Showing papers by "New York University published in 2022"

Robust immune responses are observed after one dose of BNT162b2 mRNA vaccine dose in SARS-CoV-2–experienced individuals

Abstract: The use of coronavirus disease 2019 (COVID-19) vaccines will play the major role in helping to end the pandemic that has killed millions worldwide. COVID-19 vaccines have resulted in robust humoral responses and protective efficacy in human trials, but efficacy trials excluded individuals with a prior diagnosis of COVID-19. As a result, little is known about how immune responses induced by mRNA vaccines differ in individuals who recovered from COVID-19. Here, we evaluated longitudinal immune responses to two-dose BNT162b2 mRNA vaccination in 15 adults who had experienced COVID-19, compared to 21 adults who did not have prior COVID-19. Consistent with prior studies of mRNA vaccines, we observed robust cytotoxic CD8+ T cell responses in both cohorts after the second dose. Furthermore, SARS-CoV-2–naive individuals had progressive increases in humoral and antigen-specific antibody-secreting cell (ASC) responses after each dose of vaccine, whereas SARS-CoV-2–experienced individuals demonstrated strong humoral and antigen-specific ASC responses to the first dose but these responses were not further enhanced after the second dose of the vaccine at the time points studied. Together, these data highlight the relevance of immunological history for understanding vaccine immune responses and may have implications for personalizing mRNA vaccination regimens used to prevent COVID-19, including for the deployment of booster shots.

NRF2: KEAPing Tumors Protected

Abstract: Abstract The Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2–related factor 2 (NRF2) pathway plays a physiologic protective role against xenobiotics and reactive oxygen species. However, activation of NRF2 provides a powerful selective advantage for tumors by rewiring metabolism to enhance proliferation, suppress various forms of stress, and promote immune evasion. Genetic, epigenetic, and posttranslational alterations that activate the KEAP1/NRF2 pathway are found in multiple solid tumors. Emerging clinical data highlight that alterations in this pathway result in resistance to multiple therapies. Here, we provide an overview of how dysregulation of the KEAP1/NRF2 pathway in cancer contributes to several hallmarks of cancer that promote tumorigenesis and lead to treatment resistance. Significance: Alterations in the KEAP1/NRF2 pathway are found in multiple cancer types. Activation of NRF2 leads to metabolic rewiring of tumors that promote tumor initiation and progression. Here we present the known alterations that lead to NRF2 activation in cancer, the mechanisms in which NRF2 activation promotes tumors, and the therapeutic implications of NRF2 activation.

E-Cigarette Toxicology.

Abstract: Since the spread of tobacco from the Americas hundreds of years ago, tobacco cigarettes and, more recently, alternative tobacco products have become global products of nicotine addiction. Within th...

A Multicenter Phase II Trial of Ipilimumab and Nivolumab in Unresectable or Metastatic Metaplastic Breast Cancer: Cohort 36 of Dual Anti–CTLA-4 and Anti–PD-1 Blockade in Rare Tumors (DART, SWOG S1609)

Abstract: Abstract Purpose: Metaplastic breast cancer (MpBC) is a rare aggressive subtype that responds poorly to cytotoxics. Median survival is approximately 8 months for metastatic disease. We report results for advanced MpBC treated with ipilimumab + nivolumab, a cohort of S1609 for rare cancers (DART: NCT02834013). Patients and Methods: Prospective, open-label, multicenter phase II (two-stage) trial of ipilimumab (1 mg/kg i.v. every 6 weeks) plus nivolumab (240 mg i.v. every 2 weeks) for advanced MpBC. Primary endpoint was objective response rate (ORR). Secondary endpoints included progression-free survival (PFS), overall survival (OS), and toxicity. Results: Overall, 17 evaluable patients enrolled. Median age was 60 years (26–85); median number of prior therapy lines was 2 (0–5). ORR was 18%; 3 of 17 patients achieved objective responses (1 complete, 2 partial responses; 2 spindle cell, 1 chondromyxoid histology), which are ongoing at 28+, 33+, and 34+ months, respectively. Median PFS and OS were 2 and 12 months, respectively. Altogether, 11 patients (65%) experienced adverse events (AE), including one grade 5 AE. Eight patients (47%) developed an immune-related AE (irAE), with adrenal insufficiency observed in all 3 responders. Responses occurred in tumors with low tumor mutational burden, low PD-L1, and absent tumor-infiltrating lymphocytes. Conclusions: The ipilimumab and nivolumab combination showed no new safety signals and met its primary endpoint with 18% ORR in advanced, chemotherapy-refractory MpBC. All responses are ongoing at >2 to almost 3 years later. The effect of ipilimumab and nivolumab was associated with exceptional responses in a subset of patients versus no activity. This combination warrants further investigation in MpBC, with special attention to understanding mechanism of action, and carefully designed to weigh against the significant risks of irAEs.

