Free-breathing, fat-corrected T1 mapping of the liver with stack-of-stars MRI, and joint estimation of T1, PDFF, R 2 * , and B 1 + .

PURPOSE: Quantitative T1 mapping has the potential to replace biopsy for noninvasive diagnosis and quantitative staging of chronic liver disease. Conventional T1 mapping methods are confounded by fat and B 1 + $$ {B}_1^{+} $$ inhomogeneities, resulting in unreliable T1 estimations. Furthermore, these methods trade off spatial resolution and volumetric coverage for shorter acquisitions with only a few images obtained within a breath-hold. This work proposes a novel, volumetric (3D), free-breathing T1 mapping method to account for multiple confounding factors in a single acquisition. THEORY AND METHODS: Free-breathing, confounder-corrected T1 mapping was achieved through the combination of non-Cartesian imaging, magnetization preparation, chemical shift encoding, and a variable flip angle acquisition. A subspace-constrained, locally low-rank image reconstruction algorithm was employed for image reconstruction. The accuracy of the proposed method was evaluated through numerical simulations and phantom experiments with a T1/proton density fat fraction phantom at 3.0 T. Further, the feasibility of the proposed method was investigated through contrast-enhanced imaging in healthy volunteers, also at 3.0 T. RESULTS: The method showed excellent agreement with reference measurements in phantoms across a wide range of T1 values (200 to 1000 ms, slope = 0.998 (95% confidence interval (CI) [0.963 to 1.035]), intercept = 27.1 ms (95% CI [0.4 54.6]), r2 = 0.996), and a high level of repeatability. In vivo imaging studies demonstrated moderate agreement (slope = 1.099 (95% CI [1.067 to 1.132]), intercept = -96.3 ms (95% CI [-82.1 to -110.5]), r2 = 0.981) compared to saturation recovery-based T1 maps. CONCLUSION: The proposed method produces whole-liver, confounder-corrected T1 maps through simultaneous estimation of T1, proton density fat fraction, and B 1 + $$ {B}_1^{+} $$ in a single, free-breathing acquisition and has excellent agreement with reference measurements in phantoms.

State-of-the-Art Quantification of Liver Iron With MRI-Vendor Implementation and Available Tools.

The role of MRI to estimate liver iron concentration (LIC) for identifying patients with iron overload and guiding the titration of chelation therapy is increasingly established for routine clinical practice. However, the existence of multiple MRI-based LIC quantification techniques limits standardization and widespread clinical adoption. In this article, we review the existing and widely accepted MRI-based LIC estimation methods at 1.5 T and 3 T: signal intensity ratio (SIR) and relaxometry (R2 and R2*) and discuss the basic principles, acquisition and analysis protocols, and MRI-LIC calibrations for each technique. Further, we provide an up-to-date information on MRI vendor implementations and available offline commercial and free software for each MRI-based LIC quantification approach. We also briefly review the emerging and advanced MRI techniques for LIC estimation and their current limitations for clinical use. Lastly, we discuss the implications of MRI-based LIC measurements on clinical use and decision-making in the management of patients with iron overload. Some of the key highlights from this review are as follows: 1) Both R2 and R2* can estimate accurate and reproducible LIC, when validated acquisition parameters and analysis protocols are applied, 2) Although the Ferriscan R2 method has been widely used, recent consensus and guidelines endorse R2*-MRI as the most accurate and reproducible method for LIC estimation, 3) Ongoing efforts aim to establish R2*-MRI as the standard approach for quantifying LIC, and 4) Emerging R2*-MRI techniques employ radial sampling strategies and offer improved motion compensation and broader dynamic range for LIC estimation. EVIDENCE LEVEL: 1 TECHNICAL EFFICACY: Stage 2.

Confounder-corrected T1 mapping in the liver through simultaneous estimation of T1 , PDFF, R 2 * , and B 1 + in a single breath-hold acquisition.

