Entactogen Effects of Ketamine: A Reverse-Translational Study.

OBJECTIVE: The authors sought to assess the prosocial, entactogen effects of ketamine. METHODS: Pleasure from social situations was assessed in a sample of participants with treatment-resistant depression from randomized, double-blind, placebo-controlled studies, using four items of the Snaith-Hamilton Pleasure Scale (SHAPS) at five time points over 1 week following treatment with ketamine (0.5 mg/kg intravenously) or placebo. The primary endpoint was postinfusion self-reported pleasure on the four SHAPS items pertaining to social situations, including the item on helping others, between the ketamine and placebo groups. In a rodent experiment, the impact of ketamine on helping behavior in rats was assessed using the harm aversion task. The primary endpoint was a reduction in lever response rate relative to baseline, which indicated the willingness of rats to forgo obtaining sucrose to help protect their cage mate from electric shock. RESULTS: Relative to placebo, ketamine increased ratings of feeling pleasure from being with family or close friends, seeing other people's smiling faces, helping others, and receiving praise, for 1 week following treatment. In the rodent experiment, during the harm aversion task, ketamine-treated rats maintained lower response rates relative to baseline to a greater extent than what was observed in vehicle-treated rats for 6 days posttreatment and delivered fewer shocks overall. CONCLUSIONS: In patients with treatment-resistant depression, ketamine treatment was associated with increased pleasure from social situations, such as feeling pleasure from helping others. Ketamine-treated rats were more likely to protect their cage mate from harm, at the cost of obtaining sucrose. These findings suggest that ketamine has entactogen effects.

Adoptive transfer of personalized neoantigen-reactive TCR-transduced T cells in metastatic colorectal cancer: phase 2 trial interim results.

Adoptive cell transfer (ACT) with neoantigen-reactive T lymphocytes can mediate cancer regression. Here we isolated unique, personalized, neoantigen-reactive T cell receptors (TCRs) from tumor-infiltrating lymphocytes of patients with metastatic gastrointestinal cancers and incorporated the TCR α and ß chains into gamma retroviral vectors. We transduced autologous peripheral blood lymphocytes and adoptively transferred these cells into patients after lymphodepleting chemotherapy. In a phase 2 single-arm study, we treated seven patients with metastatic, mismatch repair-proficient colorectal cancers who had progressive disease following multiple previous therapies. The primary end point of the study was the objective response rate as measured using RECIST 1.1, and the secondary end points were safety and tolerability. There was no prespecified interim analysis defined in this study. Three patients had objective clinical responses by RECIST criteria including regressions of metastases to the liver, lungs and lymph nodes lasting 4 to 7 months. All patients received T cell populations containing ≥50% TCR-transduced cells, and all T cell populations were polyfunctional in that they secreted IFNγ, GM-CSF, IL-2 and granzyme B specifically in response to mutant peptides compared with wild-type counterparts. TCR-transduced cells were detected in the peripheral blood of five patients, including the three responders, at levels ≥10% of CD3+ cells 1 month post-ACT. In one patient who responded to therapy, ~20% of CD3+ peripheral blood lymphocytes expressed transduced TCRs more than 2 years after treatment. This study provides early results suggesting that ACT with T cells genetically modified to express personalized neoantigen-reactive TCRs can be tolerated and can mediate tumor regression in patients with metastatic colorectal cancers. ClinicalTrials.gov registration: NCT03412877 .

Ketamine metabolism via hepatic CYP450 isoforms contributes to its sustained antidepressant actions.