Ti ₃ C ₂ T _x /PANI/Liquid Metal Composite Microspheres with 3D Nanoflower Structure: Preparation, Characterization, and Applications in EMI Shielding

Abstract: Conductive fabrics are promising candidates for developing flexible, lightweight, and high conductivity electromagnetic (EM) shielding materials to meet the requirements of next-generation flexible and wearable electronics. Herein, an effective strategy to construct a conductive titanium carbide (Ti3C2Tx)/Polyaniline (PANI) composite with 3D nanoflower structure by deposition of PANI on the surface of single-layer Ti3C2Tx nanosheets through in situ and oxidant-free polymerization of aniline monomer to avoid the restacking/aggregation and easy oxidation of Ti3C2Tx MXene is developed. In addition, GaIn liquid metal (LM) nanoparticles are also incorporated into the Ti3C2Tx/PANI microsphere to increase conductivity and stability. This method solves the existing problems of poor connectivity between LM nanoparticles and discontinuity of the Ti3C2Tx MXene nanosheets. Eventually, by using carbon fabrics (CF) as the substrate, a flexible, stable, and efficient electromagnetic interference (EMI) shielding conductive composite fabric with an optimal EMI shielding efficiency (EMI SE) value of 52.0 dB in the range of 8.2–12.4 GHz at a thickness of 0.27 mm is developed. Meanwhile, the as-prepared fabrics demonstrate superior Joule heating property, high mechanical flexibility, and excellent bending-release stability. The study provides a simple and efficient method to fabricate multifunctional conductive textiles to meet the need for practical application in EMI shielding area.

A neural circuit for wind-guided olfactory navigation

Abstract: To navigate towards a food source, animals frequently combine odor cues about source identity with wind direction cues about source location. Where and how these two cues are integrated to support navigation is unclear. Here we describe a pathway to the Drosophila fan-shaped body that encodes attractive odor and promotes upwind navigation. We show that neurons throughout this pathway encode odor, but not wind direction. Using connectomics, we identify fan-shaped body local neurons called h∆C that receive input from this odor pathway and a previously described wind pathway. We show that h∆C neurons exhibit odor-gated, wind direction-tuned activity, that sparse activation of h∆C neurons promotes navigation in a reproducible direction, and that h∆C activity is required for persistent upwind orientation during odor. Based on connectome data, we develop a computational model showing how h∆C activity can promote navigation towards a goal such as an upwind odor source. Our results suggest that odor and wind cues are processed by separate pathways and integrated within the fan-shaped body to support goal-directed navigation.

The Gut Microbiome, Metformin, and Aging.

Abstract: Metformin has been extensively used for the treatment of type 2 diabetes, and it may also promote healthy aging. Despite its widespread use and versatility, metformin's mechanisms of action remain elusive. The gut typically harbors thousands of bacterial species, and as the concentration of metformin is much higher in the gut as compared to plasma, it is plausible that microbiome-drug-host interactions may influence the functions of metformin. Detrimental perturbations in the aging gut microbiome lead to the activation of the innate immune response concomitant with chronic low-grade inflammation. With the effectiveness of metformin in diabetes and antiaging varying among individuals, there is reason to believe that the gut microbiome plays a role in the efficacy of metformin. Metformin has been implicated in the promotion and maintenance of a healthy gut microbiome and reduces many age-related degenerative pathologies. Mechanistic understanding of metformin in the promotion of a healthy gut microbiome and aging will require a systems-level approach. Expected final online publication date for the Annual Review of Pharmacology and Toxicology, Volume 62 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Sarcopenia Is an Independent Risk Factor for Proximal Junctional Disease Following Adult Spinal Deformity Surgery.

