Search

Head-fixed linear treadmill tasks have been used to study hippocampal physiology in mice. Although some hippocampal neurons establish place fields along linear treadmills, it is not clear if the hippocampus is required for spatial memory on this task. Using a Designer Receptors Exclusively Activated by Designer Drugs (DREADDs) approach, we found that silencing hippocampal output on rewarded treadmill tasks impaired search for rewards signaled by spatial cues but did not impair search for rewards signaled by local cues, recapitulating findings from other behavior tasks. These findings serve to contextualize data on hippocampal physiology from mice performing this task.

The use of CRISPR‐Cas proteins for the creation of multiplex genome engineering represents an important avenue for crop improvement, and further improvements for creation of knock‐in plant lines via CRISPR‐based technologies may enable the high‐throughput creation of designer alleles. To circumvent limitations of the commonly used CRISPR‐Cas9 system for multiplex genome engineering, we explored the use of Moraxella bovoculi 3 Cas12a (Mb3Cas12a) for multiplex genome editing in Arabidopsis thaliana. We identified optimized cis‐regulatory sequences for driving expression of single‐transcript multiplex crRNA arrays in A. thaliana, resulting in stable germline transmission of Mb3Cas12a‐edited alleles at multiple target sites. By utilizing this system, we demonstrate single‐transcript multiplexed genome engineering using of up to 13 crRNA targets. We further show high target specificity of Mb3Cas12a‐based genome editing via whole‐genome sequencing. Taken together, our method provides a simplified platform for efficient multiplex genome engineering in plant‐based systems.

Summary Several mouse in vivo neuronal recording techniques require head fixation. Head-fixed treadmill walking can be used to design tasks that enable the study of neural activity in the context of behavior. Here, we provide a detailed protocol for constructing a treadmill with tactile spatial cues, training mice on a rewarded behavioral task, and analyzing behavioral data. We discuss common problems and solutions we have developed to optimize training. Finally, we demonstrate how to test spatial memory performance using this task., Graphical abstract, Highlights • Protocol for a rewarded head-fixed treadmill task for mice • Assembly of treadmill and overview of a surgical procedure • Training of mice on head-fixed, rewarded spatial memory tasks • Analysis of reward search by spatial analysis of lick behavior along a treadmill, Several mouse in vivo neuronal recording techniques require head fixation. Head-fixed treadmill walking can be used to design tasks that enable the study of neural activity in the context of behavior. Here, we provide a detailed protocol for constructing a treadmill with tactile spatial cues, training mice on a rewarded behavioral task, and analyzing behavioral data. We discuss common problems and solutions we have developed to optimize training. Finally, we demonstrate how to test spatial memory performance using this task.

Iceland exemplifies the potential for generation of abundant silicic magma in the absence of mature island arc or preexisting continental crust. Zircon ages (U-Th and U-Pb) and isotope comp...

Norrish Type I (NTI) α-bond cleavage is the dominant photolysis mechanism in small carbonyls and is an important source of radicals in the troposphere. In nonsymmetric species two cleavages are possible, NTIa and NTIb, forming larger and smaller alkyl radicals, respectively. For a data set of 20 small, atmospherically relevant carbonyls we predict NTIa and NTIb thresholds on the S0, S1, and T1 electronic states. The calculated NTIa T1 thresholds give a mean absolute deviation (MAD) of 5.8 kJ/mol with respect to the available experimental thresholds of five carbonyls. In addition, the intrinsic barrier heights to dissociation on the S0, S1, and T1 electronic states are predicted. We find RI-B2GP-PLYP/def2-TZVP calculations on S0 and unrestricted RI-B2GP-PLYP/def2-TZVP calculations on T1 give MADs of 6.1 kJ/mol for S0 asymptotic energies and 6.3 kJ/mol for S0 → T1 0-0 excitation energies, with respect to available experimental data. A composite method is used to determine S1 thresholds, with bt-STEOM-CCSD/cc-pVQZ calculation of vertical excitation energies and TD-RI-B3LYP/def2-TZVP calculations on S1, which achieves a MAD of 7.2 kJ/mol, with respect to experimental 0-0 excitation energies. Our calculations suggest, with the exception of bifunctional carbonyls and enones, NTI reactions on S1 are unlikely to be important at tropospherically relevant photolysis energies (

Venetoclax is approved for older untreated acute myeloid leukemia (AML) patients. Venetoclax was available prior to approval off-label. We assessed our single-institution off-label experience with venetoclax/azacitidine, comparing outcomes with a clinical trial cohort that administered this regimen at the same institution. Thirty-three untreated AML patients unfit or unwilling to receive induction chemotherapy and prescribed venetoclax/azacitidine off-trial were retrospectively analyzed and compared with 33 patients who received the same therapy on trial. Outcomes were compared, and comparisons were made to a theoretical scenario in which off-trial patients received induction. Digital droplet polymerase chain reaction evaluated measurable residual disease (MRD). Off-trial venetoclax was attainable in nearly all patients for whom this was desired. The complete remission (CR)/CR with incomplete blood count recovery rate was 63.3% for off-trial patients who received treatment and 84.9% for trial patients (P = .081). The median overall survival for off-trial patients who received treatment was 381 days (95% confidence interval [CI], 174, not reached) vs 880 days (95% CI, 384, not reached) for trial patients (P = .041). Prior exposure to hypomethylating agents was associated with worse outcomes. Response rates with venetoclax/azacitidine were not inferior to a theoretical scenario in which patients received induction, and early death rates were less than expected with induction. MRD negativity was achievable. Newly diagnosed AML patients treated in a “real-world” scenario with off-trial venetoclax/azacitidine had inferior outcomes compared with patients treated in the setting of a clinical trial. Additionally, this therapy may be as effective, and less toxic, when compared with induction chemotherapy.

Although marine recreational fisheries are socially and economically important, there is often limited funding for their monitoring and assessment. With South African anglers reporting catch declin...

