AAV-IL-27-treated mice, CD11b+Gr1+ cells are largely F4/80+ and express high levels of MHC class I/II and M1 macrophage markers. Thus, IL-27 gene therapy induces Stat3-mediated expansion of CD11b+Gr1+ myeloid cells and promotes accumulation of M1 macrophages in the tumor microenvironment.

IL-27 Induces CCL5 Production by T Lymphocytes, Which Contributes to Antitumor Activity.

IL-27 is a pleiotropic cytokine that exhibits stimulatory/regulatory functions on multiple lineages of immune cells including T lymphocytes. In this study, we demonstrate that IL-27 directly induces CCL5 production by T lymphocytes, particularly CD8+ T cells in vitro and in vivo. IL-27-induced CCL5 production is IL-27R-dependent. In CD4+ T cells, IL-27-induced CCL5 production was primarily dependent on Stat1 activation, whereas in CD8+ T cells, Stat1 deficiency does not abrogate CCL5 induction. A chromatin immunoprecipitation assay revealed that in the CCL5 promoter region, both putative Stat3 binding sites exhibit significant binding to Stat3, whereas only one out of four Stat1 binding sites displays moderate binding to Stat1. In tumor-bearing mice, IL-27 induced dramatic production of CCL5 in tumor-infiltrating T cells. IL-27-induced CCL5 appears to contribute to an IL-27-mediated antitumor effect. This is signified by diminished tumor inhibition in anti-CCL5- and IL-27-treated mice. Additionally, intratumor delivery of CCL5 mRNA using lipid nanoparticles significantly inhibited tumor growth. Thus, IL-27 induces robust CCL5 production by T cells, which contributes to antitumor activity.

Impact of concurrent glomerulonephritis on outcomes of diffuse alveolar haemorrhage in antineutrophil cytoplasmic antibody-associated vasculitis.

OBJECTIVES: Antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) commonly presents with diffuse alveolar haemorrhage (DAH) and/or glomerulonephritis. Patients who present with DAH but without kidney involvement have been understudied. METHODS: Patients with DAH diagnosed by bronchoscopy and attributed to AAV over 8.5 years were retrospectively identified through electronic medical records and bronchoscopy reporting software. Patients with end-stage kidney disease (ESKD) or prior kidney transplant were excluded. Characteristics, treatments, and outcomes were abstracted. RESULTS: 30 patients were identified with DAH secondary to AAV. Five with ESKD or prior kidney transplant, and one with concomitant anti-glomerular basement membrane disease, were excluded, leaving 24 patients for analysis. At the time of qualifying bronchoscopy, six patients had no apparent kidney involvement by AAV, while eight of 18 with kidney involvement required dialysis. Of the eight patients dialysed during the initial hospitalisation, four were declared to have ESKD and three died in the subsequent year (one of whom did both). None of the 16 patients without initial dialysis requirement developed kidney involvement requiring dialysis in the subsequent year, though three of the six without initial evidence of kidney involvement by AAV ultimately developed it. No patient without initial kidney involvement died during follow-up. CONCLUSIONS: In our cohort, patients with DAH due to AAV without initial kidney involvement did not develop kidney involvement requiring dialysis or die during the follow-up period, though half of patients without initial evidence of kidney involvement subsequently developed it. Larger studies are warranted to better characterise this population and guide medical management.

A randomized crossover single-case series comparing blocked versus random treatment for anomia.

The motor learning literature has demonstrated that blocked practice facilitates better acquisition of motor skills, whereas random practice facilitates retention and transfer. The verbal learning and memory literature offers similar evidence. The purpose of this study was to investigate effects of blocked versus random practice in treatment for anomia. The study used a single site, randomized crossover design, with two replicated experimental phases (two blocked and two random) for each of 10 individuals with anomia. Each phase consisted of a cued picture-naming treatment. Individual treatment and maintenance effects, as well as weighted averages and group effects, were calculated using Tau-U based on the proportion of correctly named probes. Nine of 10 participants demonstrated treatment effects during each of the four phases. Acquisition was comparable for blocked and random practice. Maintenance effects were observed following seven blocked phases of treatment and 12 random phases of treatment across participants. For four of 10 participants the random schedule resulted in better maintenance of trained items. Although further research is needed, the present data suggest that for word retrieval treatment with multiple repetitions of the same items, a random presentation may benefit maintenance of treatment gains.