Abstract: Study Design:Retrospective cohort study.Objectives:Sarcopenia is a risk factor for medical complications following spine surgery. However, the role of sarcopenia as a risk factor for proximal junct...

Trips and neurotransmitters: Discovering principled patterns across 6850 hallucinogenic experiences

Abstract: Psychedelics probably alter states of consciousness by disrupting how the higher association cortex governs bottom-up sensory signals. Individual hallucinogenic drugs are usually studied in participants in controlled laboratory settings. Here, we have explored word usage in 6850 free-form testimonials about 27 drugs through the prism of 40 neurotransmitter receptor subtypes, which were then mapped to three-dimensional coordinates in the brain via their gene transcription levels from invasive tissue probes. Despite high interindividual variability, our pattern-learning approach delineated how drug-induced changes of conscious awareness are linked to cortex-wide anatomical distributions of receptor density proxies. Each discovered receptor-experience factor spanned between a higher-level association pole and a sensory input pole, which may relate to the previously reported collapse of hierarchical order among large-scale networks. Coanalyzing many psychoactive molecules and thousands of natural language descriptions of drug experiences, our analytical framework finds the underlying semantic structure and maps it directly to the brain.

Determinants of the COVID-19 vaccine hesitancy spectrum

Abstract: Vaccine hesitancy remains an issue in the United States. This study conducted an online survey [N = 3,013] using the Social Science Research Solution [SSRS] Opinion Panel web panelists, representative of U.S. adults age 18 and older who use the internet, with an oversample of rural-dwelling and minority populations between April 8 and April 22, 2021- as vaccine eligibility opened to the country. We examined the relationship between COVID-19 exposure and socio-demographics with vaccine intentions [eager-to-take, wait-and-see, undecided, refuse] among the unvaccinated using multinomial logistic regressions [ref: fully/partially vaccinated]. Results showed vaccine intentions varied by demographic characteristics and COVID-19 experience during the period that eligibility for the vaccine was extended to all adults. At the time of the survey approximately 40% of respondents were unvaccinated; 41% knew someone who had died of COVID-19, and 38% had experienced financial hardship as a result of the pandemic. The vaccinated were more likely to be highly educated, older adults, consistent with the United States initial eligibility criteria. Political affiliation and financial hardship experienced during the pandemic were the two most salient factors associated with being undecided or unwilling to take the vaccine.

Polaromics: deriving polarization parameters from a Mueller matrix for quantitative characterization of biomedical specimen

Abstract: Mueller matrix is a comprehensive representation of the polarization transformation properties of the sample and encode very rich information on the microstructure of the scattering objects. However, it is often inconvenient to use individual Mueller matrix elements to characterize the microstructure due to lack of explicit connections between the matrix elements and the physics properties of the scattering samples. In this review, we summarize the methods to derive groups of polarization parameters, which have clear physical meanings and associations with certain structural properties of turbid media, including various Mueller matrix decomposition (MMD) methods and Mueller matrix transformation (MMT) technique. Previously, experimentalists will choose the most suitable method for specific measurement scheme. In this review, we introduce an emerging novel research paradigm called "polaromics". In this paradigm, both MMD and MMT parameters are considered as polarimetry basis parameters (PBP), which are used to construct polarimetry feature parameters (PFP) for quantitative characterization of complex biomedical samples. Machine learning techniques are involved for finding PFPs that are sensitive to specific micro- or macro-structural features. The goal of this review is to provide an overview of the emerging "polaromics" paradigm, which may pave the way for biomedical and clinical applications of polarimetry.

