Suppression Of Response Research Articles

Extracorporeal organ support for critically ill patients: Overcoming the past, achieving the maximum at present, and redefining the future

Extracorporeal organ support (ECOS) has made remarkable progress over the last few years. Renal replacement therapy, introduced a few decades ago, was the first available application of ECOS. The subsequent evolution of ECOS enabled the enhanced support to many other organs, including the heart [veno-arterial extracorporeal membrane oxygenation (ECMO), slow continuous ultrafiltration], the lungs (veno-venous ECMO, extracorporeal carbon dioxide removal), and the liver (blood purification techniques for the detoxification of liver toxins). Moreover, additional indications of these methods, including the suppression of excessive inflammatory response occurring in severe disorders such as sepsis, coronavirus disease 2019, pancreatitis, and trauma (blood purification techniques for the removal of exotoxins, endotoxins, or cytokines), have arisen. Multiple organ support therapy is crucial since a vast majority of critically ill patients present not with a single but with multiple organ failure (MOF), whereas, traditional therapeutic approaches (mechanical ventilation for acute respiratory failure, antibiotics for sepsis, and inotropes for cardiac dysfunction) have reached the maximum efficacy and cannot be improved further. However, several issues remain to be clarified, such as the complexity and cost of ECOS systems, standardization of indications, therapeutic protocols and initiation time, choice of the patients who will benefit most from these interventions, while evidence from randomized controlled trials supporting their use is still limited. Nevertheless, these methods are currently a part of routine clinical practice in intensive care units. This editorial presents the past, present, and future considerations, as well as perspectives regarding these therapies. Our better understanding of these methods, the pathophysiology of MOF, the crosstalk between native organs resulting in MOF, and the crosstalk between native organs and artificial organ support systems when applied sequentially or simultaneously, will lead to the multiplication of their effects and the minimization of complications arising from their use.

Juvenile Hormone as a contributing factor in establishing midgut microbiota for fecundity and fitness enhancement in adult female Aedes aegypti

Understanding the factors influencing mosquitoes’ fecundity and longevity is important for designing better and more sustainable vector control strategies, as these parameters can impact their vectorial capacity. Here, we address how mating affects midgut growth in Aedes aegypti, what role Juvenile Hormone (JH) plays in this process, and how it impacts the mosquito’s immune response and microbiota. Our findings reveal that mating and JH induce midgut growth. Additionally, the establishment of a native bacterial population in the midgut due to JH-dependent suppression of the immune response has important reproductive outcomes. Specific downregulation of AMPs with an increase in bacteria abundance in the gut results in increased egg counts and longer lifespans. Overall, these findings provide evidence of a cross-talk between JH response, gut epithelial tissue, cell cycle regulation, and the mechanisms governing the trade-offs between nutrition, immunity, and reproduction at the cellular level in the mosquito gut.

Testing the response suppression mechanism of working memory.

Many working memory (WM) paradigms involve recalling multiple items from the same memory set. Participants rarely repeat items they have already recalled, avoiding repetition errors. To prevent these errors, WM models incorporate a response suppression mechanism that removes recalled items from the set of response options. Despite its importance for our understanding of WM, response suppression has received limited direct testing. To address this gap, we used computational models implementing two hypothetical mechanisms of response suppression to derive predictions and tested these predictions experimentally. Participants were asked to recall the same items multiple times during a single trial. If already recalled items are removed from the response set to prevent repetition errors, memory performance should be impaired when the same item is tested again. Contrary to this, we found that memory performance was unimpaired when the same item was tested a second time, and even displayed a recall advantage. Therefore, this study demonstrates the implausibility of response suppression to account for how people avoid repetition errors. We discuss alternative explanations. (PsycInfo Database Record (c) 2024 APA, all rights reserved).

Enhanced suppression of vibration response and energy transfer by using nonlinear hysteresis friction damper

Enhanced suppression of vibration response and energy transfer by using nonlinear hysteresis friction damper

Pars Opercularis Underlies Efferent Predictions and Successful Auditory Feedback Processing in Speech: Evidence From Left-Hemisphere Stroke.