(R,S)-ketamine (ketamine) has rapid and sustained antidepressant (AD) efficacy at sub-anesthetic doses in depressed patients. A metabolite of ketamine, including (2R,6R)-hydroxynorketamine ((6)-HNKs) has been reported to exert antidepressant actions in rodent model of anxiety/depression. To further understand the specific role of ketamine's metabolism in the AD actions of the drug, we evaluated the effects of inhibiting hepatic cytochrome P450 enzymes on AD responses. We assessed whether pre-treatment with fluconazole (10 and 20 mg/kg, i.p.) 1 hour prior to ketamine or HNKs (10 mg/kg, i.p.) administration would alter behavioral and neurochemical actions of the drugs in male BALB/cJ mice with a highly anxious phenotype. Extracellular microdialysate levels of glutamate and GABA (Gluext, GABAext) were also measured in the medial prefrontal cortex (mPFC). Pre-treatment with fluconazole altered the pharmacokinetic profile of ketamine, by increasing both plasma and brain levels of ketamine and (R,S)-norketamine, while robustly reducing those of (6)-HNKs. At 24 hours post-injection (t24h), fluconazole prevented the sustained AD-like response of ketamine responses in the forced swim test and splash test, as well as the enhanced cortical GABA levels produced by ketamine. A single (2R,6R)-HNK administration resulted in prevention of the effects of fluconazole on the antidepressant-like activity of ketamine in mice. Overall, these findings are consistent with an essential contribution of (6)-HNK to the sustained antidepressant-like effects of ketamine and suggest potential interactions between pharmacological CYPIs and ketamine during antidepressant treatment in patients.

Adapting an Intervention to Address Barriers to Pain Management in Hospice: Formative Research to Inform EMPOWER-D for Dementia Caregivers.

Background: Nearly half of more than 1.7 million older Americans who receive hospice care each year have a primary or comorbid diagnosis of dementia. Pain is often undertreated in this patient population owing to myriad factors, including unmet informational needs among family caregivers. Objective: We sought to inform the adaptation of a pain education intervention for hospice family caregivers to the context of dementia by eliciting feedback on the educational content covered in adapted intervention materials. Design: We conducted a multimethod, formative research study to inform the adaptation of an existing, evidence-based intervention. Setting/Subjects: The study included a purposively recruited sample (n = 33) of hospice professionals (n = 18) and family caregivers (n = 15) from across the United States. Measurements: Participants quantitatively rated the importance of each of the eight pain concerns presented in the adapted intervention materials (1 = not important to 3 = very important) and provided qualitative feedback via Zoom interview on the acceptability, clinical accuracy, and potential benefits of the adapted content. We analyzed quantitative data via descriptive statistics and qualitative data via content analysis. Results: Participants rated the adapted educational content as highly important (rangemean = 2.56-3.00), particularly regarding concerns about caregivers' pain assessment, communicating with the hospice team about pain, and addressing misinformation regarding pain medication outcomes. Participants also provided suggestions to strengthen specific educational messages to improve comprehension and uptake. Conclusions: Findings support the continued development and testing of the adapted intervention.

Identification of Novel Isatin Derivative Bearing a Nitrofuran Moiety as Potent Multi-Isoform Aldehyde Dehydrogenase Inhibitor.

Aldehyde dehydrogenases (ALDHs) are a family of enzymes that aid in detoxification and are overexpressed in several different malignancies. There is a correlation between increased expression of ALDH and a poor prognosis, stemness, and resistance to several drugs. Several ALDH inhibitors have been generated due to the crucial role that ALDH plays in cancer stem cells. All of these inhibitors, however, are either ineffective, very toxic, or have yet to be subjected to rigorous testing on their effectiveness. Although various drug-like compounds targeting ALDH have been reported in the literature, none have made it to routine use in the oncology clinic. As a result, new potent, non-toxic, bioavailable, and therapeutically effective ALDH inhibitors are still needed. In this study, we designed and synthesized potent multi-ALDH isoform inhibitors based on the isatin and indazole pharmacophore. Molecular docking studies and enzymatic tests revealed that among all of the synthesized analogs, compound 3 is the most potent inhibitor of ALDH1A1, ALDH3A1, and ALDH1A3, exhibiting 51.32%, 51.87%, and 36.65% inhibition, respectively. The ALDEFLUOR assay further revealed that compound 3 acts as an ALDH broad spectrum inhibitor at 500 nM. Compound 3 was also the most cytotoxic to cancer cells, with an IC50 in the range of 2.1 to 3.8 µM for ovarian, colon, and pancreatic cancer cells, compared to normal and embryonic kidney cells (IC50 7.1 to 8.7 µM). Mechanistically, compound 3 increased ROS activity due to potent multi-ALDH isoform inhibition, which increased apoptosis. Taken together, this study identified a potent multi-isoform ALDH inhibitor that could be further developed as a cancer therapeutic.