Plants regulate molecular bioactivity in response to daily and seasonal environmental fluctuations in temperature, light, humidity, and precipitation. These rhythms interconnect, overlap, and feedback both into each other and into the plant’s endogenous circadian clock. The resulting regulatory network tightly ensures that the overall phytochemical composition is highly adaptive to the plant’s needs at any point in time. Temporally coordinated control of primary and secondary metabolism ensures phytochemicals are in tune with the demands of the environment and the available resources. As a consequence, phytochemical composition varies throughout the day and year. This variation in phytochemical abundance and composition across time can affect experimental results and conclusions. Understanding how phytochemical composition varies across time is critical for uncovering the underlying regulatory connections and ultimately improving the quality of phytochemical products. Herein, we review the mechanisms underlying diel and seasonal variations in phytochemical composition and provide examples of temporal regulation of specific compounds within phenol, terpenoid, and alkaloid phytochemical classes. Temporal regulation of phytochemical composition. The phytochemical composition of a plant is under complex control, affected by both external environmental factors and endogenous circadian rhythms. The environmental factors that directly affect phytochemical profiles and concentrations themselves vary across time of day and time of year. These cyclic environmental factors also entrain the endogenous circadian clock which imposes additional regulation on the production and processing of many phytochemicals. This concerted effort to ensure phytochemicals are exquisitely in tune with the demands of the environment results in fluctuating phytochemical composition. Variation in phytochemical abundance and composition across time can affect experimental results and conclusions. Failing to consider the factors of time of day and year can result in misleading or inconsistent estimations of the potency and composition of phytochemical extractions. Integrating temporal factors will improve our understanding of the underlying regulatory connections and ultimately improve the quality of phytochemical products.

Purpose: Acute myeloid leukemia (AML) is a hematologic malignancy characterized by the accumulation of immature myeloid precursor cells. AML is poorly responsive to conventional chemotherapy and a diagnosis of AML is usually fatal. More effective and less toxic forms of therapy are desperately needed. AML cells are known to be highly dependent on the amino acid glutamine for their survival. These studies were directed at determining the effects of glutaminase inhibition on metabolism in AML and identifying general weaknesses that can be exploited therapeutically. Experimental Design: AML cancer cell lines, primary AML cells, and mouse models of AML and acute lymphoblastic leukemia (ALL) were utilized. Results: We show that blocking glutamine metabolism through the use of a glutaminase inhibitor (CB-839) significantly impairs antioxidant glutathione production in multiple types of AML, resulting in accretion of mitochondrial reactive oxygen species (mitoROS) and apoptotic cell death. Moreover, glutaminase inhibition makes AML cells susceptible to adjuvant drugs that further perturb mitochondrial redox state, such as arsenic trioxide (ATO) and homoharringtonine (HHT). Indeed, the combination of ATO or HHT with CB-839 exacerbates mitoROS and apoptosis, and leads to more complete cell death in AML cell lines, primary AML patient samples, and in vivo using mouse models of AML. In addition, these redox-targeted combination therapies are effective in eradicating ALL cells in vitro and in vivo. Conclusions: Targeting glutamine metabolism in combination with drugs that perturb mitochondrial redox state represents an effective and potentially widely applicable therapeutic strategy for treating multiple types of leukemia.

BackgroundMuch of suicide research focuses on suicide attempt (SA) survivors. Given that more than half of the suicide decedent population dies on their first attempt, this means a significant proportion of the population that dies by suicide is overlooked in research. Little is known about persons who die by suicide on their first attempt–and characterizing this understudied population may improve efforts to identify more individuals at risk for suicide.MethodsData were derived from the National Violent Death Reporting System, from 2005 to 2013. Suicide cases were included if they were 18–89 years old, with a known circumstance leading to their death based on law enforcement and/or medical examiner reports. Decedents with and without a history of SA were compared on demographic, clinical, and suicide characteristics, and circumstances that contributed to their suicide.ResultsA total of 73 490 cases met criteria, and 57 920 (79%) died on their first SA. First attempt decedents were more likely to be male, married, African-American, and over 64. Demographic-adjusted models showed that first attempt decedents were more likely to use highly lethal methods, less likely to have a known mental health problem or to have disclosed their intent to others, and more likely to die in the context of physical health or criminal/legal problem.ConclusionsFirst attempt suicide decedents are demographically different from decedents with a history of SA, are more likely to use lethal methods and are more likely to die in the context of specific stressful life circumstances.

Objective There is an elevated risk for suicide in the year following psychiatric hospitalization. The present study examined whether perceived coercion during admission into psychiatric hospitalization increases risk for postdischarge suicide attempts. Methods Participants were 905 psychiatric inpatients from the MacArthur Violence Risk Assessment Study that were assessed every 10 weeks during the year following discharge. Perceived coercion during admission was assessed while hospitalized, and suicide attempts were assessed following discharge. Analyses adjusted for nonrandom assignment of groups via propensity score weighting and for established correlates of postdischarge suicidal behavior. Results Of 905 participants, 67% endorsed perception of coercion into psychiatric hospitalization, and 168 (19%) made a postdischarge suicide attempt. Patients who perceived coercion during hospitalization admission were more likely to make a suicide attempt after discharge than those who did not, even after adjusting for established covariates (OR = 1.29, |z| = 2.87, p = .004, 95% CI = 1.08, 1.54). There was no interaction between recent self-harm or suicidal ideation at time of admission and perceived coercion on postdischarge suicide attempts. Conclusions Patients' perception of the context in which they were hospitalized is associated with a small but significant increase in their likelihood of postdischarge suicide attempts.

Background Patients with relapsed and refractory (R/R) acute myeloid leukemia (AML) have limited treatment options. Genomically-defined personalized therapies are only applicable for a minority of patients. Therapies without identifiable targets can be effective but patient selection is challenging. The sequential combination of azacitidine with high-dose lenalidomide has shown activity; we aimed to determine the efficacy of this genomically-agnostic regimen in patients with R/R AML, with the intention of applying sophisticated methods to predict responders. Methods Thirty-seven R/R AML/myelodysplastic syndrome patients were enrolled in a phase 2 study of azacitidine with lenalidomide. The primary endpoint was complete remission (CR) and CR with incomplete blood count recovery (CRi) rate. A computational biological modeling (CBM) approach was applied retrospectively to predict outcomes based on the understood mechanisms of azacitidine and lenalidomide in the setting of each patients’ disease. Findings Four of 37 patients (11%) had a CR/CRi; the study failed to meet the alternative hypothesis. Significant toxicity was observed in some cases, with three treatment-related deaths and a 30-day mortality rate of 14%. However, the CBM method predicted responses in 83% of evaluable patients, with a positive and negative predictive value of 80% and 89%, respectively. Interpretation Sequential azacitidine and high-dose lenalidomide is effective in a minority of R/R AML patients; it may be possible to predict responders at the time of diagnosis using a CBM approach. More efforts to predict responses in non-targeted therapies should be made, to spare toxicity in patients unlikely to respond and maximize treatments for those with limited options.