For Which Children with ADHD is TBR Neurofeedback Effective? Comorbidity as a Moderator.

We examined psychiatric comorbidities moderation of a 2-site double-blind randomized clinical trial of theta/beta-ratio (TBR) neurofeedback (NF) for attention deficit hyperactivity disorder (ADHD). Seven-to-ten-year-olds with ADHD received either NF (n = 84) or Control (n = 58) for 38 treatments. Outcome was change in parent-/teacher-rated inattention from baseline to end-of-treatment (acute effect), and 13-month-follow-up. Seventy percent had at least one comorbidity: oppositional defiant disorder (ODD) (50%), specific phobias (27%), generalized anxiety (23%), separation anxiety (16%). Comorbidities were grouped into anxiety alone (20%), ODD alone (23%), neither (30%), or both (27%). Comorbidity (p = 0.043) moderated acute effect; those with anxiety-alone responded better to Control than to TBR NF (d = - 0.79, CI - 1.55- - 0.04), and the other groups showed a slightly better response to TBR NF than to Control (d = 0.22 ~ 0.31, CI - 0.3-0.98). At 13-months, ODD-alone group responded better to NF than Control (d = 0.74, CI 0.05-1.43). TBR NF is not indicated for ADHD with comorbid anxiety but may benefit ADHD with ODD.Clinical Trials Identifier: NCT02251743, date of registration: 09/17/2014.

EEG Connectivity in ADHD Compared to a Normative Database: A Cohort Analysis of 120 Subjects from the ICAN Study.

This study explores how EEG connectivity measures in children with ADHD ages 7-10 (n = 140) differ from an age-matched nonclinical database. We differentiated connectivity in networks, Brodmann area pairs, and frequencies. Subjects were in the International Collaborative ADHD Neurofeedback study, which explored neurofeedback for ADHD. Inclusion criteria were mainly rigorously diagnosed ADHD and a theta/beta power ratio (TBR) ≤ 4.5. Using statistical and machine learning algorithms, connectivity values were extracted in coherence, phase, and lag coherence at all Brodmann, subcortical, and cerebellar areas within the main networks in all EEG frequencies and then compared with a normative database. There is a higher rate of dysregulation (more than ± 1.97SD), in some cases as much as 75%, of the Brodmann pairs observed in coherence and phase between BAs 7, 10, and 11 with secondary connections from these areas to BAs 21, 30, 35, 37, 39, and 40 in the ADHD children as compared to the normative database. Left and right Brodmann areas 10 and 11 are highly disconnected to each other. The most dysregulated Brodmann Areas in ADHD are 7, 10, and 11, relevant to ADHD executive-function deficits and provide important considerations when developing interventions for ADHD children.

Update of a prognostic survival model in head and neck squamous cell carcinoma patients treated with immune checkpoint inhibitors using an expansion cohort.

BACKGROUND: Immune checkpoint inhibitors (ICI) treatment in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) offers new therapeutic venues. We have previously developed a predictive survival model in this patient population based on clinical parameters, and the purpose of this study was to expand the study cohort and internally validate the model. METHODS: A single institutional retrospective analysis of R/M HNSCC patients treated with ICI. Clinical parameters collected included p-16 status, hemoglobin (Hb), albumin (Alb), lactate dehydrogenase (LDH), neutrophil, lymphocyte and platelet counts. Cox proportional hazard regression was used to assess the impact of patient characteristics and clinical variables on survival. A nomogram was created using the rms package to generate individualized survival prediction. RESULTS: 201 patients were included, 47 females (23%), 154 males (77%). Median age was 61 years (IQR: 55-68). P-16 negative (66%). Median OS was 12 months (95% CI: 9.4, 14.9). Updated OS model included age, sex, absolute neutrophil count, absolute lymphocyte count, albumin, hemoglobin, LDH, and p-16 status. We stratified patients into three risk groups based on this model at the 0.33 and 0.66 quantiles. Median OS in the optimal risk group reached 23.7 months (CI: 18.5, NR), 13.8 months (CI: 11.1, 20.3) in the average risk group, and 2.3 months (CI: 1.7, 4.4) in the high-risk group. Following internal validation, the discriminatory power of the model reached a c-index of 0.72 and calibration slope of 0.79. CONCLUSIONS: Our updated nomogram could assist in the precise selection of patients for which ICI could be beneficial and cost-effective.

