Combining targeted DNA repair inhibition and immune-oncology approaches for enhanced tumor control.

Targeted therapy and immunotherapy have revolutionized cancer treatment. However, the ability of cancer to evade the immune system remains a major barrier for effective treatment. Related to this, several targeted DNA-damage response inhibitors (DDRis) are being tested in the clinic and have been shown to potentiate anti-tumor immune responses. Seminal studies have shown that these agents are highly effective in a pan-cancer class of tumors with genetic defects in key DNA repair genes such as BRCA1/2, BRCA-related genes, ataxia telangiectasia mutated (ATM), and others. Here, we review the molecular consequences of targeted DDR inhibition, from tumor cell death to increased engagement of the anti-tumor immune response. Additionally, we discuss mechanistic and clinical rationale for pairing targeted DDRis with immunotherapy for enhanced tumor control. We also review biomarkers for patient selection and promising new immunotherapy approaches poised to form the foundation of next-generation DDRi and immunotherapy combinations.

Prospective assessment of humoral and cellular immune responses to a 3rd COVID-19 mRNA vaccine dose among immunocompromised individuals.

BACKGROUND: Improved COVID-19 prevention is needed for immunocompromised individuals. METHODS: Prospective study of healthcare workers (HCW) and immunocompromised participants with baseline serology following 2 mRNA vaccines and who were retested after dose 3 (D3); multivariable regression was used to identify predictors of serological responses. IFNγ/TNFα T-cell responses were assessed in a subset. RESULTS: 536 participants were included: 492 immunocompromised [(206 solid organ transplant (SOT), 128 autoimmune, 80 hematologic malignancy (HM), 48 solid tumor, 25 HIV], 44 HCW. D3 significantly increased Spike IgG levels among all, but SOT and HM participants had the lowest median antibody levels post-D3 (increase from 0.09 to 0.83 and 0.27 to 1.92, respectively), versus HCW and persons with HIV, autoimmune conditions, and solid tumors (increases from 4.44 to 19.79, 2.9 to 15.75, 3.82 to 16.32, and 4.1 to 25.54, respectively). Seropositivity post-D3 was lowest for SOT (49.0%) and HM (57.8%), versus others (>90% seropositive). Neutralization post-D3 was lowest among SOT and HM. Predictors of lower antibody levels included low baseline levels and shorter intervals between vaccines. T-cell responses against Spike increased significantly among HCW and non-significantly among immunocompromised individuals. CONCLUSIONS: D3 significantly improves serological but not T-cell responses among immunocompromised individuals. SOT and HM patients have suboptimal responses to D3.

Escalation strategies, management, and outcomes of acute myocardial infarction-cardiogenic shock patients receiving percutaneous left ventricular support.

BACKGROUND: There are limited national-level data on the contemporary practices of mechanical circulatory support (MCS) use in acute myocardial infarction-cardiogenic shock (AMI-CS). METHODS: We utilized the Healthcare Cost and Utilization Project-National/Nationwide Inpatient Sample data (2005-2017) to identify adult admissions (>18 years) with AMI-CS. MCS devices were classified as intra-aortic balloon pump (IABP), percutaneous left ventricular assist devices (pLVAD), or extracorporeal membrane oxygenation (ECMO). We evaluated trends in the initial device used (IABP alone, pLVAD alone or ≥2 MCS devices), device escalation, bridging to durable LVAD/heart transplantation, and predictors of in-hospital mortality and device escalation. RESULTS: Among 327,283 AMI-CS admissions, 131,435 (40.2%) had an MCS device placed with available information on timing of placement. IABP, pLVAD, and ≥2 MCS devices were used as initial device in 120,928 (92.0%), 8202 (6.2%), and 2305 (1.7%) admissions, respectively. Most admissions were maintained on the initial MCS device with 1%-1.5% being escalated (IABP to pLVAD/ECMO, pLVAD to ECMO). Urban, medium, and large-sized hospitals and acute multiorgan failure were significant independent predictors of MCS escalation. In admissions receiving MCS, escalation of MCS device was associated with higher in-hospital mortality (adjusted odds ratio: 1.56, 95% confidence interval:  1.38-1.75; p < 0.001). Admissions receiving durable LVAD/heart transplantation increased over time in those initiated on pLVAD and ≥2 MCS devices, resulting in lower in-hospital mortality. CONCLUSIONS: In this 13-year study, escalation of MCS in AMI-CS was associated with higher in-hospital mortality suggestive of higher acuity of illness. The increase in number of durable LVAD/heart transplantations alludes to the role of MCS as successful bridge strategies.