Although insulin resistance consistently occurs with type 1 diabetes, its predominant driver is uncertain. We therefore determined the relative contributions of hyperglycemia and iatrogenic hyperinsulinemia to insulin resistance using hyperinsulinemic-euglycemic clamps in three participant groups (n = 10/group) with differing insulinemia and glycemia: healthy control subjects (euinsulinemia and euglycemia), glucokinase–maturity-onset diabetes of the young (GCK-MODY; euinsulinemia and hyperglycemia), and type 1 diabetes (hyperinsulinemia and hyperglycemia matching GCK-MODY). We assessed the contribution of hyperglycemia by comparing insulin sensitivity in control and GCK-MODY and the contribution of hyperinsulinemia by comparing GCK-MODY and type 1 diabetes. Hemoglobin A1c was normal in control subjects and similarly elevated for type 1 diabetes and GCK-MODY. Basal insulin levels in control subjects and GCK-MODY were nearly equal but were 2.5-fold higher in type 1 diabetes. Low-dose insulin infusion suppressed endogenous glucose production similarly in all groups and suppressed nonesterified fatty acids similarly between control subjects and GCK-MODY, but to a lesser extent for type 1 diabetes. High-dose insulin infusion stimulated glucose disposal similarly in control subjects and GCK-MODY but was 29% and 22% less effective in type 1 diabetes, respectively. Multivariable linear regression showed that insulinemia—but not glycemia—was significantly associated with muscle insulin sensitivity. These data suggest that iatrogenic hyperinsulinemia predominates in driving insulin resistance in type 1 diabetes.

PURPOSE The Congress of Neurological Surgeons (CNS) has developed a series of guidelines for the treatment of adults with metastatic brain tumors, including systemic therapy and supportive care topics. ASCO has a policy and set of procedures for endorsing clinical practice guidelines that have been developed by other professional organizations. METHODS Two CNS guidelines were reviewed for developmental rigor by methodologists, and an independent multidisciplinary Expert Panel was formed to review the content and assess agreement with the recommendations. The Expert Panel voted to endorse the two guidelines, and ASCO and Society for Neuro-Oncology (SNO) independently reviewed and approved the ASCO/SNO guideline endorsement. RESULTS The ASCO/SNO Expert Panel determined that the recommendations from the CNS anticonvulsants and steroids guidelines, published January 9, 2019, are clear, thorough, and based on the most relevant scientific evidence. ASCO/SNO endorsed these two CNS guidelines with minor alterations. RECOMMENDATIONS Key recommendations include the following: prophylactic antiepileptic drugs were not recommended for routine use; and corticosteroids, specifically dexamethasone, were recommended for temporary symptomatic relief in patients with neurologic symptoms and signs related to mass effect from brain metastases. Additional information is available at www.asco.org/neurooncology-guidelines .

Cognitive models of depression suggest that depressed individuals exhibit a tendency to attribute negative meaning to neutral stimuli, and enhanced processing of mood-congruent stimuli. However, evidence thus far has been inconsistent. In this study, we sought to identify both differential interpretation of neutral information as well as emotion processing biases associated with depression. Fifty adult participants completed standardized mood-related questionnaires, a novel immediate mood scale questionnaire (IMS-12), and a novel task, Emotion Matcher, in which they were required to indicate whether pairs of emotional faces show the same expression or not. We found that overall success rate and reaction time on the Emotion Matcher task did not differ as a function of severity of depression. However, more depressed participants had significantly worse performance when presented with sad-neutral face pairs, as well as increased reaction times to happy-happy pairs. In addition, accuracy of the sad-neutral pairs was found to be significantly associated with depression severity in a regression model. Our study provides partial support for the mood-congruent hypothesis, revealing only a potential bias in interpretation of sad and neutral expressions, but not a general deficit in processing of facial expressions. The potential of such bias in serving as a predictor for depression should be further examined in future studies.

Venetoclax with backbone therapies have shown promising efficacy for newly diagnosed, previously untreated, older, unfit acute myeloid leukemia patients. This review discusses this data and potential reasons for the efficacy of these venetoclax-based combinations.Venetoclax with hypomethylators and low-dose cytarabine have resulted in high response rates, promising response durations, and significant overall survival in relatively small, uncontrolled studies. There is emerging data that these responses are due to the effective targeting of leukemia stem cells through an alteration of the metabolic environment that is poorly tolerated by this population.Venetoclax with a backbone therapy in older, untreated patients with acute myeloid leukemia has shown promising efficacy in preliminary clinical trials, and at least partially works through a novel mechanism that can target the leukemia stem cell population. Future investigations will help elucidate the mechanism and the contributions being made by each agent in the regimen.

Despite the promise of its therapeutic benefits, curcumin as a free molecule has failed to demonstrate significant clinical success. Arguably, its inherently poor stability and rapid clearance is a significant reason for these negative outcomes. The incorporation of curcumin into the backbone of a crosslinked hydrogel that utilizes poly(beta-amino ester) (PBAE) chemistry can provide a tunable protective network with the ability to release at a controlled rate while improving its therapeutic potential. Kinetics of curcumin conjugated PBAE microparticles controlled release delivery system in the presence of oxidative environments was studied for the first time, where consumption rates of active curcumin and release products were obtained. The constituent amount of curcumin present in solution was improved by incorporating the active into the network in comparison to curcumin as a free drug. Modeling curcumin conjugated PBAE microparticles will provide a design platform to improve translation and overall success in delivering a therapeutic agent that matches levels of oxidative stress.

A diverse workforce is critical to providing high-quality, equitable neurologic care. Many neurologic conditions disproportionately affect Black and Latinx people, but these populations have limited access to neurologic care.1,2 Although healthcare disparities can be reduced with a diverse workforce,3-7 just 2.8% of neurologists are Black and 7.2% are Latinx, compared with the most recent US census with 12.8% of individuals identifying as Black and 18.4% as Latinx.8,9 The gap also exists at the trainee level; 4.4% of neurology residents are Black and 7.2% are Latinx.10 Recruitment of an inclusive residency class is paramount to addressing these inequities.3,5,7,11 A record of 42,508 medical students and physicians applied for residency positions in the United States in 2020–2021, as the application season moved to a virtual format because of the COVID-1912 pandemic. Future residency application seasons will likely be a hybrid of in-person and virtual recruitment. This change presents both unique opportunities and challenges for the recruitment of a diverse and inclusive residency class.13

Kinase inhibitors as targeted therapies have played an important role in improving cancer outcomes. However, there are still considerable challenges, such as resistance, non-response, patient stratification, polypharmacology, and identifying combination therapy where understanding a tumor kinase activity profile could be transformative. Here, we develop a graph- and statistics-based algorithm, called KSTAR, to convert phosphoproteomic measurements of cells and tissues into a kinase activity score that is generalizable and useful for clinical pipelines, requiring no quantification of the phosphorylation sites. In this work, we demonstrate that KSTAR reliably captures expected kinase activity differences across different tissues and stimulation contexts, allows for the direct comparison of samples from independent experiments, and is robust across a wide range of dataset sizes. Finally, we apply KSTAR to clinical breast cancer phosphoproteomic data and find that there is potential for kinase activity inference from KSTAR to complement the current clinical diagnosis of HER2 status in breast cancer patients.