Mechanical Deformation of Peripapillary Retina in Response to Acute Intraocular Pressure Elevation.

Elevated intraocular pressure (IOP) may cause mechanical injuries to the optic nerve head (ONH) and the peripapillary tissues in glaucoma. Previous studies have reported the mechanical deformation of the ONH and the peripapillary sclera (PPS) at elevated IOP. The deformation of the peripapillary retina (PPR) has not been well-characterized. Here we applied high-frequency ultrasound elastography to map and quantify PPR deformation, and compared PPR, PPS and ONH deformation in the same eye. Whole globe inflation was performed in ten human donor eyes. High-frequency ultrasound scans of the posterior eye were acquired while IOP was raised from 5 to 30 mmHg. A correlation-based ultrasound speckle tracking algorithm was used to compute pressure-induced displacements within the scanned tissue cross sections. Radial, tangential, and shear strains were calculated for the PPR, PPS, and ONH regions. In PPR, shear was significantly larger in magnitude than radial and tangential strains. Strain maps showed localized high shear and high tangential strains in PPR. In comparison to PPS and ONH, PPR had greater shear and a similar level of tangential strain. Surprisingly, PPR radial compression was minimal and significantly smaller than that in PPS. These results provide new insights into PPR deformation in response of IOP elevation, suggesting that shear rather than compression was likely the primary mode of IOP-induced mechanical insult in PPR. High shear, especially localized high shear, may contribute to the mechanical damage of this tissue in glaucoma.

The Long-Term Residual Effects of Low-Magnitude Mechanical Stimulation on Murine Femoral Mechanics.

As an alternative to drug treatments, low-magnitude mechanical stimulation (LMMS) may improve skeletal health without potential side effects from drugs. LMMS has been shown to increase bone health short term in both animal and clinical studies. Long-term changes to the mechanical properties of bone from LMMS are currently unknown, so the objective of this research was to establish the methodology and preliminary results for investigating the long-term effects of whole body vibration therapy on the elastic and viscoelastic properties of bone. In this study, 10-week-old female BALB/cByJ mice were given LMMS (15 min/day, 5 days/week, 0.3 g, 90 Hz) for 8 weeks; SHAM did not receive LMMS. Two sets of groups remained on study for an additional 8 or 16 weeks post-LMMS (N = 17). Micro-CT and fluorochrome histomorphology of these femurs were studied and results were published by Bodnyk et al. (2020, "The Long-Term Residual Effects of Low-Magnitude Mechanical Stimulation Therapy on Skeletal Health," J. Biol. Eng., 14, Article No. 9.). Femoral quasi-static bending stiffness trended 4.2% increase in stiffness after 8 weeks of LMMS and 1.3% increase 8 weeks post-LMMS compared to SHAM. Damping, tan delta, and loss stiffness significantly increased by 17.6%, 16.3%, and 16.6%, respectively, at 8 weeks LMMS compared to SHAM. Finite element models of applied LMMS signal showed decreased stress in the mid-diaphyseal region at both 8-week LMMS and 8-week post-LMMS compared to SHAM. Residual mechanical changes in bone during and post-LMMS indicate that LMMS could be used to increase long-term mechanical integrity of bone.

Parent-Reported PEDI-CAT Mobility and Gross Motor Function in Infants With Cerebral Palsy.