Classical double copy at null infinity

Abstract: Abstract We give two double copy prescriptions which construct asymptotically flat solutions in gravity from asymptotically flat gauge fields. The first prescription applies to radiative fields, which are non-linear vacuum solutions determined by characteristic data at null infinity. For any two such radiative gauge fields (linear or non-linear), the characteristic data of a radiative metric, dilaton and axion is constructed by a simple ‘squaring’ procedure, giving a classical double copy at the level of radiation fields. We demonstrate the procedure with several examples where the characteristic data can be explicitly integrated; for linear fields this also sheds light on the twistorial description of Weyl double copy. Our second prescription applies to all asymptotically flat fields at the level of their asymptotic equations of motion: we give a map between any solution of the asymptotic Maxwell equations and any solution of the asymptotic Einstein equations at null infinity. This also extends to the asymptotic charges and their duals, preserves the soft and hard sectors between gauge theory and gravity, and is related to the usual notion of double copy in scattering amplitudes.

The Telemedicine Takeover: Lessons Learned During an Emerging Pandemic

Abstract: Introduction: Health care systems rose to the challenges of COVID-19 by creating or expanding telehealth programs to ensure that patients could access care without an in-person appointment. Traditionally, physicians receive limited formal telemedicine training, making preparedness for this transition uneven. To describe challenges to and attitudes toward providing virtual patient care, we distributed a survey to physicians within our system who largely had no formal prior training/experience with telemedicine, but transitioned to routine telemedicine use. Data collected are then used to offer actionable recommendations for health system leaders and medical educators. Materials and Methods: Surveys were distributed to all faculty outpatient general internal medicine physicians working at any New York University Langone Health, New York City Health + Hospitals/Bellevue and Gouverneur, and the VA NY Harbor Health System (n = 378) in mid-2020. Survey items consisted of Likert and open-ended questions related to experience with televisits (13 items) and attitudes toward care (24 items). Results: Telehealth-related challenges varied by site and modality. Primary challenges included establishing a connection from the patient's (98%) or physician's end (84%) and difficulty in the following domains: working with team members (39%), physical examinations (95%), establishing new patient relationships (70%), and taking history (40%), among others. In thematic analysis, significant themes with illustrative qualitative commentary emerged related to technological challenges, new systems issues, and new patient/physician communication experiences. Discussion: Experience differences were rooted in the type of technology employed. Safety-net practices conducted mostly telephonic visits, whereas private outpatient sites utilized video, despite both using identical electronic medical records. As we consider a "new normal" and prolonged community transmission of COVID-19 infection, it is essential to establish telemedicine training, tools, and protocols that meet the needs of both patients and physicians.

The Impact of Inflammation-Induced Tumor Plasticity during Myeloid Transformation

Abstract: Abstract Clonal hematopoiesis (CH) is an aging-associated condition characterized by the clonal outgrowth of mutated preleukemic cells. Individuals with CH are at an increased risk of developing hematopoietic malignancies. Here, we describe a novel animal model carrying a recurrent TET2 missense mutation frequently found in patients with CH and leukemia. In a fashion similar to CH, animals show signs of disease late in life when they develop a wide range of myeloid neoplasms, including acute myeloid leukemia (AML). Using single-cell transcriptomic profiling of the bone marrow, we show that disease progression in aged animals correlates with an enhanced inflammatory response and the emergence of an aberrant inflammatory monocytic cell population. The gene signature characteristic of this inflammatory population is associated with poor prognosis in patients with AML. Our study illustrates an example of collaboration between a genetic lesion found in CH and inflammation, leading to transformation and the establishment of blood neoplasms. Significance: Progression from a preleukemic state to transformation, in the presence of TET2 mutations, is coupled with the emergence of inflammation and a novel population of inflammatory monocytes. Genes characteristic of this inflammatory population are associated with the worst prognosis in patients with AML. These studies connect inflammation to progression to leukemia. See related commentary by Pietras and DeGregori, p. 2234 . This article is highlighted in the In This Issue feature, p. 2221

Monitoring SARS-CoV-2 in wastewater during New York City's second wave of COVID-19: sewershed-level trends and relationships to publicly available clinical testing data

Abstract: SARS-CoV-2 viral loads in New York City were significantly correlated with clinical case rates in corresponding sewersheds.