PURPOSE: Quantitative volumetric T1 mapping in the liver has the potential to aid in the detection, diagnosis, and quantification of liver fibrosis, inflammation, and spatially resolved liver function. However, accurate measurement of hepatic T1 is confounded by the presence of fat and inhomogeneous B 1 + $$ {B}_1^{+} $$ excitation. Furthermore, scan time constraints related to respiratory motion require tradeoffs of reduced volumetric coverage and/or increased acquisition time. This work presents a novel 3D acquisition and estimation method for confounder-corrected T1 measurement over the entire liver within a single breath-hold through simultaneous estimation of T1 , fat and B 1 + $$ {B}_1^{+} $$ . THEORY AND METHODS: The proposed method combines chemical shift encoded MRI and variable flip angle MRI with a B 1 + $$ {B}_1^{+} $$ mapping technique to enable confounder-corrected T1 mapping. The method was evaluated theoretically and demonstrated in both phantom and in vivo acquisitions at 1.5 and 3.0T. At 1.5T, the method was evaluated both pre- and post- contrast enhancement in healthy volunteers. RESULTS: The proposed method demonstrated excellent linear agreement with reference inversion-recovery spin-echo based T1 in phantom acquisitions at both 1.5 and 3.0T, with minimal bias (5.2 and 45 ms, respectively) over T1 ranging from 200-1200 ms. In vivo results were in general agreement with reference saturation-recovery based 2D T1 maps (SMART1 Map, GE Healthcare). CONCLUSION: The proposed 3D T1 mapping method accounts for fat and B 1 + $$ {B}_1^{+} $$ confounders through simultaneous estimation of T1 , B 1 + $$ {B}_1^{+} $$ , PDFF and R 2 * $$ {R}_2^{\ast } $$ . It demonstrates strong linear agreement with reference T1 measurements, with low bias and high precision, and can achieve full liver coverage in a single breath-hold.

Addressing concomitant gradient phase errors in time-interleaved chemical shift-encoded MRI fat fraction and R2 * mapping with a pass-specific phase fitting method.

PURPOSE: Concomitant gradients induce phase errors that increase quadratically with distance from isocenter. This work proposes a complex-based fitting method that addresses concomitant gradient phase errors in chemical shift encoded (CSE) MRI estimation of proton density fat fraction (PDFF) and R2 * through joint estimation of pass-specific phase terms. This method is applicable to time-interleaved multi-echo gradient-echo acquisitions (i.e., multi-pass acquisitions) and does not require prior knowledge of gradient waveforms typically needed to address concomitant gradient phase errors. THEORY AND METHODS: A CSE-MRI spoiled gradient echo signal model, with pass-specific phase terms, is introduced for non-linear least squares estimation of PDFF and R2 * in the presence of concomitant gradient phase errors. Cramér-Rao lower bound analysis was used to determine noise performance tradeoffs of the proposed fitting method, which was then validated in both phantom and in vivo experiments. RESULTS: The proposed fitting method removed PDFF and R2 * estimation errors up to 12% and 10 s-1 , respectively, at ±12 cm off isocenter (S/I) in a water phantom. In healthy volunteers, PDFF and R2 * bias was reduced by ~10% (12 cm off-isocenter) and ~30 s-1 (16 cm off-isocenter), respectively. An evaluation in 29 clinical liver datasets demonstrated reduced PDFF bias and variability (8.4% improvement in the coefficient of variation), even with the imaging volume centered at isocenter. CONCLUSION: Concomitant gradient induced phase errors in multi-pass CSE-MRI acquisitions can result in PDFF and R2 * estimation biases away from isocenter. The proposed fitting method enables accurate PDFF and R2 * quantification in the presence of concomitant gradient phase errors without knowledge of imaging gradient waveforms.

B0 and B1 inhomogeneities in the liver at 1.5 T and 3.0 T.