PURPOSE: The purpose of this study is to determine the relationship between the Pediatric Evaluation of Disability Index-Computer Adapted Test (PEDI-CAT), a parent-reported outcome measure, and therapist-administered measures of motor function for infants with cerebral palsy (CP) with moderate to severe motor impairments. METHODS: A prospective, cohort study included 54 infants, ages 6 to 24 months, with CP or high risk of CP, Gross Motor Function Classification System (GMFCS) levels III to V. Measures included the Gross Motor Function Measure (GMFM) and the mobility domain of the PEDI-CAT (PEDI-mob). RESULTS: A significant correlation was found between PEDI-mob and GMFM scores. Significant differences were found in PEDI-mob scores as a function of GMFCS level. CONCLUSIONS: The PEDI-mob adds value to motor evaluations of infants with CP. Parents can accurately contribute information about daily motor performance for goal setting and treatment planning. The PEDI-mob offers a practical solution when longer assessments cannot be completed.

IOP-induced regional displacements in the optic nerve head and correlation with peripapillary sclera thickness.

Mechanical insult induced by intraocular pressure (IOP) is likely a driving force in the disease process of glaucoma. This study aimed to evaluate regional displacements in human optic nerve head (ONH) and peripapillary tissue (PPT) in response to acute IOP elevations, and their correlations with morphological characteristics of the posterior eye. Cross-sectional (2D) images of the ONH and PPT in 14 globes of 14 human donors were acquired with high-frequency ultrasound during whole globe inflation from 5 to 30 mm Hg. High-frequency ultrasound has a spatial resolution of tens of micrometers and is capable of imaging through the ONH and PPT thickness. Tissue displacements were calculated using a correlation-based speckle tracking algorithm for a dense matrix of kernels covering the 2D imaging plane. The ONH was manually segmented in the ultrasound B-mode images acquired at 5 mmHg based on echogenicity. The lamina cribrosa (LC) boundaries were visible in eight of the fourteen eyes and the LC region was segmented using a semi-automated superpixel-based method. The ONH had larger radial displacement than the PPT in all tested eyes and the difference increased with increasing IOP. A significant negative correlation was found between ONH-PPT displacement difference and PPT thickness (p < 0.05), while no significant correlations were found between ONH-PPT displacement difference and other morphological parameters including PPT radius of curvature, scleral canal size, LC thickness and anterior LC surface depth. Within the ONH, the radial displacement decreased in the region anterior to and across LC but not in the region posterior to LC. Finite element models using simplified geometry and material properties confirmed the role of LC in reducing the overall ONH radial displacements, but did not predict the displacement gradient change observed experimentally. These results suggested that a thinner PPT may be associated with a larger relative posterior motion of the ONH with respect to the surrounding PPT and the LC may play a major role in preventing excessive posterior displacement of ONH during acute IOP elevations.

Three-Dimensional Inflation Response of Porcine Optic Nerve Head Using High-Frequency Ultrasound Elastography.

Characterization of the biomechanical behavior of the optic nerve head (ONH) in response to intraocular pressure (IOP) elevation is important for understanding glaucoma susceptibility. In this study, we aimed to develop and validate a three-dimensional (3D) ultrasound elastographic technique to obtain mapping and visualization of the 3D distributive displacements and strains of the ONH and surrounding peripapillary tissue (PPT) during whole globe inflation from 15 to 30 mmHg. 3D scans of the posterior eye around the ONH were acquired through full tissue thickness with a high-frequency ultrasound system (50 MHz). A 3D cross-correlation-based speckle-tracking algorithm was used to compute tissue displacements at ∼30,000 kernels distributed within the region of interest (ROI), and the components of the strain tensors were calculated at each kernel by using least square estimation of the displacement gradients. The accuracy of displacement calculation was evaluated using simulated rigid-body translation on ultrasound radiofrequency (RF) data obtained from a porcine posterior eye. The accuracy of strain calculation was evaluated using finite element (FE) models. Three porcine eyes were tested showing that ONH deformation was heterogeneous with localized high strains. Substantial radial (i.e., through-thickness) compression was observed in the anterior ONH and out-of-plane (i.e., perpendicular to the surface of the shell) shear was shown to concentrate in the vicinity of ONH/PPT border. These preliminary results demonstrated the feasibility of this technique to achieve comprehensive 3D evaluation of the mechanical responses of the posterior eye, which may provide mechanistic insights into the regional susceptibility in glaucoma.