At-Home "Tips" for Headache Management: The Use of Self-Trendelenburg to Help Determine the Cause of Worsening Headaches - A Case Series.

Introduction: In-office use of the Trendelenburg position has been shown to be a beneficial clinical tool to help decipher if a CSF pressure/volume component is part of the underlying etiologic process for a patient's persistent headache. Utilizing the Trendelenburg position at home could potentially be an additional diagnostic tool for the treating headache physician. Case Series: Our headache practice has been using at-home self-Trendelenburg for the past 2 years and will present the clinical scenarios in which it seems to be the most helpful utilizing a case series of patients. These include (1) in those who just had a lumbar puncture and call for worsening headaches and do not have an obvious orthostatic component; (2) in those who had a spinal epidural blood patch for a presumed CSF leak and state there was no improvement; (3) in those who are on daily preventive CSF volume-lowering medications and call in with worsening headaches; (4) in those with known CSF pressure-dependent headaches high or low but who are not on daily preventive CSF volume modulatory medications; (5) in those with a history of migraine or other primary headache disorder to see if a new type of headache is possibly from a CSF leak or an abnormal reset of CSF pressure to an elevated state; (6) in those with triggered only headaches like cough or exertional headache. Conclusion: Utilizing at-home self-Trendelenburg can provide valuable information for the treating headache physician on possible underlying headache etiology and can guide specific treatment strategies. Its simplicity and quick declaration of results are very patient pleasing.

Further Psychometric Evaluation of the Eight-Item Hospice Philosophy Scale: Results From a National Sample of Interdisciplinary Hospice Clinicians.

This study examined the psychometric properties of the eight-item Hospice Philosophy Scale (HPS-8) through confirmatory factor analysis; differential item functioning by age, gender, race, and professional discipline; and internal consistency reliability. We administered the HPS-8 to a national convenience sample of 471 interdisciplinary hospice clinicians. Confirmatory factor analysis results supported a one-factor model with an error correlation between two similarly worded items, χ2(19) = 48.38, p < .001 (RMSEA = .06, SRMR = .03, CFI = .98, TLI = .97). "Multiple indicators, multiple causes" model results indicated differential item functioning by age, race, and/or professional discipline on five items. However, subsequent uncorrected and differential item functioning-corrected models detected no statistically significant HPS-8 mean differences by grouping variables. Composite reliability results (CR = .82) demonstrated acceptable internal consistency reliability. Our results support the HPS-8 as a valid and reliable measure of attitudes toward the hospice philosophy of care in hospice clinicians.

Room-temperature strong coupling between CdSe nanoplatelets and a metal-DBR Fabry-Pérot cavity.

The generation of exciton-polaritons through strong light-matter interactions represents an emerging platform for exploring quantum phenomena. A significant challenge in colloidal nanocrystal-based polaritonic systems is the ability to operate at room temperature with high fidelity. Here, we demonstrate the generation of room-temperature exciton-polaritons through the coupling of CdSe nanoplatelets (NPLs) with a Fabry-Pérot optical cavity, leading to a Rabi splitting of 74.6 meV. Quantum-classical calculations accurately predict the complex dynamics between the many dark state excitons and the optically allowed polariton states, including the experimentally observed lower polariton photoluminescence emission, and the concentration of photoluminescence intensities at higher in-plane momenta as the cavity becomes more negatively detuned. The Rabi splitting measured at 5 K is similar to that at 300 K, validating the feasibility of the temperature-independent operation of this polaritonic system. Overall, these results show that CdSe NPLs are an excellent material to facilitate the development of room-temperature quantum technologies.