Veno-Arterial Extracorporeal Membrane Oxygenation in Patients with Fulminant Myocarditis: A Review of Contemporary Literature.

Fulminant myocarditis is characterized by life threatening heart failure presenting as cardiogenic shock requiring inotropic or mechanical circulatory support to maintain tissue perfusion. There are limited data on the role of veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in the management of fulminant myocarditis. This review seeks to evaluate the management of fulminant myocarditis with a special emphasis on the role and outcomes with VA-ECMO use.

A Randomized Comparison of Positional Stability: The EZ-Blocker Versus Left-Sided Double-Lumen Endobronchial Tubes in Adult Patients Undergoing Thoracic Surgery.

OBJECTIVE: To assess if there is a difference in the repositioning rate of the EZ-Blocker versus a left-sided double-lumen endobronchial tube (DLT) in patients undergoing thoracic surgery and one-lung ventilation. DESIGN: Prospective, randomized. SETTING: Single center, university hospital. PARTICIPANTS: One hundred sixty-three thoracic surgery patients. INTERVENTIONS: Patients were randomized to either EZ-Blocker or a DLT. MEASUREMENTS AND MAIN RESULTS: The primary outcome was positional stability of either the EZ-Blocker or a left-sided double-lumen endobronchial tube, defined as the number of repositionings per hour of surgery and one-lung ventilation. Secondary outcomes included an ordinal isolation score from 1 to 3, in which 1 was poor, up to 3, which represented excellent isolation, and a visual analog postoperative sore throat score (0-100) on postoperative days (POD) one and two. Rate of repositionings per hour during one-lung ventilation and surgical manipulation in left-sided cases was similar between the two devices: 0.08 ± 0.15 v 0.11 ± 0.3 (p = 0.72). In right-sided cases, the rate of repositioning was higher in the EZ-Blocker group compared with DLT: 0.38 ± 0.65 v 0.09 ± 0.21 (p = 0.03). Overall, mean isolation scores for the EZ-Blocker versus the DLT were 2.76 v 2.92 (p = 0.04) in left-sided cases and 2.70 v 2.83 (p = 0.22) in right-sided cases. Median sore throat scores for left sided cases were 0 v 5 (p = 0.13) POD one and 0 v 5 (p = 0.006) POD two for the EZ-Blocker and left-sided DLT, respectively. CONCLUSION: For right-sided procedures, the positional stability of the EZ-Blocker is inferior to a DLT. In left-sided cases, the rate of repositioning for the EZ-Blocker and DLT are not statistically different.

Active-Site Tryptophan, the Target of Antineoplastic C-Terminal Binding Protein Inhibitors, Mediates Inhibitor Disruption of CtBP Oligomerization and Transcription Coregulatory Activities.