Kinase inhibitors are one of the largest classes of FDA-approved drugs and are major targets in oncology. Although kinase inhibitors have played an important role in improving cancer outcomes, major challenges still exist, including the development of resistance and failure to respond to treatments. Improvements for tumor profiling of kinase activity would be an important step in improving treatment outcomes and identifying effective kinase targets. Here, we present a graph- and statistics-based algorithm, called KSTAR, which harnesses the phosphoproteomic profiling of human cells and tissues by predicting kinase activity profiles from the observed phosphorylation of kinase substrates. The algorithm is based on the hypothesis that the more active a kinase is, the more of its substrates will be observed in a phosphoproteomic experiment. This method is error- and bias-aware in its approach, overcoming challenges presented by the variability of phosphoproteomic pipelines, limited information about kinase-substrate relationships, and limitations of global kinase-substrate predictions, such as training set bias and high overlap between predicted kinase networks. We demonstrate that the predicted kinase activities: 1) reproduce physiologically-relevant expectations and generates novel hypotheses within cell-specific experiments, 2) improve the ability to compare phosphoproteomic samples on the same tissues from different labs, and 3) identify tissue-specific kinase profiles. Global benchmarking and comparison to other algorithms demonstrates that KSTAR is particularly superior for predicting tyrosine kinase activities and, given its focus on utilizing more of the available phosphoproteomic data, significantly less sensitive to study bias. Finally, we apply the approach to complex human tissue biopsies in breast cancer, where we find that KSTAR activity predictions complement current clinical standards for identifying HER2-status – KSTAR can identify clinical false positives, patients who will fail to respond to inhibitor therapy, and clinically defined HER2-negative patients that might benefit from HER2-targeted therapy. KSTAR will be useful for both basic biological understanding of signaling networks and for improving clinical outcomes through improved clinical trial design, identification of new and/or combination therapies, and for identifying the failure to respond to targeted kinase therapies.

Acute myeloid leukemia (AML) is characterized by the presence of leukemia stem cells (LSCs), and failure to fully eradicate this population contributes to disease persistence/relapse. Prior studies have characterized metabolic vulnerabilities of LSCs, which demonstrate preferential reliance on oxidative phosphorylation (OXPHOS) for energy metabolism and survival. In the present study, using both genetic and pharmacologic strategies in primary human AML specimens, we show that signal transducer and activator of transcription 3 (STAT3) mediates OXPHOS in LSCs. STAT3 regulates AML-specific expression of MYC, which in turn controls transcription of the neutral amino acid transporter gene SLC1A5. We show that genetic inhibition of MYC or SLC1A5 acts to phenocopy the impairment of OXPHOS observed with STAT3 inhibition, thereby establishing this axis as a regulatory mechanism linking STAT3 to energy metabolism. Inhibition of SLC1A5 reduces intracellular levels of glutamine, glutathione, and multiple tricarboxylic acid (TCA) cycle metabolites, leading to reduced TCA cycle activity and inhibition of OXPHOS. Based on these findings, we used a novel small molecule STAT3 inhibitor, which binds STAT3 and disrupts STAT3-DNA, to evaluate the biological role of STAT3. We show that STAT3 inhibition selectively leads to cell death in AML stem and progenitor cells derived from newly diagnosed patients and patients who have experienced relapse while sparing normal hematopoietic cells. Together, these findings establish a STAT3-mediated mechanism that controls energy metabolism and survival in primitive AML cells.

Background Motor impairment after stroke is due not only to direct tissue loss but also to disrupted connectivity within the motor network. Mixed results from studies attempting to enhance motor recovery with Transcranial Magnetic Stimulation (TMS) highlight the need for a better understanding of both connectivity after stroke and the impact of TMS on this connectivity. This study used TMS-EEG to map the causal information flow in the motor network of healthy adult subjects and define how stroke alters these circuits. Methods Fourteen stroke patients and 12 controls received TMS to two sites (bilateral primary motor cortices) during two motor tasks (paretic/dominant hand movement vs. rest) while EEG measured the cortical response to TMS pulses. TMS-EEG based connectivity measurements were derived for each hemisphere and the change in connectivity (ΔC) between the two motor tasks was calculated. We analyzed if ΔC for each hemisphere differed between the stroke and control groups or across TMS sites, and whether ΔC correlated with arm function in stroke patients. Results Right hand movement increased connectivity in the left compared to the right hemisphere in controls, while hand movement did not significantly change connectivity in either hemisphere in stroke. Stroke patients with the largest increase in healthy hemisphere connectivity during paretic hand movement had the best arm function. Conclusions TMS-EEG measurements are sensitive to movement-induced changes in brain connectivity. These measurements may characterize clinically meaningful changes in circuit dynamics after stroke, thus providing specific targets for trials of TMS in post-stroke rehabilitation.

Carbonyls are among the most abundant volatile organic compounds in the atmosphere. They are central to atmospheric photochemistry as absorption of near-UV radiation by the C=O chromophore can lead to photolysis. If photolysis does not occur on electronic excited states, non-radiative relaxation to the ground state will form carbonyls with extremely high internal energy. These “hot” molecules can access a range of ground state reactions. Up to nine potential ground state reactions are investigated at the B2GP-PLYP-D3/def2-TZVP level of theory for a dataset of 20 representative carbonyls. Almost all are energetically accessible under tropospheric conditions. Comparison with experiment suggests the most significant ground state dissociation pathways will be concerted triple fragmentation in saturated aldehydes, Norrish type III dissociation to form another carbonyl, and H2-loss involving the formyl H atom in aldehydes. Tautomerisation, leading to more reactive unsaturated species, is also predicted to be energetically accessible and is likely to be important when there is no low-energy ground state dissociation pathway, for example in α,β-unsaturated carbonyls and some ketones. The concerted triple fragmentation and H2-loss pathways have immediate atmospheric implication to global H2 production and tautomerisaton has implication to the atmospheric production of organic acids.