Onabotulinumtoxina (craniotomy scar combined with cranial suture line injections) for persistent post craniotomy headache: Case series with long-term follow-up.

BACKGROUND: There is no defined preventive treatment protocol for persistent post-craniotomy headache. In several small case series and individual case reports onabotulinumtoxinA injected into the craniotomy scar has shown possible efficacy. What is lacking is long term follow-up and if focusing on the cranial suture lines along with the craniotomy scar can enhance improvement and provide more sustained benefit. METHODS: Retrospective chart review with case series. RESULTS: Four patients (three women, one man) with ICHD-3 defined persistent post craniotomy headache were treated using a novel onabotulinumtoxinA injection protocol. All the patients presented with continuous head pain of moderate to severe intensity. All had severe allodynia on the side of their craniotomy. All had significant reduction in quality of life. Our application of onabotulinumtoxinA involved injection into both the surgical scar and the transected/irritated cranial suture lines noted on neuroimaging and physical examination. With treatment all patients demonstrated significant benefit including a reduction in daily pain intensity (75%-100%), developing periods of pain freedom (2-7 days per week) and having a dramatic improvement in quality of life (close to 100% in all). The benefit was sustained for at least five years of follow-up. CONCLUSION: From our case series it appears that injection not only along the painful craniotomy scar but into the involved cranial suture lines provides positive efficacy and sustained improvement in patients with persistent post craniotomy headache.

Targeting Tyro3, Axl, and MerTK Receptor Tyrosine Kinases Significantly Sensitizes Triple-Negative Breast Cancer to CDK4/6 Inhibition.

Triple-negative breast cancer (TNBC) is the most aggressive subtype with high metastasis and mortality rates. Given the lack of actionable targets such as ER and HER2, TNBC still remains an unmet therapeutic challenge. Despite harboring high CDK4/6 expression levels, the efficacy of CDK4/6 inhibition in TNBC has been limited due to the emergence of resistance. The resistance to CDK4/6 inhibition is mainly mediated by RB1 inactivation. Since our aim is to overcome resistance to CDK4/6 inhibition, in this study, we primarily used the cell lines that do not express RB1. Following a screening for activated receptor tyrosine kinases (RTKs) upon CDK4/6 inhibition, we identified the TAM (Tyro3, Axl, and MerTK) RTKs as a crucial therapeutic vulnerability in TNBC. We show that targeting the TAM receptors with a novel inhibitor, sitravatinib, significantly sensitizes TNBC to CDK4/6 inhibitors. Upon prolonged HER2 inhibitor treatment, HER2+ breast cancers suppress HER2 expression, physiologically transforming into TNBC-like cells. We further show that the combined treatment is highly effective against drug-resistant HER2+ breast cancer as well. Following quantitative proteomics and RNA-seq data analysis, we extended our study into the immunophenotyping of TNBC. Given the roles of the TAM receptors in promoting the creation of an immunosuppressive tumor microenvironment (TME), we further demonstrate that the combination of CDK4/6 inhibitor abemaciclib and sitravatinib modifies the immune landscape of TNBC to favor immune checkpoint blockade. Overall, our study offers a novel and highly effective combination therapy against TNBC and potentially treatment-resistant HER2+ breast cancer that can be rapidly moved to the clinic.

Safety climate and seat belt use in the fire service.

OBJECTIVE: Motor vehicle incidents or apparatus crashes are a leading cause of firefighter fatalities in the United States. Nonuse of seat belts has been linked to some of these fatalities. This research seeks to understand the relationship between safety climate and seat belt use among firefighters, as findings will provide insights into factors that may bolster seat belt use and protect firefighters. METHODS: Data were collected from 208 career firefighters working for a city fire department in the southeastern United States. Structural equation modeling was used to test a hypothesized model and to assess the relationships between organizational safety climate, work group safety climate and seat belt use. RESULTS: It was determined that positive perceptions of workgroup safety climate, as a higher order factor, comprised of supervisor support, horizontal cohesion, and vertical cohesion, was positively associated with seat belt use within a sample of firefighters. Organizational level safety climate did not have a significant relationship with seat belt use but did positively influence workgroup safety climate perceptions. CONCLUSIONS: Safety climate has been associated with safety compliance and participation behaviors, but more research was needed to specifically examine the impact of safety climate on seat belt use in firefighters. The findings point to the importance of safety climate as a leading indicator and predictor of seat belt use. Bolstering safety climate through safety programs, commitment to safety, effective communication, supportive supervisors and cohesion should ultimately aid in bolstering seat belt use among firefighters, which is important to curtailing firefighter injuries and fatalities.