3D Motion Capture May Detect Spatiotemporal Changes in Pre-Reaching Upper Extremity Movements with and without a Real-Time Constraint Condition in Infants with Perinatal Stroke and Cerebral Palsy: A Longitudinal Case Series.

Perinatal stroke (PS), occurring between 20 weeks of gestation and 28 days of life, is a leading cause of hemiplegic cerebral palsy (HCP). Hallmarks of HCP are motor and sensory impairments on one side of the body-especially the arm and hand contralateral to the stroke (involved side). HCP is diagnosed months or years after the original brain injury. One effective early intervention for this population is constraint-induced movement therapy (CIMT), where the uninvolved arm is constrained by a mitt or cast, and therapeutic activities are performed with the involved arm. In this preliminary investigation, we used 3D motion capture to measure the spatiotemporal characteristics of pre-reaching upper extremity movements and any changes that occurred when constraint was applied in a real-time laboratory simulation. Participants were N = 14 full-term infants: N = six infants with typical development; and N = eight infants with PS (N = three infants with PS were later diagnosed with cerebral palsy (CP)) followed longitudinally from 2 to 6 months of age. We aimed to evaluate the feasibility of using 3D motion capture to identify the differences in the spatiotemporal characteristics of the pre-reaching upper extremity movements between the diagnosis group, involved versus uninvolved side, and with versus and without constraint applied in real time. This would be an excellent application of wearable sensors, allowing some of these measurements to be taken in a clinical or home setting.

Different Spectral Analysis Methods for the Theta/Beta Ratio Calculate Different Ratios But Do Not Distinguish ADHD from Controls.

There has been ongoing research on the ratio of theta to beta power (Theta/Beta Ratio, TBR) as an EEG-based test in the diagnosis of ADHD. Earlier studies reported significant TBR differences between patients with ADHD and controls. However, a recent meta-analysis revealed a marked decline of effect size for the difference in TBR between ADHD and controls for studies published in the past decade. Here, we test if differences in EEG processing explain the heterogeneity of findings. We analyzed EEG data from two multi-center clinical studies. Five different EEG signal processing algorithms were applied to calculate the TBR. Differences between resulting TBRs were subsequently assessed for clinical usability in the iSPOT-A dataset. Although there were significant differences in the resulting TBRs, none distinguished between children with and without ADHD, and no consistent associations with ADHD symptoms arose. Different methods for EEG signal processing result in significantly different TBRs. However, none of the methods significantly distinguished between ADHD and healthy controls in our sample. The secular effect size decline for the TBR is most likely explained by factors other than differences in EEG signal processing, e.g. fewer hours of sleep in participants and differences in inclusion criteria for healthy controls.

Evaluation of Mycobacterium tuberculosis lipoarabinomannan antigen assay and rapid serology blood test for the diagnosis of bovine tuberculosis in Ethiopia.

BACKGROUND: Bovine tuberculosis (bTB) is prevalent in dairy cattle in Ethiopia. Currently used diagnostic tools such as the single intradermal comparative tuberculin test (SICTT) are time consuming and labor intensive. A rapid, easy-to-use and cost-effective diagnostic test would greatly contribute to the control of bTB in developing countries like Ethiopia. In the present study, two point-of-care diagnostic tests were evaluated for the detection of bTB: LIONEX® Animal TB Rapid test, a membrane-based test for the detection of antibodies to Mycobacterium bovis in blood and ALERE® Determine TB Lipoarabinomannan (LAM) Ag, an immunoassay for the detection of lipoarabinomannan (LAM) antigen (Ag) of mycobacteria in urine. A combination of the SICTT and gamma interferon (IFN-γ) test was used as the gold standard for the validation of these point-of-care tests, as it was not feasible to slaughter the study animals to carry out the historical gold standard of mycobacterial culture. A total of 175 heads of cattle having three different bTB infection categories (positive SICTT, negative SICTT, and unknown SICTT status) were used for this study. RESULT: The sensitivity and specificity of TB LAM Ag were 72.2% (95% CI = 62.2, 80.4) and 98.8% (95% CI = 93.6, 99.7), respectively, while the sensitivity and specificity of the LIONEX Animal TB rapid test assay were 54% (95% CI = 44.1 64.3) and 98.8% (95% CI = 93.6, 99.7) respectively. The agreement between TB LAM Ag and SICTT was higher (κ = 0.85; 95% CI = 0.65-0.94) than between TB LAM Ag and IFN-γ (κ = 0.67; 95% CI = 0.52-0.81). The agreement between LIONEX Animals TB Rapid blood test and SICTT was substantial, (κ = 0.63; 95% CI = 0.49-0.77) while the agreement between LIONEX Animal TB rapid blood test and IFN-γ test was moderate (κ = 0.53; 95% CI = 0.40-0.67). Analysis of receiver operating curve (ROC) indicated that the area under the ROC curve (AUC) for TB LAM Ag was 0.85 (95% CI = 0.79-0.91) while it was 0.76 (95% CI; =0.69-0.83) for LIONEX Animal TB rapid test assay. CONCLUSION: This study showed that TB LAM Ag had a better diagnostic performance and could potentially be used as ancillary either to SICTT or IFN-γ test for diagnosis of bTB.