Hematopoietic stem cells (HSCs) are capable of entering the cell cycle to replenish the blood system in response to inflammatory cues; however, excessive proliferation in response to chronic inflammation can lead to either HSC attrition or expansion. The mechanism(s) that limit HSC proliferation and expansion triggered by inflammatory signals are poorly defined. Here, we show that long-term HSCs (HSCLT) rapidly repress protein synthesis and cell cycle genes following treatment with the proinflammatory cytokine interleukin (IL)-1. This gene program is associated with activation of the transcription factor PU.1 and direct PU.1 binding at repressed target genes. Notably, PU.1 is required to repress cell cycle and protein synthesis genes, and IL-1 exposure triggers aberrant protein synthesis and cell cycle activity in PU.1-deficient HSCs. These features are associated with expansion of phenotypic PU.1-deficient HSCs. Thus, we identify a PU.1-dependent mechanism triggered by innate immune stimulation that limits HSC proliferation and pool size. These findings provide insight into how HSCs maintain homeostasis during inflammatory stress., Journal of Experimental Medicine, 218 (6), ISSN:0022-1007, ISSN:1540-0069, ISSN:1540-9538

The combination of venetoclax (ven) and azacitidine (aza) has resulted in high response rates in the upfront treatment of AML in patients age 75 and patients unfit for intensive chemotherapy. Given the poor historical outcomes in patients age ≥ 60 treated with induction chemotherapy, ven/aza has become our institutional preference for the initial treatment of non-core binding factor (CBF) AML patients age ≥ 60. The benefit of allogeneic stem cell transplant (SCT) in patients who achieve response to ven/aza is uncertain. We report outcomes of SCT-eligible patients treated at our center. Between 1/2015 and 1/2020, 119 newly diagnosed non-CBF AML patients age ≥ 60 received ven/aza as initial therapy. 21 patients underwent SCT; 31 additional patients were potentially SCT eligible but deferred SCT. Overall survival (OS) was significantly greater among SCT patients (median survival not reached) versus potentially SCT eligible patients not undergoing SCT (median 518 days) (p = 0.01). Our data suggest that ven/aza followed by SCT in newly diagnosed AML patients older than ≥ 60 results in excellent outcomes and likely improves outcomes over maintenance therapy. Ongoing investigation will further refine the optimal timing of and selection of patients for SCT based on prognostic disease features and response assessments.

Objective Homicide-suicide is an extremely heterogeneous and rare form of lethal violence. In an effort to capture this heterogeneity to enhance research and prevention efforts, typologies have been developed from literature reviews or geographically limited samples. The purpose of the present study was to develop the first empirically derived typology of homicide-suicide decedents, using a large, geographically diverse sample. Methods Data were used from the Centers for Disease Control and Prevention's National Violent Death Reporting System from 2003 to 2015 across 27 states. Homicide-suicide decedents were included if they were ≥ 18 years of age, they were the only victim and suspect involved, they had a known relationship with the victim(s), and the circumstances surrounding the event were known. There were 2,447 decedents that met study criteria. Unsupervised machine learning was used to classify decedents by precipitating circumstances and victim types. Results Eight homicide-suicide subtypes were identified and cross-validated in a holdout sample. Three subtypes consisted of only intimate partner victims, 3 subtypes had a single victim type (children, extrafamilial, other family), and there were 2 multivictim subtypes: one that could be identified as familicide and the other in which there was indiscriminate killing, which often included an intimate partner. Subtypes were distinguishable by demographic and other characteristics (median area under the curve = 0.77). Relationship problems precipitated 60%-92% of homicide-suicides across subtypes, while mental health problems were recognized as a precipitant in 7%-72% of decedents across subtypes. Conclusions The findings expand upon and validate previously proposed homicide-suicide typologies. While relationship problems are common precipitants across homicide-suicide subtypes, known mental health problems vary across subtypes.

OBJECTIVE: To compare the prevalence of cognitive symptoms and their functional impact by age group accounting for depression and number of other health conditions. METHODS: We analyzed data from the 2011 Behavioral Risk Factor Surveillance System, a population-based, cross-sectional telephone survey of US adults. Twenty-one US states asked participants (n = 131, 273) about cognitive symptoms (worsening confusion or memory loss in the past year) and their functional impact (interference with activities and need for assistance). We analyzed the association between age, depression history and cognitive symptoms and their functional impact using logistic regression and adjusted for demographic characteristics and other health condition count. RESULTS: There was a significant interaction between age and depression (p < 0.0001). In adults reporting depression, the adjusted odds of cognitive symptoms in younger age groups (< 75 years) were comparable or greater to those in the oldest age group (≥ 75 years) with a peak in the middle age (45–54 years) group (OR 1.9 (95% Confidence Interval: 1.4–2.5). In adults without depression, adults < 75 years had a significantly lower adjusted odds of cognitive symptoms compared to the oldest age group with the exception of the middle-aged group where the difference was not statistically significant. Over half of adults under age 65 with depression reported that cognitive symptoms interfered with life activities compared to 35.7% of adults ≥ 65 years. CONCLUSIONS: Cognitive symptoms are not universally higher in older adults; middle-aged adults are also particularly vulnerable. Given the adverse functional impact associated with cognitive symptoms in younger adults, clinicians should assess cognitive symptoms and their functional impact in adults of all ages and consider treatments that impact both cognition and functional domains.

BACKGROUND Individuals with neurofibromatosis type 1 (NF1) frequently have peripheral nerve sheath tumors (PNST), including plexiform neurofibromas (PNF), atypical neurofibromas (ANF), and malignant peripheral nerve sheath tumors (MPNST). These tumors reflect a histologic spectrum from benign to malignant. Various clinical and MRI-based features are proposed as risk factors for MPNST development based on small single-institution studies. A major barrier to study these risk factors is collation and annotation of multi-center serial MRIs. To address this, we created a standardized database of clinical data and longitudinal MRIs from NF1-associated PNST from nine international NF1 referral centers. METHODS Clinical data from NF1 patients are collected in Research Electronic Data Capture databases housed at Massachusetts General Hospital and Washington University, including demographic information, genotype, disease course, treatment history, and survival. ANF and MPNST require histologic confirmation whereas a diagnosis of PNF can also be made based on clinical/radiographic stability. Longitudinal MRIs predating the histologic diagnosis are uploaded to a HIPAA-compliant cloud-based system. RESULTS Data from 200 patients (87 females, 113 males) with 217 tumors (75 PNF, 40 ANF, 102 MPNST) have been collected. 280 regional and 108 whole-body MRIs have been identified. Median age at the time of histologic diagnosis is 30 years (range 5-64). All tumors are histologically confirmed except for 6 PNF which remained stable over time. Median follow-up time is 32 months. Of 147 patients with available survival data, 32 (21.7%) have died from MPNST progression; estimated median overall survival is 20 months. CONCLUSIONS In this ongoing work, we have assembled one of the largest systematically annotated clinical and MRI repositories of NF1-associated PNST from pediatric and adult NF1 patients. The data will be accessible to outside researchers which will promote interdisciplinary and multi-center collaborations. Active efforts include the identification of radiomic MRI features to differentiate between PNF and MPNST.