Expansion of pneumococcal serotype 23F and 14 lineages with genotypic changes in capsule polysaccharide locus and virulence gene profiles post introduction of pneumococcal conjugate vaccine in Blantyre, Malawi.

Since the introduction of the 13-valent pneumococcal conjugate vaccine (PCV13) in Malawi in 2011, there has been persistent carriage of vaccine serotype (VT) Streptococcus pneumoniae, despite high vaccine coverage. To determine if there has been a genetic change within the VT capsule polysaccharide (cps) loci since the vaccine's introduction, we compared 1022 whole-genome-sequenced VT isolates from 1998 to 2019. We identified the clonal expansion of a multidrug-resistant, penicillin non-susceptible serotype 23F GPSC14-ST2059 lineage, a serotype 14 GPSC9-ST782 lineage and a novel serotype 14 sequence type GPSC9-ST18728 lineage. Serotype 23F GPSC14-ST2059 had an I253T mutation within the capsule oligosaccharide repeat unit polymerase Wzy protein, which is predicted in silico to alter the protein pocket cavity. Moreover, serotype 23F GPSC14-ST2059 had SNPs in the DNA binding sites for the cps transcriptional repressors CspR and SpxR. Serotype 14 GPSC9-ST782 harbours a non-truncated version of the large repetitive protein (Lrp), containing a Cna protein B-type domain which is also present in proteins associated with infection and colonisation. These emergent lineages also harboured genes associated with antibiotic resistance, and the promotion of colonisation and infection which were absent in other lineages of the same serotype. Together these data suggest that in addition to serotype replacement, modifications of the capsule locus associated with changes in virulence factor expression and antibiotic resistance may promote vaccine escape. In summary, the study highlights that the persistence of vaccine serotype carriage despite high vaccine coverage in Malawi may be partly caused by expansion of VT lineages post-PCV13 rollout.

Collaborative robots can augment human cognition in regret-sensitive tasks.

Despite theoretical benefits of collaborative robots, disappointing outcomes are well documented by clinical studies, spanning rehabilitation, prostheses, and surgery. Cognitive load theory provides a possible explanation for why humans in the real world are not realizing the benefits of collaborative robots: high cognitive loads may be impeding human performance. Measuring cognitive availability using an electrocardiogram, we ask 25 participants to complete a virtual-reality task alongside an invisible agent that determines optimal performance by iteratively updating the Bellman equation. Three robots assist by providing environmental information relevant to task performance. By enabling the robots to act more autonomously-managing more of their own behavior with fewer instructions from the human-here we show that robots can augment participants' cognitive availability and decision-making. The way in which robots describe and achieve their objective can improve the human's cognitive ability to reason about the task and contribute to human-robot collaboration outcomes. Augmenting human cognition provides a path to improve the efficacy of collaborative robots. By demonstrating how robots can improve human cognition, this work paves the way for improving the cognitive capabilities of first responders, manufacturing workers, surgeons, and other future users of collaborative autonomy systems.

US Immigration Policy Stressors and Latinx Youth Mental Health.