Randomized placebo-controlled pilot trial of omega 3 fatty acids for prevention of aromatase inhibitor-induced musculoskeletal pain.

PURPOSE: Aromatase inhibitor (AI)-induced joint symptoms negatively impact drug adherence and quality of life in breast cancer survivors. Mechanisms underlying symptoms may include inflammation. It is hypothesized that n - 3 polyunsaturated fatty acids (PUFAs) have anti-inflammatory properties and may reduce symptoms. METHODS: We conducted a randomized, double-blind, placebo-controlled study comparing 4.3 g/day n - 3 PUFA supplements vs placebo for 24 weeks in postmenopausal breast cancer patients starting adjuvant AIs. Primary endpoints were adherence and tolerability; secondary outcomes included inflammatory cytokines and symptoms assessed by the Brief Pain Inventory short form (BPI-SF) and Functional Assessment of Cancer Treatment-Endocrine Symptoms (FACT-ES) at 0, 12, and 24 weeks. RESULTS: Forty-four women were randomized, of which 35 completed the study. Adherence was ≥ 88% based on these 35 patients with pill counts as well as change in red blood cell (RBC) n - 3 PUFAs. Common toxicities included grade 1 flatulence (55% of both groups) and belching (45% of n - 3 group). Mean pain severity scores (BPI-SF) did not change significantly by time or treatment arm. Quality of life, based on FACT-ES scores, significantly decreased within placebo (p = 0.04), but not the n - 3 group (p = 0.58), with a trend toward between-group differences (p = 0.06) at 12 weeks, but no significant differences at 24 weeks. RBC n - 3 levels were strongly positively correlated with FACT-ES at 12 weeks, but attenuated at 24 weeks. CONCLUSION: High-dose n - 3 PUFA supplementation is feasible and well tolerated when administered with AIs. Additional studies are needed to evaluate efficacy in prevention of joint symptoms.

Outcomes and Direct Costs of Inferior Vena Cava Filter Placement and Retrieval within the IR and Surgical Settings.

PURPOSE: To compare the outcomes and costs of inferior vena cava (IVC) filter placement and retrieval in the interventional radiology (IR) and surgical departments at a tertiary-care center. MATERIALS AND METHODS: Retrospective review was performed of 142 sequential outpatient IVC filter placements and 244 retrievals performed in the IR suite and operating room (OR) from 2013 to 2016. Patient demographic data, procedural characteristics, outcomes, and direct costs were compared between cohorts. RESULTS: Technical success rates of 100% were achieved for both IR and OR filter placements, and 98% of filters were successfully retrieved by IR means, compared with 83% in the OR (P < .01). Fluoroscopy time was similar for IR and OR filter insertions, but IR retrievals required half the fluoroscopy time, with an average of 9 minutes vs 18 minutes in the OR (P = .02). There was no significant difference between cohorts in the incidences of complications for filter retrievals, but more postprocedural complications were observed for OR placements (8%) vs IR placements (1%; P = .05). The most severe complication occurred during an OR filter retrieval, resulting in entanglement of the snare device and conversion to an emergent open filter removal by vascular surgery. Direct costs were approximately 20% higher for OR vs IR IVC filter placements ($2,246 vs $2,671; P = .01). CONCLUSIONS: Filter placements are equally successfully performed in IR and OR settings, but OR patients experienced significantly higher postprocedural complication rates and incurred higher costs. In contrast, higher technical success rates and shorter fluoroscopy times were observed for IR filter retrievals compared with those performed in the OR.