PURPOSE: The purpose of this work is to characterize the magnitude and variability of B0 and B1 inhomogeneities in the liver in large cohorts of patients at both 1.5 T and 3.0 T. METHODS: Volumetric B0 and B1 maps were acquired over the liver of patients presenting for routine abdominal MRI. Regions of interest were drawn in the nine Couinaud segments of the liver, and the average value was recorded. Magnitude and variation of measured averages in each segment were reported across all patients. RESULTS: A total of 316 B0 maps and 314 B1 maps, acquired at 1.5 T and 3.0 T on a variety of GE Healthcare MRI systems in 630 unique exams, were identified, analyzed, and, in the interest of reproducible research, de-identified and made public. Measured B0 inhomogeneities ranged (5th-95th percentiles) from -31.7 Hz to 164.0 Hz for 3.0 T (-14.5 Hz to 81.3 Hz at 1.5 T), while measured B1 inhomogeneities (ratio of actual over prescribed flip angle) ranged from 0.59 to 1.13 for 3.0 T (0.83 to 1.11 at 1.5 T). CONCLUSION: This study provides robust characterization of B0 and B1 inhomogeneities in the liver to guide the development of imaging applications and protocols. Field strength, bore diameter, and sex were determined to be statistically significant effects for both B0 and B1 uniformity. Typical clinical liver imaging at 3.0 T should expect B0 inhomogeneities ranging from approximately -100 Hz to 250 Hz (-50 Hz to 150 Hz at 1.5 T) and B1 inhomogeneities ranging from approximately 0.4 to 1.3 (0.7 to 1.2 at 1.5 T).

Limits of Fat Quantification in the Presence of Iron Overload.

BACKGROUND: Chemical shift encoded magnetic resonance imaging (CSE-MRI)-based tissue fat quantification is confounded by increased R2* signal decay rate caused by the presence of excess iron deposition. PURPOSE: To determine the upper limit of R2* above which it is no longer feasible to quantify proton density fat fraction (PDFF) reliably, using CSE-MRI. STUDY TYPE: Prospective. POPULATION: Cramér-Rao lower bound (CRLB) calculations, Monte Carlo simulations, phantom experiments, and a prospective study in 26 patients with known or suspected liver iron overload. FIELD STRENGTH/SEQUENCE: Multiecho gradient echo at 1.5 T and 3.0 T. ASSESSMENT: CRLB calculations were used to develop an empirical relationship between the maximum R2* value above which PDFF estimation will achieve a desired number of effective signal averages. A single voxel multi-TR, multi-TE stimulated echo acquisition mode magnetic resonance spectroscopy acquisition was used as a reference standard to estimate PDFF. Reconstructed PDFF and R2* maps were analyzed by one analyst using multiple regions of interest drawn in all nine Couinaud segments. STATISTICAL TESTS: None. RESULTS: Simulations, phantom experiments, and in vivo measurements demonstrated unreliable PDFF estimates with increased R2*, with PDFF errors as large as 20% at an R2* of 1000 s-1 . For typical optimized Cartesian acquisitions (TE1 = 0.75 msec, ΔTE = 0.67 msec at 1.5 T, TE1 = 0.65 msec, ΔTE = 0.58 msec at 3.0 T), an empirical relationship between PDFF estimation errors and acquisition parameters was developed that suggests PDFF estimates are unreliable above an R2* of ~538 s-1 and ~779 s-1 at 1.5 T and 3 T, respectively. This empirical relationship was further investigated with phantom experiments and in vivo measurements, with PDFF errors at an R2* of 1000 s-1 at 3.0 T as large as 10% with TE1 = 1.24 msec, ΔTE = 1.01 msec compared to 3% with TE1 = 0.65 msec, ΔTE = 0.58 msec. DATA CONCLUSION: We successfully developed a theoretically-based empirical formula that may provide an easily calculable guideline to identify R2* values above which PDFF is not reliable in research and clinical applications using CSE-MRI to quantify PDFF in the presence of iron overload. LEVEL OF EVIDENCE: 1 TECHNICAL EFFICACY STAGE: 1.

Posterior reversible encephalopathy syndrome in the emergency department: A single center retrospective study.