Importance: The youth mental health crisis is exacerbated for Latinx adolescents, a group whose families are targets of anti-immigrant rhetoric and policy. Objective: To investigate how immigration-related stressors are associated with disruptions in parent-child relationships and, in turn, the mental health symptoms of Latinx adolescents. Design, Setting, and Participants: Data for this prospective cohort study of adolescent-mother dyads were derived from surveys completed at 3 time points spanning 4 years (time 1 [T1] in 2018, time 2 [T2] in 2020, and time 3 [T3] in 2022). Mediation analyses estimated paths from immigration-related stressors to parent-child relationship qualities to mental health symptoms from early to late adolescence. Multivariable and multivariate linear models within a structural equation modeling framework regressed mediators and outcome variables on their own T1 values, offering a scientifically rigorous test of mediation. The setting was a school district in suburban Atlanta, Georgia, and included Latinx adolescents (ages 11-16 years) randomly selected from grade and gender strata. Data were analyzed from June 2023 to March 2024. Exposures: The primary independent variables were T1 mother reports of anti-immigrant worry and behavioral modification and adolescent reports of family member detention or deportation. Mediating variables were the reports of parental support and parent-child conflict of T2 adolescents. Main Outcomes and Measures: T3 adolescent reports of past 6-month internalizing and externalizing symptoms. Results: A total of 547 Latinx adolescents (mean [SD] age, 13.3 [1.0] years; 303 female [55.4%]; 244 male [44.6%]) were included in this study. Response rates were 65.2% (547 of 839) among contacted parents and 95.3% (547 of 574) among contacted adolescents with parental permission. Four-year retention rates were 67% (366 of 547 adolescents) and 65% (177 of 271 mothers). Structural model results showed that T1 anti-immigrant worry and behavioral modification was associated with T3 increases in externalizing symptoms indirectly through T1 to T2 increases in parent-child conflict (ß = 0.03; SE = 0.02; 95% CI, 0-0.08). For girls, T1 family member deportation or detention was associated with T1 to T3 increases in internalizing and externalizing symptoms indirectly through T1 to T2 declines in parental support (internalizing: ß = 0.04; SE = 0.02; 95% CI, 0-0.08; externalizing: ß = 0.03; SE = 0.02; 95% CI, 0-0.07). Sensitivity analyses supported structural model findings. Conclusion and Relevance: Results of this cohort study suggest that legislative bodies, the health care system, and educational institutions should implement safeguards to mitigate potential harm conferred by anti-immigrant environments for parent-child relationships and, in turn, Latinx adolescents' mental health.

Cavity Quantum Electrodynamics Enables para- and ortho-Selective Electrophilic Bromination of Nitrobenzene.

Coupling molecules to a quantized radiation field inside an optical cavity has shown great promise to modify chemical reactivity. In this work, we show that the ground-state selectivity of the electrophilic bromination of nitrobenzene can be fundamentally changed by strongly coupling the reaction to the cavity, generating ortho- or para-substituted products instead of the meta product. Importantly, these are products that are not obtained from the same reaction outside the cavity. A recently developed ab initio approach was used to theoretically compute the relative energies of the cationic Wheland intermediates, which indicate the kinetically preferred bromination site for all products. Performing an analysis of the ground-state electron density for the Wheland intermediates inside and outside the cavity, we demonstrate how strong coupling induces reorganization of the molecular charge distribution, which in turn leads to different bromination sites directly dependent on the cavity conditions. Overall, the results presented here can be used to understand cavity induced changes to ground-state chemical reactivity from a mechanistic perspective as well as to directly connect frontier theoretical simulations to state-of-the-art, but realistic, experimental cavity conditions.

The impact of safety behavior, perceived risk, and workplace resources on COVID outcomes for U.S. Aircraft Rescue and Firefighting personnel.

