Genetically modified T cells expressing chimeric antigen receptors (CARs) demonstrate robust responses against lineage restricted, non-essential targets in hematologic cancers. However, in solid ...tumors, the full potential of CAR T cell therapy is limited by the availability of cell surface antigens with sufficient cancer-specific expression. The majority of CAR targets have been normal self-antigens on dispensable hematopoietic tissues or overexpressed shared antigens. Here, we established that abnormal self-antigens can serve as targets for tumor rejection. We developed a CAR that recognized cancer-associated Tn glycoform of MUC1, a neoantigen expressed in a variety of cancers. Anti-Tn-MUC1 CAR T cells demonstrated target-specific cytotoxicity and successfully controlled tumor growth in xenograft models of T cell leukemia and pancreatic cancer. These findings demonstrate the therapeutic efficacy of CAR T cells directed against Tn-MUC1 and present aberrantly glycosylated antigens as a novel class of targets for tumor therapy with engineered T cells.
•Cancer cells of many tissues express an abnormal glycoform of MUC1, Tn-MUC1•Normal human tissue does not express detectable Tn-MUC1 on the cellular surface•CAR T cells are engineered to target Tn-MUC1 lyse tumor cells in vitro and in vivo•Abnormal glycoform epitopes are valid clinical targets for CAR T cells
Posey and colleagues developed a CAR T cell therapy to break immune tolerance to solid tumors by targeting an aberrantly glycosylated, cancer-specific glycoprotein in multiple cancer histotypes and demonstrated efficacy and safety in tumors as diverse as leukemia and pancreatic cancer.
Overwhelming evidence has shown that, from the Industrial Revolution to the present, human activities influence ground-level ozone (O3) concentrations. Past studies demonstrate links between O3 ...exposure and health. However, knowledge gaps remain in our understanding concerning the impacts of climate change mitigation policies on O3 concentrations and health. Using a hybrid downscaling approach, we evaluated the separate impact of climate change and emission control policies on O3 levels and associated excess mortality in the US in the 2050s under two Representative Concentration Pathways (RCPs). We show that, by the 2050s, under RCP4.5, increased O3 levels due to combined climate change and emission control policies, could contribute to an increase of approximately 50 premature deaths annually nationwide in the US. The biggest impact, however, is seen under RCP8.5, where rises in O3 concentrations are expected to result in over 2,200 additional premature deaths annually. The largest increases in O3 are seen in RCP8.5 in the Northeast, the Southeast, the Central, and the West regions of the US. Additionally, when O3 increases are examined by climate change and emissions contributions separately, the benefits of emissions mitigation efforts may significantly outweigh the effects of climate change mitigation policies on O3-related mortality.
Display omitted Average annual change in tropospheric O3 concentrations between 2000s and 2050s from the effects of climate change, emissions mitigation, and a combination of the two (shown for both RCP4.5 and RCP8.5).
•The largest increases in O3 are seen in the combined sources RCP8.5 scenario in the Northeast, Southeast, Central, and West regions of the US•By 2050s, under RCP4.5, increased O3 levels due to combined climate change and emission control policies, contribute 50 excess deaths annually•Rises in O3 concentrations due to combined sources under RCP8.5 have a larger impact, resulting in over 2,200 additional premature deaths annually•The benefits of emissions mitigation may significantly outweigh the effect of climate change mitigation policies on O3-related mortality
Gallium-68 (
Ga) is a positron-emitting isotope used for clinical PET imaging of peptide receptor expression.
Ga radiopharmaceuticals used in molecular PET imaging consist of disease-targeting ...biomolecules tethered to chelators that complex
Ga
. Ideally, the chelator will rapidly, quantitatively and stably coordinate
Ga
at room temperature, near neutral pH and low chelator concentration, allowing for simple routine radiopharmaceutical formulation. Identification of chelators that fulfil these requirements will facilitate development of kit-based
Ga radiopharmaceuticals. Herein the reaction of a range of widely used macrocyclic and acyclic chelators with
Ga
is reported. Radiochemical yields have been measured under conditions of varying chelator concentrations, pH (3.5 and 6.5) and temperature (25 and 90 °C). These chelators are: 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), 1,4,7-triazacyclononane-1,4,7-triacetic acid (NOTA), 1,4,7-triazacyclononane macrocycles substituted with phosphonic (NOTP) and phosphinic (TRAP) groups at the amine, bis(2-hydroxybenzyl)ethylenediaminediacetic acid (HBED), a tris(hydroxypyridinone) containing three 1,6-dimethyl-3-hydroxypyridin-4-one groups (THP) and the hexadentate tris(hydroxamate) siderophore desferrioxamine-B (DFO). Competition studies have also been undertaken to assess relative complexation efficiencies of each chelator for
Ga
under different pH and temperature conditions. Performing radiolabelling reactions at pH 6.5, 25 °C and 5-50 μM chelator concentration resulted in near quantitative radiochemical yields for all chelators, except DOTA. Radiochemical yields either decreased or were not substantially improved when the reactions were undertaken at lower pH or at higher temperature, except in the case of DOTA. THP and DFO were the most effective
Ga
chelators at near-neutral pH and 25 °C, rapidly providing near-quantitative radiochemical yields at very low chelator concentrations. NOTP and HBED were only slightly less effective under these conditions. In competition studies with all other chelators, THP demonstrated highest reactivity for
Ga
complexation under all conditions. These data point to THP possessing ideal properties for rapid, one-step kit-based syntheses of
Ga-biomolecules for molecular PET imaging. LC-MS and
H,
C{
H} and
Ga NMR studies of HBED complexes of Ga
showed that under the analytical conditions employed in this study, multiple HBED-bound Ga complexes exist. X-ray diffraction data indicated that crystals isolated from these solutions contained octahedral Ga(HBED)(H
O), with HBED coordinated in a pentadentate N
O
mode, with only one phenolic group coordinated to Ga
, and the remaining coordination site occupied by a water molecule.