Hearing one's own speech allows for acoustic self-monitoring in real time. Left-hemisphere motor planning regions are thought to give rise to efferent predictions that can be compared to true feedback in sensory cortices, resulting in neural suppression commensurate with the degree of overlap between predicted and actual sensations. Sensory prediction errors thus serve as a possible mechanism of detection of deviant speech sounds, which can then feed back into corrective action, allowing for online control of speech acoustics. The goal of this study was to assess the integrity of this detection-correction circuit in persons with aphasia (PWA) whose left-hemisphere lesions may limit their ability to control variability in speech output. We recorded magnetoencephalography (MEG) while 15 PWA and age-matched controls spoke monosyllabic words and listened to playback of their utterances. From this, we measured speaking-induced suppression of the M100 neural response and related it to lesion profiles and speech behavior. Both speaking-induced suppression and cortical sensitivity to deviance were preserved at the group level in PWA. PWA with more spared tissue in pars opercularis had greater left-hemisphere neural suppression and greater behavioral correction of acoustically deviant pronunciations, whereas sparing of superior temporal gyrus was not related to neural suppression or acoustic behavior. In turn, PWA who made greater corrections had fewer overt speech errors in the MEG task. Thus, the motor planning regions that generate the efferent prediction are integral to performing corrections when that prediction is violated.

Suppression of nonlinear aeroelastic responses of graphene platelet-reinforced composite lattice sandwich plates using a nonlinear energy sink

Suppression of nonlinear aeroelastic responses of graphene platelet-reinforced composite lattice sandwich plates using a nonlinear energy sink

Effect of co-infection with Newcastle disease virus on Mycoplasma gallisepticum pathogenesis in vivo and in vitro

The co-infection of Newcastle disease virus (NDV) and Mycoplasma gallisepticum (MG) has a detrimental effect on chicken production performance, exerts a deleterious impact on poultry production performance, resulting in substantial economic losses. However, the exact impact and underlying mechanisms remain ambiguous. In this study, co-infection models were established both in vivo and in vitro. Through these models, it was found that the co-infection facilitated the replication of MG and NDV, as well as MG induced pathogenesis. The administration of lentogenic NDV resulted in the suppression of the innate immune response in vivo. At cellular level, co-infection promoted MG induced apoptosis through caspase-dependent mitochondrial endogenous pathway and suppressed the inflammatory secretion. This research contributes novel insights in co-infection.

Transcriptome analysis of Phytophthora cactorum infecting strawberry identified RXLR effectors that induce cell death when transiently expressed in Nicotiana benthamiana

Phytophthora cactorum is a plant pathogenic oomycete that causes crown rot in strawberry leading to significant economic losses every year. To invade the host, P. cactorum secretes an arsenal of effectors that can manipulate host physiology and impair its defense system promoting infection. A transcriptome analysis was conducted on a susceptible wild strawberry genotype (Fragaria vesca) 48 hours post inoculation with P. cactorum to identify effectors expressed during the early infection stage. The analysis revealed 4,668 P. cactorum genes expressed during infection of F. vesca. A total of 539 secreted proteins encoded by transcripts were identified, including 120 carbohydrate-active enzymes, 40 RXLRs, 23 proteolytic enzymes, nine elicitins, seven cysteine rich proteins, seven necrosis inducing proteins and 216 hypothetical proteins with unknown function. Twenty of the 40 RXLR effector candidates were transiently expressed in Nicotiana benthamiana using agroinfiltration and five previously unreported RXLR effector genes (Pc741, Pc8318, Pc10890, Pc20813, and Pc22290) triggered cell death when transiently expressed. The identified cell death inducing RXLR effectors showed 31–66% identity to known RXLR effectors in different Phytophthora species having roles in pathogenicity including both activation and suppression of defense response in the host. Furthermore, homology analysis revealed that these cell death inducing RXLR effectors were highly conserved (82 - 100% identity) across 23 different strains of P. cactorum originating from apple or strawberry.