Multidrug Resistance-associated Protein-1 (MRP-1)-dependent Glutathione Disulfide (GSSG) Efflux as a Critical Survival Factor for Oxidant-enriched Tumorigenic Endothelial Cells.

Endothelial cell tumors are the most common soft tissue tumors in infants. Tumor-forming endothelial (EOMA) cells are able to escape cell death fate despite excessive nuclear oxidant burden. Our previous work recognized perinuclear Nox-4 as a key contributor to EOMA growth. The objective of this work was to characterize the mechanisms by which EOMA cells evade oxidant toxicity and thrive. In EOMA cells, compared with in the cytosol, the nuclear GSSG/GSH ratio was 5-fold higher. Compared to the ratio observed in healthy murine aortic endothelial (MAE) cells, GSSG/GSH was over twice as high in EOMA cells. Multidrug resistance-associated protein-1 (MRP-1), an active GSSG efflux mechanism, showed 2-fold increased activity in EOMA compared with MAE cells. Hyperactive YB-1 and Ape/Ref-1 were responsible for high MRP-1 expression in EOMA. Proximity ligand assay demonstrated MRP-1 and YB-1 binding. Such binding enabled the nuclear targeting of MRP-1 in EOMA in a leptomycin-B-sensitive manner. MRP-1 inhibition as well as knockdown trapped nuclear GSSG, causing cell death of EOMA. Disulfide loading of cells by inhibition of GSSG reductase (bischoloronitrosourea) or thioredoxin reductase (auranofin) was effective in causing EOMA death as well. In sum, EOMA cells survive a heavy oxidant burden by rapid efflux of GSSG, which is lethal if trapped within the cell. A hyperactive MRP-1 system for GSSG efflux acts as a critical survival factor for these cells, making it a potential target for EOMA therapeutics.

Gait, balance, and patient-reported outcomes during taxane-based chemotherapy in early-stage breast cancer patients.

BACKGROUND: Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting toxicity of several commonly used chemotherapy drugs including taxanes, vinca alkaloids, and platinum compounds. Development of CIPN is highly variable, both in self-reported symptoms and functional consequences, and can be severe enough to alter dose intensity. PURPOSE: To describe the natural histories of both patient-reported symptoms of CIPN and functional impairments in breast cancer patients undergoing taxane-based chemotherapy. METHODS: Thirty-three breast cancer patients (32 female/1 male; 47.8 ± 11.2 years; n = 17 stage II/n = 16 stage III) were enrolled. Patients completed self-reports of symptoms and function (e.g., EORTC QLQ-CIPN20) and objective measures of physical function (i.e., balance and gait testing) in an outpatient oncology clinic at five timepoints: (1) baseline-prior to starting chemotherapy, (2-4) before starting subsequent chemotherapy cycles, and (5) 1-3 months after receiving their last taxane infusion. RESULTS: Significant negative changes in both patient-reported outcomes and objective functional measures were observed. Decreased balance was observed after the first chemotherapy cycle (28% increase in medial-lateral excursion of the center of pressure, p = 0.016) and progressed with cumulative exposure (43% increase, p < 0.001). Patients also demonstrated slower walking speeds (5% decrease, p = 0.003) as they progressed through treatment. These functional deficits were mirrored with increased patient-reported symptom severity for all EORTC QLQ-CIPN20 subscales (all p < 0.05). CONCLUSION: This study longitudinally assessed patient-reported outcomes concurrently with balance and gait testing in patients undergoing taxane therapy. Taxane treatment was associated with the development of clinically relevant problems in both CIPN symptoms and patient function.