C-terminal binding proteins (CtBP1/2) are oncogenic transcriptional coregulators and dehydrogenases often overexpressed in multiple solid tumors, including breast, colon, and ovarian cancer, and associated with poor survival. CtBPs act by repressing expression of genes responsible for apoptosis (e.g., PUMA, BIK) and metastasis-associated epithelial-mesenchymal transition (e.g., CDH1), and by activating expression of genes that promote migratory and invasive properties of cancer cells (e.g., TIAM1) and genes responsible for enhanced drug resistance (e.g., MDR1). CtBP's transcriptional functions are also critically dependent on oligomerization and nucleation of transcriptional complexes. Recently, we have developed a family of CtBP dehydrogenase inhibitors, based on the parent 2-hydroxyimino-3-phenylpropanoic acid (HIPP), that specifically disrupt cancer cell viability, abrogate CtBP's transcriptional function, and block polyp formation in a mouse model of intestinal polyposis that depends on CtBP's oncogenic functions. Crystallographic analysis revealed that HIPP interacts with CtBP1/2 at a conserved active site tryptophan (W318/324; CtBP1/2) that is unique among eukaryotic D2-dehydrogenases. To better understand the mechanism of action of HIPP-class inhibitors, we investigated the contribution of W324 to CtBP2's biochemical and physiologic activities utilizing mutational analysis. Indeed, W324 was necessary for CtBP2 self-association, as shown by analytical ultracentrifugation and in vivo cross-linking. Additionally, W324 supported CtBP's association with the transcriptional corepressor CoREST, and was critical for CtBP2 induction of cell motility. Notably, the HIPP derivative 4-chloro-HIPP biochemically and biologically phenocopied mutational inactivation of CtBP2 W324. Our data support further optimization of W318/W324-interacting CtBP dehydrogenase inhibitors that are emerging as a novel class of cancer cell-specific therapeutic.

Dynamic contrast-enhanced MRI promotes early detection of toxin-induced acute kidney injury.

Acute kidney injury (AKI) is a common cause of morbidity and mortality in hospitalized patients. Nevertheless, there is limited ability to diagnose AKI in its earliest stages through the collection of structural and functional information. Magnetic resonance imaging (MRI) is increasingly being used to provide structural and functional data that characterize the injured kidney. Dynamic contrast-enhanced (DCE) MRI is an imaging modality with robust spatial and temporal resolution; however, its ability to detect changes in kidney function following AKI has not been determined. We hypothesized that DCE MRI would detect a prolongation in contrast transit time following toxin-induced AKI earlier than commonly used serum and tissue biomarkers. To test our hypothesis, we injected mice with either vehicle or cisplatin (30 mg/kg) and performed DCE MRI at multiple time points. We found that commonly used kidney injury biomarkers, including creatinine, blood urea nitrogen, and neutrophil gelatinase-associated lipocalin, did not rise until day 2 following cisplatin. Tissue levels of the proinflammatory cytokines and chemokines, tumor necrosis factor-α, interleukin (IL)-1ß, IL-1α, IL-6, C-C motif chemokine ligand 2, and C-X-C motif chemokine ligand 2 similarly did not upregulate until day 2 following cisplatin. However, the time to peak intensity of contrast in the renal collecting system was already prolonged at day 1 following cisplatin compared with vehicle-treated mice. This intensity change mirrored changes in kidney injury as measured by histological analysis and in transporter expression in the proximal tubule. Taken together, DCE MRI is a promising preclinical imaging modality that is useful for assessing functional capacity of the kidney in the earliest stages following AKI.

Assisted Work Distillation.

We study the process of assisted work distillation. This scenario arises when two parties share a bipartite quantum state ρ_{AB} and their task is to locally distill the optimal amount of work when one party is restricted to thermal operations, whereas the other can perform general quantum operations and they are allowed to communicate classically. We demonstrate that this question is intimately related to the distillation of classical and quantum correlations. In particular, we show that the advantage of one party performing global measurements over many copies of ρ_{AB} is related to the nonadditivity of the entanglement of formation. We also show that there may exist work bound in the quantum correlations of the state that is only extractable under the wider class of local Gibbs-preserving operations.

NF-κB upregulates glutamine-fructose-6-phosphate transaminase 2 to promote migration in non-small cell lung cancer.