Usp14 deficiency removes α-synuclein by regulating S100A8/A9 in Parkinson’s disease

Ubiquitin-proteasome system dysfunction triggers α-synuclein aggregation, a hallmark of neurodegenerative diseases, such as Parkinson’s disease (PD). However, the crosstalk between deubiquitinating enzyme (DUBs) and α-synuclein pathology remains unclear. In this study, we observed a decrease in the level of ubiquitin-specific protease 14 (USP14), a DUB, in the cerebrospinal fluid (CSF) of PD patients, particularly females. Moreover, CSF USP14 exhibited a dual correlation with α-synuclein in male and female PD patients. To investigate the impact of USP14 deficiency, we crossed USP14 heterozygous mouse (USP14+/−) with transgenic A53T PD mouse (A53T-Tg) or injected adeno-associated virus (AAV) carrying human α-synuclein (AAV-hα-Syn) in USP14+/− mice. We found that Usp14 deficiency improved the behavioral abnormities and pathological α-synuclein deposition in female A53T-Tg or AAV-hα-Syn mice. Additionally, Usp14 inactivation attenuates the pro-inflammatory response in female AAV-hα-Syn mice, whereas Usp14 inactivation demonstrated opposite effects in male AAV-hα-Syn mice. Mechanistically, the heterodimeric protein S100A8/A9 may be the downstream target of Usp14 deficiency in female mouse models of α-synucleinopathies. Furthermore, upregulated S100A8/A9 was responsible for α-synuclein degradation by autophagy and the suppression of the pro-inflammatory response in microglia after Usp14 knockdown. Consequently, our study suggests that USP14 could serve as a novel therapeutic target in PD.

The Anti-Inflammatory Potential of Beclometasone Loaded Filomicelles on Activated Human Monocytes.

Polymeric micelles with a hydrophobic core represent versatile nanostructures for encapsulation and delivery of water-insoluble drugs. Here, water-insoluble beclometasone dipropionate (BDP) which is a potent anti-inflammatory therapeutic agent but limited to topical applications so far, was encapsulated. Therefore, we used an amphiphilic block copolymer self-assembling into flexible polymeric filomicelles, which have recently proven to selectively target inflamed areas in patients with inflammatory bowel disease. The small diameter and flexibility of these filomicelles is considered beneficial for transepithelial passages, while their length minimizes the unspecific uptake into non-targeted cells. We successfully established a protocol to load the water-insoluble BDP into the core of the filomicelles, while maintaining the particle stability to prevent any premature drug release. The anti-inflammatory efficacy of BDP-loaded filomicelles was further investigated on LPS-stimulated human monocytes. In these ex vivo assays, the BDP-loaded filomicelles significantly reduce TNF-α, IL-6, IL-1ß, IL-12p70, IL-17a and IL-23 release after 24 h. An additional time course study of drug-loaded filomicelles and their comparison with a common water-soluble and unspecific corticosteroid demonstrated promising results with significant immune response suppression in stimulated monocytes after 2 h and 6 h. These findings demonstrate the potential of polymeric filomicelles as a vehicle for potent water-insoluble corticosteroids. This article is protected by copyright. All rights reserved.

CD200R activation on naïve T cells by B cells induces suppressive activity of T cells via IL-24

CD200 is an anti-inflammatory protein that facilitates signal transduction through its receptor, CD200R, in cells, resulting in immune response suppression. This includes reducing M1-like macrophages, enhancing M2-like macrophages, inhibiting NK cell cytotoxicity, and downregulating CTL responses. Activation of CD200R has been found to modulate dendritic cells, leading to the induction or enhancement of Treg cells expressing Foxp3. However, the precise mechanisms behind this process are still unclear. Our previous study demonstrated that B cells in Peyer’s patches can induce Treg cells, so-called Treg-of-B (P) cells, through STAT6 phosphorylation. This study aimed to investigate the role of CD200 in Treg-of-B (P) cell generation. To clarify the mechanisms, we used wild-type, STAT6 deficient, and IL-24 deficient T cells to generate Treg-of-B (P) cells, and antagonist antibodies (anti-CD200 and anti-IL-20RB), an agonist anti-CD200R antibody, CD39 inhibitors (ARL67156 and POM-1), a STAT6 inhibitor (AS1517499), and soluble IL-20RB were also applied. Our findings revealed that Peyer’s patch B cells expressed CD200 to activate the CD200R on T cells and initiate the process of Treg-of-B (P) cells generation. CD200 and CD200R interaction triggers the phosphorylation of STAT6, which regulated the expression of CD200R, CD39, and IL-24 in T cells. CD39 regulated the expression of IL-24, which sustained the expression of CD223 and IL-10 and maintained the cell viability. In summary, the generation of Treg-of-B (P) cells by Peyer’s patch B cells was through the CD200R-STAT6-CD39-IL-24 axis pathway.