After decades of simply being referred to as the body’s sewage system, the lymphatic system has recently been recognized as a key player in numerous physiological and pathological processes. As an essential site of immune cell interactions, the lymphatic system is a potential target for next-generation drug delivery approaches in treatments for cancer, infections, and inflammatory diseases. However, the lack of cell-based assays capable of recapitulating the required biological complexity combined with unreliable in vivo animal models currently hamper scientific progress in lymph-targeted drug delivery. To gain more in-depth insight into the blood-lymph interface, we established an advanced chip-based microvascular model to study mechanical stimulation’s importance on lymphatic sprout formation. Our microvascular model’s key feature is the co-cultivation of spatially separated 3D blood and lymphatic vessels under controlled, unidirectional interstitial fluid flow while allowing signaling molecule exchange similar to the in vivo situation. We demonstrate that our microphysiological model recreates biomimetic interstitial fluid flow, mimicking the route of fluid in vivo, where shear stress within blood vessels pushes fluid into the interstitial space, which is subsequently transported to the nearby lymphatic capillaries. Results of our cell culture optimization study clearly show an increased vessel sprouting number, length, and morphological characteristics under dynamic cultivation conditions and physiological relevant mechanobiological stimulation. For the first time, a microvascular on-chip system incorporating microcapillaries of both blood and lymphatic origin in vitro recapitulates the interstitial blood-lymph interface.

Medical students need to understand core neuroscience principles as a foundation for their required clinical experiences in neurology. In fact, they need a solid neuroscience foundation for their clinical experiences in all other medical disciplines also because the nervous system plays such a critical role in the function of every organ system. Because of the rapid pace of neuroscience discoveries, it is unrealistic to expect students to master the entire field. It is also unnecessary, as students can expect to have ready access to electronic reference sources no matter where they practice. In the preclerkship phase of medical school, the focus should be on providing students with the foundational knowledge to use those resources effectively and interpret them correctly. This article describes an organizational framework for teaching the essential neuroscience background needed by all physicians. This is particularly germane at a time when many medical schools are reassessing traditional practices and instituting curricular changes such as competency-based approaches, earlier clinical immersion, and increased emphasis on active learning. This article reviews factors that should be considered when developing the preclerkship neuroscience curriculum, including goals and objectives for the curriculum, the general topics to include, teaching and assessment methodology, who should direct the course, and the areas of expertise of faculty who might be enlisted as teachers or content experts. These guidelines were developed by a work group of experienced educators appointed by the Undergraduate Education Subcommittee (UES) of the American Academy of Neurology (AAN). They were then successively reviewed, edited, and approved by the entire UES, the AAN Education Committee, and the AAN Board of Directors.

Summary Isolation of leukemia stem cells presents a challenge due to the heterogeneity of the immunophenotypic markers commonly used to identify blood stem cells. Several studies have reported that relative levels of reactive oxygen species (ROS) can be used to enrich for stem cell populations, suggesting a potential alternative to surface antigen-based methods. Here, we describe a protocol to enrich for stem cells from human acute myeloid leukemia specimens using relative levels of ROS. This protocol provides consistent enrichment of leukemia stem cells. For complete details on the use and execution of this protocol, please refer to Lagadinou et al. (2013) and Pei et al. (2018)., Graphical abstract, Highlights • Low levels of reactive oxygen species are a hallmark of stem cells • Relative levels of reactive oxygen species allow for enrichment of leukemia stem cells • This protocol is an alternative to surface antigen-based methods, Isolation of leukemia stem cells presents a challenge due to the heterogeneity of the immunophenotypic markers commonly used to identify blood stem cells. Several studies have reported that relative levels of reactive oxygen species (ROS) can be used to enrich for stem cell populations, suggesting a potential alternative to surface antigen-based methods. Here, we describe a protocol to enrich for stem cells from human acute myeloid leukemia specimens using relative levels of ROS. This protocol provides consistent enrichment of leukemia stem cells.

PurposeThe coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on the provision of medical care for genetic disorders. The purpose of this study was to assess the effects of the pandemic on neurofibromatosis (NF) care and research.MethodsSixty-three United States NF clinics were surveyed to identify the impact of the pandemic on clinician role, patient volume, continuity of guideline-driven surveillance, research protocols, and use of (and satisfaction with) telehealth for the delivery of NF care.ResultsFifty-two clinic directors or their representatives completed the survey (83% response rate). About 2/3 of the clinics reported a greater than 50% decrease in the number of available patient appointments, and modified clinical surveillance and research protocols. Fifty-one clinics (98%) newly instituted telehealth during the pandemic. Barriers to telehealth prior to the pandemic were insurance reimbursement concerns and lack of infrastructure. Since telehealth was initiated, high provider satisfaction was reported with ease of use. The most common area of concern was related to inability to perform a physical examination.ConclusionResults show marked impacts on NF care and research since the beginning of the pandemic, with potential long-term changes related to the introduction (or adoption) of telehealth for clinical care.