BACKGROUND: Epithelial-to-mesenchymal transition (EMT) results in changes that promote de-differentiation, migration, and invasion in non-small cell lung cancer (NSCLC). While it is recognized that EMT promotes altered energy utilization, identification of metabolic pathways that link EMT with cancer progression is needed. Work presented here indicates that mesenchymal NSCLC upregulates glutamine-fructose-6-phosphate transaminase 2 (GFPT2). GFPT2 is the rate-limiting enzyme in the synthesis of uridine diphosphate N-acetylglucosamine (UDP-GlcNAc). UDP-GlcNAc is the obligate activator of O-linked N-acetylglucosamine transferase (OGT). METHODS: Analysis of our transcriptomic data indicates that GFPT2 is one of the most significantly upregulated metabolic genes in mesenchymal NSCLC. Ectopic GFPT2 expression, as well as gene silencing strategies were used to determine the importance of this metabolic enzyme in regulating EMT-driven processes of cell motility and invasion. RESULTS: Our work demonstrates that GFPT2 is transcriptionally upregulated by NF-κB and repressed by the NAD+-dependent deacetylase SIRT6. Depletion of GFPT2 expression in NSCLC highlights its importance in regulating cell migration and invasion during EMT. CONCLUSIONS: Consistent with GFPT2 promoting cancer progression, we find that elevated GFPT2 expression correlates with poor clinical outcome in NSCLC. Modulation of GFPT2 activity offers a potentially important therapeutic target to combat NSCLC disease progression.

Pushing the limits of the reaction-coordinate mapping.

The reaction-coordinate mapping is a useful technique to study complex quantum dissipative dynamics into structured environments. In essence, it aims to mimic the original problem by means of an "augmented system," which includes a suitably chosen collective environmental coordinate-the "reaction coordinate." This composite then couples to a simpler "residual reservoir" with short-lived correlations. If, in addition, the residual coupling is weak, a simple quantum master equation can be rigorously applied to the augmented system, and the solution of the original problem just follows from tracing out the reaction coordinate. But, what if the residual dissipation is strong? Here, we consider an exactly solvable model for heat transport-a two-node linear "quantum wire" connecting two baths at different temperatures. We allow for a structured spectral density at the interface with one of the reservoirs and perform the reaction-coordinate mapping, writing a perturbative master equation for the augmented system. We find that (a) strikingly, the stationary state of the original problem can be reproduced accurately by a weak-coupling treatment even when the residual dissipation on the augmented system is very strong, (b) the agreement holds throughout the entire dynamics under large residual dissipation in the overdamped regime; and (c) such a master equation can grossly overestimate the stationary heat current across the wire, even when its nonequilibrium steady state is captured faithfully. These observations can be crucial when using the reaction-coordinate mapping to study the largely unexplored strong-coupling regime in quantum thermodynamics.

A Prospective Comparison of Intraluminal and Extraluminal Placement of the 9-French Arndt Bronchial Blocker in Adult Thoracic Surgery Patients.

OBJECTIVE: To compare the standard intraluminal approach with the placement of the 9-French Arndt endobronchial blocker with an extraluminal approach by measuring the time to positioning and other relevant intraoperative and postoperative parameters. DESIGN: A prospective, randomized, controlled trial. SETTING: University hospital. PARTICIPANTS: The study comprised 41 patients (20 intraluminal, 21 extraluminal) undergoing thoracic surgery. INTERVENTION: Placement of a 9-French Arndt bronchial blocker either intraluminally or extraluminally. Comparisons between the 2 groups included the following: (1) time for initial placement, (2) quality of isolation at 1-hour intervals during one-lung ventilation, (3) number of repositionings during one-lung ventilation, and (4) presence or absence of a sore throat on postoperative days 1 and 2 and, if present, its severity. MEASUREMENTS AND MAIN RESULTS: Median time to placement (min:sec) in the extraluminal group was statistically faster at 2:42 compared with 6:24 in the intraluminal group (p < 0.05). Overall quality of isolation was similar between groups, even though a significant number of blockers in both groups required repositioning (extraluminal 47%, intraluminal 40%, p > 0.05), and 1 blocker ultimately had to be replaced intraoperatively. No differences in the incidence or severity of sore throat postoperatively were observed. CONCLUSIONS: A statistically significant reduction in time to placement using the extraluminal approach without any differences in the rate of postoperative sore throat was observed. Whether placed intraluminally or extraluminally, a significant percentage of Arndt endobronchial blockers required at least one intraoperative repositioning.