BACKGROUND: Aircraft rescue and firefighting (ARFF) personnel are first responders located at airports in the United States who provide emergency response, mitigation, evacuation, and rescue of passengers and crew of aircraft at airports. The nature of their work puts ARFF personnel in close contact with travelers on a regular basis and at elevated risk for COVID-19 exposure. OBJECTIVE: In this study, we focused on safety behavior, perceived risk, and workplace resources to understand COVID-19 outcomes in the early pandemic among the overlooked worker population of ARFF personnel. The goal of this study was to examine how a self-reported positive COVID test were associated with safety behavior, perceived risk, and workplace resources. METHODS: Cross-sectional survey data were collected among ARFF personnel a year into the COVID-19 pandemic. RESULTS: Regression results showed that each additional unit increase in perceived susceptibility to COVID-19 was associated with a 133% increase in the odds of testing positive for COVID-19 (OR = 2.33, p <  0.05), and with each additional unit increase in perceived severity level, the odds of getting COVID-19 decreased by 47% (OR = 0.53, p <  0.05). CONCLUSIONS: Infection control among first responders may be improved by providing relevant information physical and emotional resources, and support that help shape perceptions of risk and adoption of prevention behaviors.

Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes.

BACKGROUND: Tumor-infiltrating lymphocytes (TILs) targeting neoantigens can effectively treat a selected set of metastatic solid cancers. However, harnessing TILs for cancer treatments remains challenging because neoantigen-reactive T cells are often rare and exhausted, and ex vivo expansion can further reduce their frequencies. This complicates the identification of neoantigen-reactive T-cell receptors (TCRs) and the development of TIL products with high reactivity for patient treatment. METHODS: We tested whether TILs could be in vitro stimulated against neoantigens to achieve selective expansion of neoantigen-reactive TILs. Given their prevalence, mutant p53 or RAS were studied as models of human neoantigens. An in vitro stimulation method, termed "NeoExpand", was developed to provide neoantigen-specific stimulation to TILs. 25 consecutive patient TILs from tumors harboring p53 or RAS mutations were subjected to NeoExpand. RESULTS: We show that neoantigenic stimulation achieved selective expansion of neoantigen-reactive TILs and broadened the neoantigen-reactive CD4+ and CD8+ TIL clonal repertoire. This allowed the effective isolation of novel neoantigen-reactive TCRs. Out of the 25 consecutive TIL samples, neoantigenic stimulation enabled the identification of 16 unique reactivities and 42 TCRs, while conventional TIL expansion identified 9 reactivities and 14 TCRs. Single-cell transcriptome analysis revealed that neoantigenic stimulation increased neoantigen-reactive TILs with stem-like memory phenotypes expressing IL-7R, CD62L, and KLF2. Furthermore, neoantigenic stimulation improved the in vivo antitumor efficacy of TILs relative to the conventional OKT3-induced rapid TIL expansion in p53-mutated or KRAS-mutated xenograft mouse models. CONCLUSIONS: Taken together, neoantigenic stimulation of TILs selectively expands neoantigen-reactive TILs by frequencies and by their clonal repertoire. NeoExpand led to improved phenotypes and functions of neoantigen-reactive TILs. Our data warrant its clinical evaluation. TRIAL REGISTRATION NUMBER: NCT00068003, NCT01174121, and NCT03412877.

Modeling Population Growth under Climate Stressors Using Age-structured Matrix Models.

Climate resilience, a focus of many recent studies, has been examined from ecological, physiological, and evolutionary perspectives. However, sampling biases towards adults, males, and certain species have made establishing the link between environmental change and population-level change problematic. Here we used data from four laboratory studies, in which we administered pre- and post-natal stressors, such as suboptimal incubation temperature, heat stress, and food restriction, to zebra finches and quantified hatching success, post-hatch survival, and reproductive success, to parameterize age-structured population dynamics models with the goal of estimating the effect of the stressors on relative population growth rates. Using the same model structure, we tested the hypothesis that early life stages influence population growth rate more than later life stages. Our models suggested that stressful events during embryonic development, such as suboptimal incubation temperatures and reduced gas exchange for the embryos, have a greater total impact on population growth than post-hatch stressors, such as heat stress and food restriction. However, among life history traits, differences in hatching success and sex ratio of offspring in response to stressors changed population growth rates more than differences in any other demographic rate estimates. These results suggest that when predicting population resilience against climate change, it is critical to account for effects of climate change on all life stages, including early stages of life, and to incorporate individuals' physiology and stress tolerance that likely influence future stress responses, reproduction, and survival.