Introduction: Multiple myeloma (MM) is a plasma cell malignancy that remains incurable, with patients enduring multiple relapses and development of drug resistance. Immunomodulatory drugs (IMiDs) are critical anti-MM agents. IMiDs act by inducing CRBN-dependent proteasomal degradation of the transcription factors IKZF1 and IKZF3, which leads to IRF4 and MYC downregulation (collectively termed the “Ikaros axis”). Although CRBN aberrations occur, whether they are a functional mechanism of resistance in patients remains unclear. Based on the importance of CRBN in IMiD response, we hypothesized that IMiD treatment fails to downregulate the Ikaros axis in IMiD-resistant MM cells. Methods: To measure IMiD-induced Ikaros axis downregulation, we designed an intracellular flow cytometry assay that measured relative IKZF1, IKZF3, IRF4 and MYC protein levels in MM cells following ex vivo pomalidomide (Pom) treatment. We established this assay using IMiD-sensitive parental and dose-escalated Pom resistant MM1S and H929 cell lines before utilizing it in patient samples (isolated mononuclear cells). To assess the Ikaros axis in the context of MM intratumoral heterogeneity, we used mass cytometry to simultaneously characterize MM subpopulations in patient samples. Lastly, we determined ex vivo drug sensitivity in patient samples via flow cytometry. Results: Our hypothesis was supported in MM cell lines, as sensitive parental lines showed a significant decrease in all Ikaros axis protein levels following Pom treatment, while resistant lines showed no IMiD-induced decrease in any Ikaros axis protein. However, when assessed in CD38+CD138+ cells from patient samples, Pom treatment caused a significant decrease in IKZF1, IKZF3 and IRF4 regardless of IMiD sensitivity. Mass cytometry in patient samples revealed that individual Ikaros axis proteins were differentially expressed between subpopulations. When correlating this with ex vivo Pom sensitivity of MM subpopulations, we observed that low IKZF1 and IKZF3 corresponded to Pom resistance. Interestingly, most of these resistant populations still expressed MYC. We therefore assessed whether IMiD resistant MM was MYC dependent by treating Pom resistant MM cells with MYCi975. In 88% (7/8) of patient samples tested, IMiD resistant MM cells were sensitive to MYC inhibition. Conclusions: Our findings did not support our initial hypothesis, as IMiD-induced IKZF1 and IKZF3 degradation remains intact in IMiD resistant MM cells from patient samples. However, our data support a mechanism where the Ikaros axis no longer drives MYC expression in IMiD-resistant MM. Therefore, we propose that the critical mediator of IMiD resistance is conversion to a cell state where MYC expression is Ikaros axis independent. This suggests targeting MYC directly or via the as yet uncharacterized mechanism controlling MYC may be an effective strategy to eradicate IMiD resistant MM. Citation Format: Lorraine N. Davis, Zachary J. Walker, Denis Ohlstrom, Brett M. Stevens, Peter A. Forsberg, Tomer M. Mark, Craig T. Jordan, Daniel W. Sherbenou. MYC inhibition overcomes IMiD resistance in heterogeneous multiple myeloma populations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3956.

2030 Background: Glioblastoma (GBM) and tumor endothelial cells express phosphatidylserine (PS), a highly immunosuppressive membrane phospholipid. PS receptors engage with immune cells, leading to expansion of myeloid-derived suppressor cells (MDSCs) which promote an immunosuppressive and pro-angiogenic tumor microenvironment. Bavituximab (BAV) – a chimeric monoclonal antibody – binds to β2-glycoprotein 1 (β2-GP1) to form a complex of β2-GP1 with PS, resulting in immune activation against tumor cells and anti-angiogenic effects. Pre-clinical data in GBM models suggest synergistic effects of PS blockade, radiation (RT), and temozolomide (TMZ). Here, we present results from a phase II trial (NCT03139916) of BAV, RT and TMZ in GBM patients. Methods: 33 adults with newly diagnosed IDH-wild-type GBM were enrolled and received 6 weeks of RT+TMZ, followed by 6 cycles of TMZ. BAV (3 mg/kg) was given weekly, starting at week 1 of RT+TMZ, for 18 weeks with the option to continue if tolerated. The primary endpoint was the proportion of patients alive at 12 months (OS-12). The null hypothesis would be rejected if OS-12 was ≥ 72%. As an exploratory endpoint, the immune profile in tumor tissue and peripheral blood mononuclear cells (PBMCs) was assessed using nanoString and multispectral immunofluorescence, with the goal to assess on-target effects of BAV in longer vs. shorter surviving patients (split based on median survival). Relative cerebral blood flow (rCBF) from dynamic susceptibility contrast MRI was also obtained. Results: 24 patients were alive at 12 months and OS-12 was 73% (95% CI 59-90%) so the study met its primary endpoint. Median OS was 15.4 months. As best response, 79% of patients had stable disease, 12% had a partial response and 9% had progressive disease. Eight grade 3 or 4 adverse events were seen (no grade 5 AEs). Ten pre-treatment and 7 post-treatment tissue samples were available. Analysis of RNA from pre-treatment tumor specimens showed a significantly positive shift in myeloid-related gene expression in patients with longer survival, with enrichment of 116 and 120 transcripts as well as downregulation of 2 and 1 gene for PFS and OS, respectively. There was no differential expression in PBMCs. Including all tissue samples, there was a marked reduction of MDSCs after BAV compared to time of diagnosis (p = 0.011). Decreased rCBF post-RT/pre-cycle 1 TMZ was associated with improved OS (HR 4.63, p = 0.029). Conclusions: OS-12 was 73%, meeting the primary endpoint and suggesting potential activity of BAV in newly diagnosed GBM. BAV leads to on-target depletion of intratumoral immunosuppressive MDSCs and anti-angiogenic effects. As expected, based on the mechanism of action of BAV, there was no difference in PBMC gene expression profile in patients with long and short survival. Combining BAV with immune checkpoint inhibitors in the future may augment tumor immune response. Clinical trial information: NCT03139916.

PURPOSE: Although uncommon, detection of BRAF V600E mutations in adult patients with glioblastoma has become increasingly relevant given the widespread application of molecular diagnostics and encouraging therapeutic activity of BRAF/MEK inhibitors. METHODS: We performed a retrospective study of adult glioblastoma patients treated at Dana-Farber Cancer Institute/Brigham and Women’s Hospital or Massachusetts General Hospital from January 2011 to July 2019 with an identified BRAF V600E mutation by either immunohistochemistry or molecular testing. Patient characteristics, molecular genomics, and preoperative MRI were analyzed. RESULTS: Nineteen glioblastoma patients were included, with median age at diagnosis of 41-years-old (range 22–69). Only 1/18 was IDH1/2-mutant; 10/17 had MGMT unmethylated tumors. The most common additional molecular alterations were CDKN2A/2B biallelic loss/loss-of-function (10/13, 76.9%), polysomy 7 (8/12, 66.7%), monosomy 10 (5/12, 41.7%), PTEN biallelic loss/loss-of-function (5/13, 38.5%) and TERT promoter mutations (5/15, 33.3%). Most tumors were well-circumscribed (11/14) and all were contrast-enhancing on MRI. Twelve patients eventually developed subependymal or leptomeningeal dissemination. Six patients were treated with BRAF/MEK inhibition following disease progression after standard of care therapy, with 4/6 patients showing partial response or stable disease as best response. Median time to progression after BRAF/MEK inhibition was 6.0 months (95% CI 1.2–11.8). Grade 1 skin rash was present in 2 patients, but no other adverse events were reported. Median OS for the entire cohort was 24.1 months (95% CI 15.7–38.9). CONCLUSION: Understanding the natural history and features of BRAF V600E glioblastoma may help better identify patients for BRAF/MEK inhibition and select therapeutic strategies.