Reno-protective effect of nicorandil and pentoxifylline against potassium dichromate-induced acute renal injury via modulation p38MAPK/Nrf2/HO-1 and Notch1/TLR4/NF-κB signaling pathways

BackgroundOccupational and environmental exposure to chromium compounds such as potassium dichromate (PDC) (K2Cr2O7) has emerged as a potential aetiologic cause for renal disease through apoptotic, and inflammatory reactions. The known potent antioxidants such as nicorandil (NIC) and/or pentoxifylline (PTX) were studied for their possible nephroprotective effect in PDC-treated rats. MethodsForty male Wistar rats were divided into five groups; control, PDC group, NIC+PDC, PTX+PDC group, and combination+PDC group. Nephrotoxicity was evaluated histopathologically and biochemically. Invasive blood pressure, renal function parameters urea, creatinine, uric acid and albumin, glomerular filtration rate markers Cys-C, Kim-1 and NGAL, inflammatory markers IL-1β, IL-6, TNF-α, TGF-β, COX-II, p38MAPK, NF-κB and TLR4, oxidative stress SOD, GSH, MDA, MPO, HO-1 and Nrf2 and apoptotic mediators Notch1 and PCNA were evaluated. Besides, renal cortical histopathology was assayed as well. ResultsPDC led to a considerable increase in indicators for kidney injury, renal function parameters, invasive blood pressure, oxidative stress, and inflammatory markers. They were markedly reduced by coadministration of PDC with either/or NIC and PTX. The NIC and PTX combination regimen showed a more significant improvement than either medication used alone. Our results demonstrated the nephroprotective effect of NIC, PTX, and their combined regimen on PDC-induced kidney injury through suppression of oxidative stress, apoptosis, and inflammatory response. ConclusionRenal recovery from PDC injury was achieved through enhanced MAPK/Nrf2/HO-1 and suppressed Notch1/TLR4/NF-κB signaling pathways. This study highlights the role of NIC and PTX as effective interventions to ameliorate nephrotoxicity in patients undergoing PDC toxicity.

Effect of SiC particle content on the mechanical behavior and deformation mechanism of SiCp/Al composite under high-frequency dynamic loading

SiCp/Al composites exhibit excellent structural properties but suffer from inherent brittleness, which has brought rigorous challenges on the materials processing. Ultrasonic-vibration-assisted approach offers a promising solution to improve the processability. However, the underlying mechanisms of mechanical response and defect suppression under ultrasonic action have been rarely studied for SiCp/Al composites, hindering the development of high-efficiency processing. This work aims to investigate the mechanical behavior and microstructural evolution in this class of composites with varying SiC volume fractions up to 45% under high-frequency dynamic load induced by ultrasonic vibration. The results showed that the deformation stress of SiCp/Al composites under ultrasonic compression was significantly reduced to only about 1/10 of that under conventional quasi-static loading. Moreover, as the SiC fractions increasing, this ultrasonic softening effect of SiCp/Al became more pronounced. The plastic limit of SiCp/Al with 45% SiC fraction nearly doubled under ultrasonic compression without any macroscopic cracks. The subsequent nanoindentation tests revealed a transition in work-hardening behavior of SiCp/Al with different SiC fractions under ultrasonic loading. Microstructure characterization was conducted to analyze the grain refinement, recrystallization, and deformation textures within the deformed areas, revealing the deformation mechanism of SiCp/Al under different loading mode. TEM observations confirmed the distribution of dislocations in Al matrix and dense stacking faults in SiC particles after ultrasonic compression, indicating that the plastic behaviors were enhanced in both Al matrix and SiC phase under the high-frequency cyclic stress. This research revealed the distinct deformation mechanisms of SiCp/Al composites under high-frequency dynamic loading, exhibiting extremely low deformation stress accompanied with significantly enhanced plasticity. The results provide theoretical insights for the high-efficiency processing and rapid property regulation of particle-reinforced-composites based on ultrasonic-vibration-assisted technologies.