INTRODUCTION: Posterior Reversible Encephalopathy Syndrome (PRES) and the related term Reversible Posterior Leukoencephalopathy Syndrome (RPLS) denote a constellation of clinical symptoms paired with key radiological findings. These symptoms may include headache, altered mental status, visual changes, and seizures. PRES is a rare condition and remains a challenging diagnosis to make in the emergency department. Data on risk factors and clinical presentation are limited, and there is no recent literature-supported diagnostic criteria. Our primary objective was to identify initial symptoms, clinical presentation, and risk factors that should guide the emergency clinician to consider a diagnosis of PRES. A secondary objective was to identify associations between risk factors and the outcomes of mortality and ICU admissions. METHODS: This was a retrospective, observational study that evaluated patients seen in the Emergency Department (ED) in an urban tertiary care center with the diagnosis of PRES or RPLS from 1/1/2008 to 1/1/2018. The Health System's Electronic Medical Record was used to collect data. Search criteria included any patient diagnosed with Posterior Reversible Encephalopathy Syndrome (PRES) or Reversible Posterior Leukoencephalopathy Syndrome (RPLS), and excluded patients under 18 years of age, transfer patients, or patients that were not evaluated in our emergency department. RESULTS: We identified 98 patients based on our initial search criteria. After a chart review, 27 patients met our predefined eligibility criteria. In patients with confirmed diagnosis of PRES, the majority were female (70%) and 37% were either on an immunomodulator or undergoing chemotherapy at the time of presentation. 67% of patients presented with altered mental status, 41% had a focal neurologic deficit, and 37% had a witnessed seizure prior to diagnosis. Headache (48%), nausea (33%), and vision changes (30%) were the next most common reported symptoms. The majority of patients were hypertensive at time of presentation (82%) and many had a past medical history of hypertension (78%); twelve were given anti-hypertensive medications. 33% of the patients were admitted to the ICU and 26% died. There were no statistical associations found between documented ED interventions and the outcome of mortality. CONCLUSION: PRES is difficult to identify and diagnose in the emergency department. Significant risk factors such as female gender, hypertension, and those currently undergoing active immunotherapy/chemotherapy are associated with PRES. Common presenting complaints and exam findings include headache, altered mental status, and neurologic deficits. Emergency providers should consider PRES in patients presenting with altered mental status with significant risk factors, especially with neurologic deficits for which stroke has been ruled out.

T1 -corrected quantitative chemical shift-encoded MRI.

PURPOSE: To develop and validate a T1 -corrected chemical-shift encoded MRI (CSE-MRI) method to improve noise performance and reduce bias for quantification of tissue proton density fat-fraction (PDFF). METHODS: A variable flip angle (VFA)-CSE-MRI method using joint-fit reconstruction was developed and implemented. In computer simulations and phantom experiments, sources of bias measured using VFA-CSE-MRI were investigated. The effect of tissue T1 on bias using low flip angle (LFA)-CSE-MRI was also evaluated. The noise performance of VFA-CSE-MRI was compared to LFA-CSE-MRI for liver fat quantification. Finally, a prospective pilot study in patients undergoing gadoxetic acid-enhanced MRI of the liver to evaluate the ability of the proposed method to quantify liver PDFF before and after contrast. RESULTS: VFA-CSE-MRI was accurate and insensitive to transmit B1 inhomogeneities in phantom experiments and computer simulations. With high flip angles, phase errors because of RF spoiling required modification of the CSE signal model. For relaxation parameters commonly observed in liver, the joint-fit reconstruction improved the noise performance marginally, compared to LFA-CSE-MRI, but eliminated T1 -related bias. A total of 25 patients were successfully recruited and analyzed for the pilot study. Strong correlation and good agreement between PDFF measured with VFA-CSE-MRI and LFA-CSE-MRI (pre-contrast) was observed before (R2 = 0.97; slope = 0.88, 0.81-0.94 95% confidence interval [CI]; intercept = 1.34, -0.77-1.92 95% CI) and after (R2 = 0.93; slope = 0.88, 0.78-0.98 95% CI; intercept = 1.90, 1.01-2.79 95% CI) contrast. CONCLUSION: Joint-fit VFA-CSE-MRI is feasible for T1 -corrected PDFF quantification in liver, is insensitive to B1 inhomogeneities, and can eliminate T1 bias, but with only marginal SNR advantage for T1 values observed in the liver.

Noise properties of proton density fat fraction estimated using chemical shift-encoded MRI.