Circulating autoantibodies (auto-Abs) neutralizing high concentrations (10 ng/ml; in plasma diluted 1:10) of IFN-α and/or IFN-ω are found in about 10% of patients with critical COVID-19 (coronavirus disease 2019) pneumonia but not in individuals with asymptomatic infections. We detect auto-Abs neutralizing 100-fold lower, more physiological, concentrations of IFN-α and/or IFN-ω (100 pg/ml; in 1:10 dilutions of plasma) in 13.6% of 3595 patients with critical COVID-19, including 21% of 374 patients >80 years, and 6.5% of 522 patients with severe COVID-19. These antibodies are also detected in 18% of the 1124 deceased patients (aged 20 days to 99 years; mean: 70 years). Moreover, another 1.3% of patients with critical COVID-19 and 0.9% of the deceased patients have auto-Abs neutralizing high concentrations of IFN-β. We also show, in a sample of 34,159 uninfected individuals from the general population, that auto-Abs neutralizing high concentrations of IFN-α and/or IFN-ω are present in 0.18% of individuals between 18 and 69 years, 1.1% between 70 and 79 years, and 3.4% >80 years. Moreover, the proportion of individuals carrying auto-Abs neutralizing lower concentrations is greater in a subsample of 10,778 uninfected individuals: 1% of individuals 80 years. By contrast, auto-Abs neutralizing IFN-β do not become more frequent with age. Auto-Abs neutralizing type I IFNs predate SARS-CoV-2 infection and sharply increase in prevalence after the age of 70 years. They account for about 20% of both critical COVID-19 cases in the over 80s and total fatal COVID-19 cases. © 2021 The Authors, some rights reserved.

Bipolar disorder (BD) and cannabis use are highly comorbid and are each associated with cognitive impairment. Given the prevalence of cannabis use in people with BD, it is important to understand whether the two interact to impact cognitive function. We performed a systematic scoping review to determine what is currently known in this field. We systematically searched PubMed, Embase, CINAHL, Web of Science, and PsycINFO for studies on the relationship between cannabis use and cognition in people with BD or relevant animal models. Six observational human studies and no animal studies met inclusion criteria. Two studies found cannabis use in BD was associated with better performance in some cognitive domains, while three studies found no association. One study found cannabis use in BD was associated with worse overall cognition. Overall, most identified studies suggest cannabis use is not associated with significant cognitive impairment in BD; however, the scope of knowledge in this field is limited, and more systematic studies are clearly required. Future studies should focus on longitudinal and experimental trials, and well-controlled observational studies with rigorous quantification of the onset, frequency, quantity, duration, and type of cannabis use, as well as BD illness features.

Bimanual coordination is essential for the performance of many everyday tasks. There are several types of bimanually coordinated movements, classified according to whether the arms are acting to achieve a single goal (cooperative) or separate goals (independent), and whether the arms are moving symmetrically or asymmetrically. Symmetric bimanual movements are thought to facilitate corticomotor excitability (CME), while asymmetric bimanual movements are thought to recruit interhemispheric inhibition to reduce functional coupling between the motor cortices. The influences of movement symmetry and goal conceptualisation on interhemispheric interactions have not been studied together, and not during bimanually active dynamic tasks. The present study used transcranial magnetic stimulation (TMS) to investigate the modulation of CME and short- and long-latency interhemispheric inhibition (SIHI and LIHI, respectively) during bimanually active dynamic tasks requiring different types of bimanual coordination. Twenty healthy right-handed adults performed four bimanual tasks in which they held a dumbbell in each hand (independent) or a custom device between both hands (cooperative) while rhythmically flexing and extending their wrists symmetrically or asymmetrically. Motor-evoked potentials were recorded from the right extensor carpi ulnaris. We found CME was greater during asymmetric tasks than symmetric tasks, and movement symmetry did not modulate SIHI or LIHI. There was no effect of goal conceptualisation nor any interaction with movement symmetry for CME, SIHI or LIHI. Based on these results, movement symmetry and goal conceptualisation may not modulate interhemispheric inhibition during dynamic bimanual tasks. These findings contradict prevailing thinking about the roles of CME and interhemispheric inhibition in bimanual coordination.

MERTK is ectopically expressed and promotes survival in acute lymphoblastic leukemia (ALL) cells and is thus a potential therapeutic target. Here we demonstrate both direct therapeutic effects of MERTK inhibition on leukemia cells and induction of anti-leukemia immunity via suppression of the coinhibitory PD-1 axis. A MERTK-selective tyrosine kinase inhibitor, MRX-2843, mediated therapeutic anti-leukemia effects in immunocompromised mice bearing a MERTK-expressing human leukemia xenograft. In addition, inhibition of host MERTK by genetic deletion (Mertk-/- mice) or treatment with MRX-2843 significantly decreased tumor burden and prolonged survival in immune-competent mice inoculated with a MERTK-negative ALL, suggesting immune-mediated therapeutic activity. In this context, MERTK inhibition led to significant decreases in expression of the coinhibitory ligands PD-L1 and PD-L2 on CD11b+ monocytes/macrophages in the leukemia microenvironment. Furthermore, although T cells do not express MERTK, inhibition of MERTK indirectly decreased PD-1 expression on CD4+ and CD8+ T cells and decreased the incidence of splenic FOXP3+ Tregs at sites of leukemic infiltration, leading to increased T cell activation. These data demonstrate direct and immune-mediated therapeutic activities in response to MERTK inhibition in ALL models and provide validation of a translational agent targeting MERTK for modulation of tumor immunity.

OBJECTIVE To quantify and contextualize the risk for coronavirus disease 2019 (COVID-19)–related hospitalization and illness severity in type 1 diabetes. RESEARCH DESIGN AND METHODS We conducted a prospective cohort study to identify case subjects with COVID-19 across a regional health care network of 137 service locations. Using an electronic health record query, chart review, and patient contact, we identified clinical factors influencing illness severity. RESULTS We identified COVID-19 in 6,138, 40, and 273 patients without diabetes and with type 1 and type 2 diabetes, respectively. Compared with not having diabetes, people with type 1 diabetes had adjusted odds ratios of 3.90 (95% CI 1.75–8.69) for hospitalization and 3.35 (95% CI 1.53–7.33) for greater illness severity, which was similar to risk in type 2 diabetes. Among patients with type 1 diabetes, glycosylated hemoglobin (HbA1c), hypertension, race, recent diabetic ketoacidosis, health insurance status, and less diabetes technology use were significantly associated with illness severity. CONCLUSIONS Diabetes status, both type 1 and type 2, independently increases the adverse impacts of COVID-19. Potentially modifiable factors (e.g., HbA1c) had significant but modest impact compared with comparatively static factors (e.g., race and insurance) in type 1 diabetes, indicating an urgent and continued need to mitigate severe acute respiratory syndrome coronavirus 2 infection risk in this community.