Design and optimization of a two-degrees-of-freedom single-sided vibro-impact nonlinear energy sink for transient vibration suppression of a thin plate

To rapidly suppress the transient vibration response of a thin plate, a two-degrees-of-freedom single-sided vibro-impact nonlinear energy sink (TSSVI NES) is proposed in this paper. Based on the Kirchhoff hypothesis, the coupled equations of motion between the plate and the TSSVI NES are established. The system is modeled by the Galerkin technique and numerically solved using the fourth order Runge-Kutta method. To obtain the optimal parameters of the TSSVI NES, a particle swarm optimization method is adopted. The system response with the TSSVI NES is compared with that of the cubic nonlinear energy sink (CNES) and the single-sided vibro-impact nonlinear energy sink (SSVI NES), showing that the vibration suppression ability of the TSSVI NES is better. The mechanism of rapid response suppression of the TSSVI NES is demonstrated by way of simulations. A parametric study is also conducted to determine the effects of damping, the coefficient of restitution, mass, stiffness, and installation position of TSSVI NES on the efficacy of the vibration control device. The numerical results demonstrate that the performance of the TSSVI NES is robust to the damping, coefficient of restitution, and installation position, but sensitive to mass difference and stiffness difference. Finally, the effect of the TSSVI NES is examined when the plate is excited by seismic loads, demonstrating a good response suppression performance.

Preliminary Exploration of Potential Active Ingredients and Molecular Mechanisms of Yanggan Yishui Granules for Treating Hypertensive Nephropathy Using UPLC-Q-TOF/MS Coupled with Network Pharmacology and Molecular Docking Strategy.

Hypertensive nephropathy (HN) is a prevalent complication of hypertension and stands as the second primary reason for end-stage renal disease. Research in clinical settings has revealed that Yanggan Yishui Granule (YGYSG) has significant therapeutic effects on HN. However, the material basis and action mechanisms of YGYSG against HN remain unclear. Consequently, this study utilized a comprehensive method integrating ultraperformance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS), network pharmacology, and molecular docking to delineate the active ingredients and potential therapeutic mechanisms of YGYSG for treating HN. Firstly, sixty distinct components were recognized in total as potential active ingredients in YGYSG by UPLC-Q-TOF/MS. Subsequently, the mechanisms of YGYSG against HN were revealed for the first time using network pharmacology. 23 ingredients played key roles in the complete network and were the key active ingredients, which could affect the renin-angiotensin system, fluid shear stress and atherosclerosis, HIF-1 signaling pathway, and AGE-RAGE signaling pathway in diabetic complications by regulating 29 key targets such as TNF, IL6, ALB, EGFR, ACE, and MMP2. YGYSG could treat HN through the suppression of inflammatory response and oxidative stress, attenuating the proliferation of renal vascular smooth muscle cells, lessening glomerular capillary systolic pressure, and ameliorating renal dysfunction and vascular damage through the aforementioned targets and pathways. Molecular docking results revealed that most key active ingredients exhibited a high affinity for binding to the key targets. This study pioneers in clarifying the bioactive compounds and molecular mechanisms of YGYSG against HN and offers scientific reference into the clinical application.