PURPOSE: The purpose of this work is to characterize the noise distribution of proton density fat fraction (PDFF) measured using chemical shift-encoded MRI, and to provide alternative strategies to reduce bias in PDFF estimation. THEORY: We derived the probability density function for PDFF estimated using chemical shift-encoded MRI, and found it to exhibit an asymmetric noise distribution that contributes to signal-to-noise-ratio dependent bias. METHODS: To study PDFF noise bias, we performed (at 1.5 T) numerical simulations, phantom acquisitions, and a retrospective in vivo experiment. In each experiment, we compared the performance of three statistics (mean, median, and maximum likelihood estimator) in estimating the PDFF in a region of interest. RESULTS: We demonstrated the presence of the asymmetric noise distribution in simulations, phantoms, and in vivo. In each experiment we demonstrated that both the median and proposed maximum likelihood estimator statistics outperformed the mean statistic in mitigating noise-related bias for low signal-to-noise-ratio acquisitions. CONCLUSIONS: Characterization of the noise distribution of PDFF estimated using chemical shift-encoded MRI enabled new strategies based on median and maximum likelihood estimator statistics to mitigate noise-related bias for accurate PDFF measurement from a region of interest. Such strategies are important for quantitative chemical shift-encoded MRI applications that typically operate in low signal-to-noise-ratio regimes. Magn Reson Med 80:685-695, 2018. © 2018 International Society for Magnetic Resonance in Medicine.

A chemical shift encoding (CSE) approach for spectral selection in fluorine-19 MRI.

PURPOSE: To develop a chemical shift encoding (CSE) approach for fluorine-19 MRI of perfluorocarbons in the presence of multiple known fluorinated chemical species. THEORY AND METHODS: A multi-echo CSE technique is applied for spectral separation of the perfluorocarbon perfluoro-15-crown-5-ether (PFCE) and isoflurane (ISO) based on their chemical shifts at 4.7 T. Cramér-Rao lower bound analysis is used to identify echo combinations with optimal signal-to-noise performance. Signal contributions are fit with a multispectral fluorine signal model using a non-linear least squares estimation reconstruction directly from k-space data. This CSE approach is tested in fluorine-19 phantoms and in a mouse with a 2D and 3D spoiled gradient-echo acquisition using multiple echo times determined from Cramér-Rao lower bound analysis. RESULTS: Cramér-Rao lower bound analysis for PFCE and ISO separation shows signal-to-noise performance is maximized with a 0.33 ms echo separation. A linear behavior (R2 = 0.987) between PFCE signal and known relative PFCE volume is observed in CSE reconstructed images using a mixed PFCE/ISO phantom. Effective spatial and spectral separation of PFCE and ISO is shown in phantoms and in vivo. CONCLUSION: Feasibility of a gradient-echo CSE acquisition and image reconstruction approach with optimized noise performance is demonstrated through fluorine-19 MRI of PFCE with effective removal of ISO signal contributions. Magn Reson Med 79:2183-2189, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Oxaliplatin disrupts pathological features of glioma cells and associated macrophages independent of apoptosis induction.

INTRODUCTION: Emerging evidence suggests that effective treatment of glioblastoma (GBM), the most common and deadly form of adult primary brain cancer, will likely require concurrent treatment of multiple aspects of tumor pathobiology to overcome tumor heterogeneity and the complex tumor-supporting microenvironment. Recent studies in non-central nervous system (CNS) tumor cells have demonstrated that oxaliplatin (OXA) can induce multi-faceted anti-tumor effects, in particular at drug concentrations below those required to induce apoptosis. These findings motivated re-investigation of OXA for the treatment of GBM. METHODS: The effects of OXA on murine KR158 and GL261 glioma cells including cell growth, cell death, inhibition of signal transducer and activator of transcription (STAT) activity, O-6-methylguanine-DNA methyltransferase (MGMT) expression, and immunogenic cell death (ICD) initiation, were evaluated by cytotoxicity assays, Western blot analysis, STAT3-luciferase reporter assays, qRT-PCR assays, and flow cytometry. Chemical inhibitors of endoplasmic reticulum (ER) stress were used to investigate the contribution of this cell damage response to the observed OXA effects. The effect of OXA on bone marrow-derived macrophages (BMDM) exposed to glioma conditioned media (GCM) was also analyzed by Western blot analysis. RESULTS: We identified the OXA concentration threshold for induction of apoptosis and from this determined the drug dose and treatment period for sub-cytotoxic treatments of glioma cells. Under these experimental conditions, OXA reduced STAT3 activity, reduced MGMT levels and increased temozolomide sensitivity. In addition, there was evidence of immunogenic cell death (elevated EIF2α phosphorylation and calreticulin exposure) following prolonged OXA treatment. Notably, inhibition of ER stress reversed the OXA-mediated inhibition of STAT3 activity and MGMT expression in the tumor cells. In BMDMs exposed to GCM, OXA also reduced levels of phosphorylated STAT3 and decreased expression of Arginase 1, an enzyme known to contribute to pro-tumor functions in the tumor-immune environment. CONCLUSIONS: OXA can induce notable multi-faceted biological effects in glioma cells and BMDMs at relatively low drug concentrations. These findings may have significant therapeutic relevance against GBM and warrant further investigation.