Design, synthesis, and biological evaluation of substrate-competitive inhibitors of C-terminal Binding Protein (CtBP).

C-terminal Binding Protein (CtBP) is a transcriptional co-regulator that downregulates the expression of many tumor-suppressor genes. Utilizing a crystal structure of CtBP with its substrate 4-methylthio-2-oxobutyric acid (MTOB) and NAD(+) as a guide, we have designed, synthesized, and tested a series of small molecule inhibitors of CtBP. From our first round of compounds, we identified 2-(hydroxyimino)-3-phenylpropanoic acid as a potent CtBP inhibitor (IC50=0.24µM). A structure-activity relationship study of this compound further identified the 4-chloro- (IC50=0.18µM) and 3-chloro- (IC50=0.17µM) analogues as additional potent CtBP inhibitors. Evaluation of the hydroxyimine analogues in a short-term cell growth/viability assay showed that the 4-chloro- and 3-chloro-analogues are 2-fold and 4-fold more potent, respectively, than the MTOB control. A functional cellular assay using a CtBP-specific transcriptional readout revealed that the 4-chloro- and 3-chloro-hydroxyimine analogues were able to block CtBP transcriptional repression activity. This data suggests that substrate-competitive inhibition of CtBP dehydrogenase activity is a potential mechanism to reactivate tumor-suppressor gene expression as a therapeutic strategy for cancer.

Changing self-reported physical activity using different types of affectively and cognitively framed health messages, in a student population.

The present research focused upon the power of different messages to increase self-reported physical activity (PA). Five hundered and ninety six participants were randomised to one of five conditions that varied in the content of message: short-term affective, short-term cognitive, long-term affective, long-term cognitive and a no message control. PA was measured at baseline and follow-up (seven days later) was done using the Godin Leisure Time Exercise Questionnaire over the subsequent seven day period. The affective short-term message (ASM) was shown to be equally effective at increasing self-reported PA as a cognitive long-term message. Furthermore, when controlling for baseline activity levels, the ASM emerged as being the message that produced the highest levels of self-reported PA at follow-up. The findings point to the value of distinguishing between health messages in terms of the focus on affective and cognitive outcomes and the temporal nature of the outcomes (short-term or long-term).

Thymine DNA glycosylase is a CRL4Cdt2 substrate.

The E3 ubiquitin ligase CRL4(Cdt2) targets proteins for destruction in S phase and after DNA damage by coupling ubiquitylation to DNA-bound proliferating cell nuclear antigen (PCNA). Coupling to PCNA involves a PCNA-interacting peptide (PIP) degron motif in the substrate that recruits CRL4(Cdt2) while binding to PCNA. In vertebrates, CRL4(Cdt2) promotes degradation of proteins whose presence in S phase is deleterious, including Cdt1, Set8, and p21. Here, we show that CRL4(Cdt2) targets thymine DNA glycosylase (TDG), a base excision repair enzyme that is involved in DNA demethylation. TDG contains a conserved and nearly perfect match to the PIP degron consensus. TDG is ubiquitylated and destroyed in a PCNA-, Cdt2-, and PIP degron-dependent manner during DNA repair in Xenopus egg extract. The protein can also be destroyed during DNA replication in this system. During Xenopus development, TDG first accumulates during gastrulation, and its expression is down-regulated by CRL4(Cdt2). Our results expand the group of vertebrate CRL4(Cdt2) substrates to include a bona fide DNA repair enzyme.