208 The antiviral and immunomodulating properties from glycerides of lauric acid in PRRSV-infected PAM cells

Abstract The objective of this study was to assess the ability of a commercially available blend of glycerides of C12 to inhibit porcine reproductive and respiratory syndrome virus (PRRSV) replication in porcine alveolar macrophages (PAM) and to investigate the immunomodulatory effect during PRRSV infection in vitro. PAM were collected by lung lavage from 4-wk-old piglets, free of PRRSV. PRRSV strain 13V091 was used in this study and a commercially available mixture of mono-, di- and tri-glycerides of lauric acid (GC12). The product concentrations tested were 0.022% (T1), 0.044% (T2) and 0.088% (T3). Three different infection assays were used: (1) Co-incubation; PRRSV was inoculated together with GC12 for 1 h, (2) Pre- and Post-infection; GC12 was added to PAM cells for 24 h before infection and after 1 h of incubation for another 24 h, and (3) Post-infection; GC12 was added only after PRRSV infection for 24 h. Titration of the progeny virus was performed on PAM from all three infection assays. Cytokine analysis was only performed for infection assay 2 and 3. Collected supernatants were subjected to multiplex ELISA to measure the level of TNF-α and IL-8. Two-tailed t test P value was used to determine statistically significant differences. P < 0.05 was considered to be statistically significant. Addition of GC12 in the Co-incubation assay did not reduce PRRSV infectivity at 24-h post infection (hpi; Table 1). In contrast, the Pre- and Post-infection assay showed significantly reduced PRRSV titer from 6 hpi onwards at concentration 0.044%. At concentration 0.088% a significant reduction was observed at 24 hpi. Addition of GC12 after PRRSV inoculation (post-infection) also showed significantly reduced PRRSV titer from 6 hpi onwards at concentration 0.044% and 0.088%. In the Pre- and Post-infection assay, all treatments with GC12 numerically increased the production of TNF-α at 24 hpi. A dose response effect was observed at 24 hpi with increasing concentrations of GC12 resulting in increasing levels of TNF-α. However, in the Post-infection assay only treatment with 0.088% GC12 numerically increased the production of TNF-α by 1.5-fold. Compared with the control (PAM+PRRSV), a significantly greater concentration of IL-8 was observed with 0.044% (P = 0.019) and 0.088% (P = 0.007) GC12 24 hpi in the Pre- and Post-infection assay (1,806 ± 376; 3,751 ± 636; 3,439 ± 420 pg/mL respectively). These two concentrations resulted in numeric increase of IL-8 24 hpi in the Post-infection assay and no effect was observed with 0.022% GC12 (Control 2,332 ± 998; T1 2,079 ± 964; T2 3,525 ± 344; T3 4,475 ± 295). From this study it can be concluded that GC12 exhibited antiviral activity against PRRSV strain 13V091 and influences the cytokine production of PAM during PRRSV infection, potentially neutralizing the suppression of the immune response by PRRSV.

Inhibitory mechanisms of decoy receptor 3 in cecal ligation and puncture-induced sepsis.

Sepsis affects millions of hospitalized patients worldwide each year, but there are no sepsis-specific drugs, which makes sepsis therapies urgently needed. Suppression of excessive inflammatory responses is important for improving the survival of patients with sepsis. Our results demonstrate that DcR3 ameliorates sepsis in mice by attenuating systematic inflammation and modulating gut microbiota, and unveil the molecular mechanism underlying its anti-inflammatory effect.