Successful metabolic adaptations leading to the prevention of high fat diet-induced murine cardiac remodeling.

BACKGROUND: Cardiomyopathy is a devastating complication of obesity and type 2 diabetes mellitus (T2DM). It arises even in patients with normoglycemia (glycosylated hemoglobin, A1C ≤7 %). As obesity and T2DM are approaching epidemic levels worldwide, the cardiomyopathy associated with these diseases must be therapeutically addressed. We have recently analyzed the systemic effects of a 12-week high fat diet (HFD) on wild type mice from the C57Bl/6 (B6) strain and the wild type super-healing Murphy Roths Large (MRL) mouse strain. The MRL HFD mice gained significantly more weight than their control diet counterparts, but did not present any of the other usual systemic T2DM phenotypes. METHODS: Cardiac pathology and adaptation to HFD-induced obesity in the MRL mouse strain compared to the HFD C57Bl/6 mice were thoroughly analyzed with echocardiography, histology, qPCR, electron microscopy and immunoblots. RESULTS: The obese HFD C57Bl/6 mice develop cardiac hypertrophy, cardiomyocyte lipid droplets, and initiate an ineffective metabolic adaptation of an overall increase in electron transport chain complexes. In contrast, the obese HFD MRL hearts do not display hypertrophy nor lipid droplets and their metabolism adapts quite robustly by decreasing pAMPK levels, decreasing proteins in the carbohydrate metabolism pathway and increasing proteins utilized in the ß-oxidation pathway. The result of these metabolic shifts is the reduction of toxic lipid deposits and reactive oxygen species in the hearts of the obese HFD fed MRL hearts. CONCLUSIONS: We have identified changes in metabolic signaling in obese HFD fed MRL mice that confer resistance to diabetic cardiomyopathy. The changes include a reduction of cardiac pAMPK, Glut4 and hexokinase2 in the MRL HFD hearts. Overall the MRL hearts down regulate glucose metabolism and favor lipid metabolism. These adaptations are essential to pursue for the identification of novel therapeutic targets to combat obesity related cardiomyopathy.

Combination of facial and nose features of Amur tigers to determine age.

We found that the area of black round or irregular-shaped spots on the tiger's nose increased with age, indicating a positive relationship between age and nose features. We used the deep learning model to train the facial and nose image features to identify the age of Amur tigers, using a combination of classification and prediction methods to achieve age determination with an accuracy of 87.81%.

The genetic status and rescue measure for a geographically isolated population of Amur tigers.

The Amur tiger is currently confronted with challenges of anthropogenic development, leading to its population becoming fragmented into two geographically isolated groups: smaller and larger ones. Small and isolated populations frequently face a greater extinction risk, yet the small tiger population's genetic status and survival potential have not been assessed. Here, a total of 210 samples of suspected Amur tiger feces were collected from this small population, and the genetic background and population survival potentials were assessed by using 14 microsatellite loci. Our results demonstrated that the mean number of alleles in all loci was 3.7 and expected heterozygosity was 0.6, indicating a comparatively lower level of population genetic diversity compared to previously reported studies on other subspecies. The genetic estimates of effective population size (Ne) and the Ne/N ratio were merely 7.6 and 0.152, respectively, representing lower values in comparison to the Amur tiger population in Sikhote-Alin (the larger group). However, multiple methods have indicated the possibility of genetic divergence within our isolated population under study. Meanwhile, the maximum kinship recorded was 0.441, and the mean inbreeding coefficient stood at 0.0868, both of which are higher than those observed in other endangered species, such as the African lion and the grey wolf. Additionally, we have identified a significant risk of future extinction if the lethal equivalents were to reach 6.26, which is higher than that of other large carnivores. Further, our simulation results indicated that an increase in the number of breeding females would enhance the prospects of this population. In summary, our findings provide a critical theoretical basis for further bailout strategies concerning Amur tigers.

Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

Myeloid-derived suppressor cell mitochondrial fitness governs chemotherapeutic efficacy in hematologic malignancies.

Myeloid derived suppressor cells (MDSCs) are key regulators of immune responses and correlate with poor outcomes in hematologic malignancies. Here, we identify that MDSC mitochondrial fitness controls the efficacy of doxorubicin chemotherapy in a preclinical lymphoma model. Mechanistically, we show that triggering STAT3 signaling via ß2-adrenergic receptor (ß2-AR) activation leads to improved MDSC function through metabolic reprograming, marked by sustained mitochondrial respiration and higher ATP generation which reduces AMPK signaling, altering energy metabolism. Furthermore, induced STAT3 signaling in MDSCs enhances glutamine consumption via the TCA cycle. Metabolized glutamine generates itaconate which downregulates mitochondrial reactive oxygen species via regulation of Nrf2 and the oxidative stress response, enhancing MDSC survival. Using ß2-AR blockade, we target the STAT3 pathway and ATP and itaconate metabolism, disrupting ATP generation by the electron transport chain and decreasing itaconate generation causing diminished MDSC mitochondrial fitness. This disruption increases the response to doxorubicin and could be tested clinically.

Bystander interaction with a novel multipurpose medical drone: A simulation trial.

Intro: Medical drones are an emerging technology which may facilitate rapid treatment in time-sensitive emergencies. However, drones rely on lay rescuers, whose interactions with multipurpose medical drones have not been studied, and the optimal drone design remains unclear. Methods: We conducted 24 simulations of adult out-of-hospital cardiac arrest (OHCA) and pediatric anaphylaxis with a prototype drone equipped with spoken and visual cues and a multipurpose medical kit. 24 layperson volunteers encountered one of the two scenarios and were supported through administering treatment by a simulated 911 dispatcher. Bystander-drone interactions were evaluated via a convergent parallel mixed methods approach using surveys, video event review, and semi-structured interviews. Results: 83% (20/24) of participants voiced comfort interacting with the drone. 96% (23/24) were interested in future interaction. Participants appreciated the drone's spoken instructions but found visual cues confusing. Participants retrieved the medical kit from the drone in a mean of 5 seconds (range 2-14) of drone contact; 79% (19/24) found this step easy or very easy. The medical kit's layered design caused difficulty in retrieving appropriate equipment. Participants expressed a wide range of reactions to the unique drone design. Conclusions: Laypeople can effectively and comfortably interact with a medical drone with a novel design. Feedback on design elements will result in further refinements and valuable insights for other drone designers. A multipurpose medical kit created more challenges and indicates the need for further refinement to facilitate use of the equipment.

Impact of drone-specific dispatch instructions on the safety and efficacy of drone-delivered emergency medical treatments: A randomized simulation pilot study.

Introduction: Medical drones have potential for improving the response times to out-of-hospital emergencies. However, widespread adoption is hindered by unanswered questions surrounding medical dispatch and bystander safety. This study evaluated the impact of novel drone-specific dispatch instructions (DSDI) on bystanders' ability to interact effectively with a medical drone and provide prompt, safe, and high-quality treatment in a simulated emergency scenario. We hypothesized DSDI would improve bystanders' performance and facilitate safer bystander-drone interactions. Methods: Twenty-four volunteers were randomized to receive either DSDI and standard Medical Priority Dispatch (MPD) instructions or MPD alone in a simulated out-of-hospital cardiac arrest (OHCA) or pediatric anaphylaxis.,3 Participants in the DSDI group received detailed instructions on locating and interacting with the drone and its enclosed medical kit. The simulations were video recorded. Participants completed a semi-structured interview and survey. Results: The addition of DSDI did not lead to statistically significant changes to the overall time to provide care in either the anaphylaxis or OHCA simulations. However, DSDI did have an impact on bystander safety. In the MPD only group, 50% (6/12) of participants ignored the audio and visual safety cues from the drone instead of waiting for it to be declared safe compared to no DSDI participants ignoring these safety cues. Conclusions: All participants successfully provided patient care. However, this study indicates that DSDI may be useful to ensure bystander safety and should be incorporated in the continued development of emergency medical drones.