Plant and animal pathogenic bacteria can suppress host immunity by injecting type III secreted effector (T3SE) proteins into host cells. However, T3SEs can also elicit host immunity if the host has ...evolved a means to recognize the presence or activity of specific T3SEs. The diverse YopJ/HopZ/AvrRxv T3SE superfamily, which is found in both animal and plant pathogens, provides examples of T3SEs playing this dual role. The T3SE HopZ1a is an acetyltransferase carried by the phytopathogen Pseudomonas syringae that elicits effector-triggered immunity (ETI) when recognized in Arabidopsis thaliana by the nucleotide-binding leucine-rich repeat (NB-LRR) protein ZAR1. However, recognition of HopZ1a does not require any known ETI-related genes. Using a forward genetics approach, we identify a unique ETI-associated gene that is essential for ZAR1-mediated immunity. The hopZ-ETI-deficient1 (zed1) mutant is specifically impaired in the recognition of HopZ1a, but not the recognition of other unrelated T3SEs or in pattern recognition receptor (PRR)-triggered immunity. ZED1 directly interacts with both HopZ1a and ZAR1 and is acetylated on threonines 125 and 177 by HopZ1a. ZED1 is a nonfunctional kinase that forms part of small genomic cluster of kinases in Arabidopsis . We hypothesize that ZED1 acts as a decoy to lure HopZ1a to the ZAR1–resistance complex, resulting in ETI activation.
Although depressive symptoms represent a promising therapeutic target to promote recovery from substance use disorders (SUD), heterogeneity in their diagnostic presentation often hinders the ability ...to effectively tailor treatment. We sought to identify subgroups of individuals varying in depressive symptom phenotypes (i.e., demoralization, anhedonia), and examined whether these subgroups were associated with patient demographics, psychosocial health, and treatment attrition.
Patients (N = 10,103, 69.2 % male) were drawn from a dataset of individuals who presented for admission to SUD treatment in the US. Participants reported on their demoralization and anhedonia approximately weekly for the first month of treatment, and on their demographics, psychosocial health, and primary substance at intake. Longitudinal latent profile analysis examined patterns of demoralization and anhedonia with treatment attrition as a distal outcome.
Four subgroups of individuals emerged: (1) High demoralization and anhedonia, (2) Remitting demoralization and anhedonia, (3) High demoralization, low anhedonia, and (4) Low demoralization and anhedonia. Relative to the Low demoralization and anhedonia subgroup, all the other profiles were more likely to discontinue treatment. Numerous between-profile differences were observed with regard to demographics, psychosocial health, and primary substance.
The racial and ethnic background of the sample was skewed towards White individuals; future research is needed to determine the generalizability of our findings to minoritized racial and ethnic groups.
We identified four clinical profiles that varied in the joint course of demoralization and anhedonia. Findings suggest specific subgroups might benefit from additional interventions and treatments that address their unique mental health needs during SUD recovery.
•Demoralization and anhedonia occur in people in substance use disorder treatment.•We examined these symptom trajectories during substance use disorder recovery.•Patient demographics, health, and substance use were associated with trajectories.•High demoralization and anhedonia trajectories were linked to treatment attrition.
We have developed a diphosphine (DP) platform for radiolabeling peptides with
Tc and
Cu for molecular SPECT and PET imaging, respectively. Two diphosphines, 2,3-bis(diphenylphosphino)maleic anhydride ...(DP
) and 2,3-bis(di-
-tolylphosphino)maleic anhydride (DP
), were each reacted with a Prostate Specific Membrane Antigen-targeted dipeptide (PSMAt) to yield the bioconjugates DP
-PSMAt and DP
-PSMAt, as well as an integrin-targeted cyclic peptide, RGD, to yield the bioconjugates DP
-RGD and DP
-RGD. Each of these DP-PSMAt conjugates formed geometric
/
-MO
(DP
-PSMAt)
(M =
Tc,
Tc,
Re; X = Ph, Tol) complexes when reacted with MO
motifs. Furthermore, both DP
-PSMAt and DP
-PSMAt could be formulated into kits containing reducing agent and buffer components, enabling preparation of the new radiotracers
/
-
TcO
(DP
-PSMAt)
and
/
-
TcO
(DP
-PSMAt)
from aqueous
TcO
in 81% and 88% radiochemical yield (RCY), respectively, in 5 min at 100 °C. The consistently higher RCYs observed for
/
-
TcO
(DP
-PSMAt)
are attributed to the increased reactivity of DP
-PSMAt over DP
-PSMAt. Both
/
-
TcO
(DP
-PSMAt)
and
/
-
TcO
(DP
-PSMAt)
exhibited high metabolic stability, and
SPECT imaging in healthy mice revealed that both new radiotracers cleared rapidly from circulation, via a renal pathway. These new diphosphine bioconjugates also furnished
Cu(DP
-PSMAt)
(X = Ph, Tol) complexes rapidly, in a high RCY (>95%), under mild conditions. In summary, the new DP platform is versatile: it enables straightforward functionalization of targeting peptides with a diphosphine chelator, and the resulting bioconjugates can be simply radiolabeled with both the SPECT and PET radionuclides,
Tc and
Cu, in high RCYs. Furthermore, the DP platform is amenable to derivatization to either increase the chelator reactivity with metallic radioisotopes or, alternatively, modify the radiotracer hydrophilicity. Functionalized diphosphine chelators thus have the potential to provide access to new molecular radiotracers for receptor-targeted imaging.
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