An effector index to predict target genes at GWAS loci

Abstract: Drug development and biological discovery require effective strategies to map existing genetic associations to causal genes. To approach this problem, we selected 12 common diseases and quantitative traits for which highly powered genome-wide association studies (GWAS) were available. For each disease or trait, we systematically curated positive control gene sets from Mendelian forms of the disease and from targets of medicines used for disease treatment. We found that these positive control genes were highly enriched in proximity of GWAS-associated single-nucleotide variants (SNVs). We then performed quantitative assessment of the contribution of commonly used genomic features, including open chromatin maps, expression quantitative trait loci (eQTL), and chromatin conformation data. Using these features, we trained and validated an Effector Index (Ei), to map target genes for these 12 common diseases and traits. Ei demonstrated high predictive performance, both with cross-validation on the training set, and an independently derived set for type 2 diabetes. Key predictive features included coding or transcript-altering SNVs, distance to gene, and open chromatin-based metrics. This work outlines a simple, understandable approach to prioritize genes at GWAS loci for functional follow-up and drug development, and provides a systematic strategy for prioritization of GWAS target genes.

Neurophysiology of Remembering.

Abstract: By linking the past with the future, our memories define our sense of identity. Because human memory engages the conscious realm, its examination has historically been approached from language and introspection and proceeded largely along separate parallel paths in humans and other animals. Here, we first highlight the achievements and limitations of this mind-based approach and make the case for a new brain-based understanding of declarative memory with a focus on hippocampal physiology. Next, we discuss the interleaved nature and common physiological mechanisms of navigation in real and mental spacetime. We suggest that a distinguishing feature of memory types is whether they subserve actions for single or multiple uses. Finally, in contrast to the persisting view of the mind as a highly plastic blank slate ready for the world to make its imprint, we hypothesize that neuronal networks are endowed with a reservoir of neural trajectories, and the challenge faced by the brain is how to select and match preexisting neuronal trajectories with events in the world. Expected final online publication date for the Annual Review of Psychology, Volume 73 is January 2022. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Monetary Policy and Asset Valuation

Abstract: We document large, longer term, joint regime shifts in asset valuations and the real federal funds rate- r * $r^{\ast }$ spread. To interpret these findings, we estimate a novel macrofinance model of monetary transmission and find that the documented regimes coincide with shifts in the parameters of a policy rule, with long-term consequences for the real interest rate. Estimates imply that two-thirds of the decline in the real interest rate since the early 1980s is attributable to regime changes in monetary policy. The model explains how infrequent changes in the stance of monetary policy can generate persistent changes in asset valuations and the equity premium.

Antibody Response to a Fourth Dose of SARS-CoV-2 Vaccine in Solid Organ Transplant Recipients: An Update

Abstract: Solid organ transplant recipients (SOTRs) have suboptimal antibody responses to 2-dose severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, with some improvement after receiving a third dose.1,2 Further boosting with a fourth dose (D4) has been suggested in small cohorts of SOTRs, but the evidence remains limited and restricted to kidney recipients with poor preceding seroresponse.3-5 To expand on these early observations, we updated our original case series of 18 participants to a more granular evaluation of 128 participants, diverse in organ type and pre-D4 vaccine response. One-hundred twenty-eight SOTRs without prior reported SARS-CoV-2 infection who reported 4 doses of SARS-CoV-2 vaccine were identified from a previously described national, prospective observational cohort.1 Semiquantitative anti-spike (anti-S) serologic testing was performed using the Roche Elecsys anti-SARS-CoV-2 S enzyme immunoassay, which tests for the receptor-binding domain (RBD), or the EUROIMMUN Anti-SARS-CoV-2 enzyme immunoassay, which tests for the S1 domain of the SARS-CoV-2 spike protein, 2–4 wk after D4. Using the pre-D4 antibody response (defined as most recent titer before D4), participants were stratified into 3 groups (negative [anti-RBD<0.8 or anti-S<1.1], low [anti-RBD <250 U/mL or anti-S <4 AU/mL], or high [anti-RBD ≥250 U/mL or anti-S ≥4 AU/mL] titer) based on levels associated with in vitro neutralization.1 Clinical characteristics were compared between the 3 groups using the Kruskal–Wallis test for continuous and Fisher exact test for categorical variables. This study was approved by the Johns Hopkins Institutional Review Board (IRB00248540), and participants provided informed consent electronically. The median (interquartile range [IQR]) age of participants at D4 was 62 y (49–69 y), 55% (n = 70) were female, and 59% (n = 75) were kidney transplant recipients. Pre-D4, 27% (n = 35) of SOTRs had negative titers, whereas 34% (n = 43) had low and 39% (n = 50) had high titers. The median (IQR) pre-D4 titers were 207.0 U/mL (11.6–1500.0 U/mL) (anti-RBD) and 2.1 AU/mL (0.5–6.0 AU/mL) (anti-S). Post-D4, 11% of SOTRs had persistently negative titers (nonresponders), whereas 14% had low and 75% had high titers (responders). The median (IQR) post-D4 titers were 2132.5 U/mL (96.9 to ≥2500.0 U/mL) (anti-RBD) and 8.8 AU/mL (5.3 to ≥8.94 AU/mL) (anti-S). Stratifying by pre-D4 antibody status, 61% (n = 21) of seronegative participants seroconverted and 84% (n = 36) of pre-D4 seroresponders boosted from low to high antibody titers post-D4 (Table 1). When stratified by post-D4 response, there were no statistically significant differences in any clinical factors between responders and nonresponders. TABLE 1. - Demographics and antibody responses of solid organ transplant recipients who received 4 doses of SARS-CoV-2 vaccine, stratified by pre-dose 4 anti-spike antibody response Factor Pre-dose 4 antibody levels a P Negative Low High N 35 43 50 Age, median (IQR) 63.5 (54.2–71.6) (n = 35) 62.3 (49.6–69.5) (n = 43) 58.4 (48.4–68.0) (n = 50) 0.54 Female, n (%) 20 (57) 24 (56) 26 (52) 0.90 Years since transplant, median (IQR) 4.6 (1.1–11.3) 4.9 (1.5–11.5) 7.2 (3.4–14.9) 0.11 Organ transplanted, n (%) 0.052 Kidney 27 (77) 23 (53) 25 (50) Liver 2 (6) 6 (14) 6 (12) Pancreas 0 (0) 0 (0) 2 (4) Lung 4 (11) 4 (9) 2 (4) Heart 1 (3) 4 (9) 11 (22) Multiorgan 1 (3) 6 (14) 4 (8) MMF, n (%) 30 (86) 31 (72) 37 (74) 0.33 Triple immunosuppression, n (%) 22 (63) 18 (42) 20 (40) 0.090 Initial vaccine series, n (%) 0.21 BNT162b2 22 (63) 28 (65) 24 (48) mRNA-1273 13 (37) 15 (35) 26 (52) Dose 3 vaccine type, n (%) 0.31 BNT162b2 16 (46) 15 (35) 17 (34) mRNA-1273 12 (34) 13 (30) 23 (46) Ad.26.CoV2.S 7 (20) 15 (35) 10 (20) Dose 4 vaccine type, n (%) 0.75 BNT162b2 15 (43) 14 (33) 17 (34) mRNA-1273 17 (49) 27 (63) 30 (60) Ad.26.CoV2.S 3 (9) 2 (5) 3 (6) Post-D4 antibody response category, a n (%) <0.001 Negative 14 (40) 0 (0) 0 (0) Low 11 (31) 7 (16) 0 (0) High 10 (29) 36 (84) 50 (100) Pre-D4 anti-RBD titer, median (IQR) <0.8 (<0.8 to <0.8) (n = 17) 103.3 (46.4–197.9) (n = 32) 1945.5 (1035.0 to >2500.0) (n = 34) <0.001 Post-D4 anti-RBD titer, median (IQR) b 2.0 (<0.8 to 54.9) (n = 26) 2027.0 (475.0 to >2500.0) (n = 37) >2500.0 (>2500.0 to >2500.0) (n = 35) <0.001 Pre-D4 anti-S titer, median (IQR) 0.3 (0.1–0.6) (n = 18) 2.3 (2.0–2.9) (n = 11) 7.0 (5.4–8.8) (n = 16) <0.001 Post-D4 anti-S titer, median (IQR) b 5.1 (2.0–8.2) (n = 9) 7.1 (5.1–8.9) (n = 6) 8.9 (8.6 to ≥8.94) (n = 15) 0.023 aNegative: Anti-RBD <0.8 U/mL anti-S <1.1 AU, low: anti-RBD <250 U/mL anti-S <4 AU high: anti-RBD ≥250 U/mL anti-S ≥4 AU.bTiters were collected at a median (IQR) 28.5 d (17.0–32.0 d) post-D4.anti-RBD, anti-receptor binding domain; anti-S, anti-spike; D4, dose 4; IQR, interquartile range; MMF, mycophenolate mofetil; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2. In this cohort of SOTRs receiving a D4 of SARS-CoV-2 vaccine, 89% of participants had positive anti-spike antibody post-D4 with a high rate of seroconversion among prior nonresponders. Additionally, titers were boosted in 75% to levels consistent with live virus neutralization. This is the largest study of SOTRs receiving 4 doses of SARS-CoV-2 vaccine, encompassing a breadth of organ recipients, and demonstrates the immunogenic potential of booster vaccination.3-5 Limitations include the observational nature of the cohort, lack of formal neutralization against variants of concern including omicron, and the lack of cellular analyses. These findings support recommendations for booster vaccination in SOTRs, with post-booster antibody testing to identify individuals who remain seronegative and may be targeted for additional vaccination or passive immunoprophylactic interventions. ACKNOWLEDGMENTS The authors thank the participants of the Johns Hopkins COVID-19 Transplant Vaccine Study, without whom this research could not be possible. The authors also thank the members of the study team, including Brian J. Boyarsky, MD, PhD; Alexa Jefferis, BS; Nicole Fortune Hernandez, BS; Letitia Thomas; Rivka Abedon; Chunyi Xia; Kim Hall; Mary Sears, BA; and Alex Alex; Jonathan Susilo. The authors also thank Andrew H. Karaba, MD, PhD and Ms. Yolanda Eby for project support and guidance.

Exploiting cancer’s drinking problem: regulation and therapeutic potential of macropinocytosis

Abstract: By delivering vital metabolic substrates to cancer cells, macropinocytosis presents an attractive and targetable vulnerability in tumors. Macropinocytosis facilitates the uptake of a wide assortment of extracellular macromolecules and metabolites in addition to protein. Emerging evidence illustrates that many different tumor types engage in macropinocytosis through multiple oncogenic drivers. The delivery of therapeutic agents via macropinocytosis offers an alternative approach for selective targeting of tumor cells. Macropinocytosis, an evolutionarily conserved endocytic mechanism that mediates non-specific fluid-phase uptake, is potently upregulated by various oncogenic pathways. It is now well appreciated that high macropinocytic activity is a hallmark of many human tumors, which use this adaptation to scavenge extracellular nutrients for fueling cell growth. In the context of the nutrient-scarce tumor microenvironment, this process provides tumor cells with metabolic flexibility. However, dependence on this scavenging mechanism also illuminates a potential metabolic vulnerability. As such, there is a great deal of interest in understanding the molecular underpinnings of macropinocytosis. In this review, we will discuss the most recent advances in characterizing macropinocytosis: the pathways that regulate it, its contribution to the metabolic fitness of cancer cells, and its therapeutic potential. Macropinocytosis, an evolutionarily conserved endocytic mechanism that mediates non-specific fluid-phase uptake, is potently upregulated by various oncogenic pathways. It is now well appreciated that high macropinocytic activity is a hallmark of many human tumors, which use this adaptation to scavenge extracellular nutrients for fueling cell growth. In the context of the nutrient-scarce tumor microenvironment, this process provides tumor cells with metabolic flexibility. However, dependence on this scavenging mechanism also illuminates a potential metabolic vulnerability. As such, there is a great deal of interest in understanding the molecular underpinnings of macropinocytosis. In this review, we will discuss the most recent advances in characterizing macropinocytosis: the pathways that regulate it, its contribution to the metabolic fitness of cancer cells, and its therapeutic potential.