Transfected SARS-CoV-2 spike DNA for mammalian cell expression inhibits p53 activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2 proteins in cancer cells and increases cancer cell viability after chemotherapy exposure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and COVID-19 infection has led to worsened outcomes for patients with cancer. SARS-CoV-2 spike protein mediates host cell infection and cell-cell fusion that causes stabilization of tumor suppressor p53 protein. In-silico analysis previously suggested that SARS-CoV-2 spike interacts with p53 directly but this putative interaction has not been demonstrated in cells. We examined the interaction between SARS-CoV-2 spike, p53 and MDM2 (E3 ligase, which mediates p53 degradation) in cancer cells using an immunoprecipitation assay. We observed that SARS-CoV-2 spike protein interrupts p53-MDM2 protein interaction but did not detect SARS-CoV-2 spike bound with p53 protein in the cancer cells. We further observed that SARS-CoV-2 spike suppresses p53 transcriptional activity in cancer cells including after nutlin exposure of wild-type p53-, spike-expressing tumor cells and inhibits chemotherapy-induced p53 gene activation of p21(WAF1), TRAIL Death Receptor DR5 and MDM2. The suppressive effect of SARS-CoV-2 spike on p53-dependent gene activation provides a potential molecular mechanism by which SARS-CoV-2 infection may impact tumorigenesis, tumor progression and chemotherapy sensitivity. In fact, cisplatin-treated tumor cells expressing spike were found to have increased cell viability as compared to control cells. Further observations on γ-H2AX expression in spike-expressing cells treated with cisplatin may indicate altered DNA damage sensing in the DNA damage response pathway. The preliminary observations reported here warrant further studies to unravel the impact of SARS-CoV-2 and its various encoded proteins including spike on pathways of tumorigenesis and response to cancer therapeutics. More efforts should be directed at studying the effects of the SARS-CoV-2 spike and other viral proteins on host DNA damage sensing, response and repair mechanisms. A goal would be to understand the structural basis for maximal anti-viral immunity while minimizing suppression of host defenses including the p53 DNA damage response and tumor suppression pathway. Such directions are relevant and important including not only in the context of viral infection and mRNA vaccines in general but also for patients with cancer who may be receiving cytotoxic or other cancer treatments.

Abstract PO4-23-08: Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer

Abstract Although clinical evidence indicates that treatment with estrogens elicits anti-cancer effects in ~30% of patients with advanced endocrine-resistant ER+ breast cancer, the underlying mechanism of action is unclear and this treatment remains under-utilized. ER+ breast cancer cells with acquired resistance to long-term estrogen deprivation (LTED) were used to model resistance to aromatase inhibitors (AIs) seen clinically. Genome-wide CRISPR/Cas9 knockout screening and transcriptomic profiling of LTED cells highlighted DNA Damage Response as a required pathway for therapeutic response to the estrogen 17b-estradiol. Tumor specimens from 2 patients with advanced ER+ breast cancer showed increased DNA damage response upon treatment with 17b-estradiol therapy compared to baseline. LTED cells treated with 17b-estradiol exhibited replication-dependent markers of DNA damage and the DNA damage response prior to apoptosis, while parental cells did not. Such DNA damage was partially driven by the formation of DNA:RNA hybrids (R-loops), and RNase H1-mediated prevention of R-loop formation abrogated 17b-estradiol-induced DNA damage. Pharmacological suppression of the DNA damage response via poly(ADP-ribose) polymerase (PARP) inhibition with olaparib enhanced 17b-estradiol-induced DNA damage. PARP inhibition synergized with 17b-estradiol to suppress growth and prevent tumor recurrence in both BRCA1/2-mutant and BRCA1/2-wild-type cell line and patient-derived xenograft models. We therefore conclude that 17b-estradiol-induced ER activity drives DNA damage and growth inhibition in endocrine-resistant breast cancer cells, and inhibition of the DNA damage response using drugs such as PARP inhibitors can exacerbate transcriptional stress and enhance therapeutic response to 17b-estradiol. This concept is being explored clinically in the PHOEBE trial testing the combination of 17b-estradiol and olaparib (NCT05900895). These findings also warrant further study of other DNA damage response inhibitors in advanced ER+ breast cancer. Moreover, these data indicate that PARP inhibitors may have applications beyond homologous recombination-deficient tumors. Citation Format: Nicole Traphagen, Gary Schwartz, Steven Tau, Alyssa Roberts, Amanda Jiang, Sarah Hosford, Jonathan Marotti, Abigail Goen, Bianca Romo, Anneka Johnson, Emily Duffy, Eugene Demidenko, Paul Heverly, Yaron Mosesson, Shannon Soucy, Fred Kolling, Todd Miller. Estrogen therapy induces receptor-dependent DNA damage enhanced by PARP inhibition in ER+ breast cancer [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO4-23-08.

H1FOO-DD promotes efficiency and uniformity in reprogramming to naive pluripotency

Heterogeneity among both primed and naive pluripotent stem cell lines remains a major unresolved problem. Here we show that expressing the maternal-specific linker histone H1FOO fused to a destabilizing domain (H1FOO-DD), together with OCT4, SOX2, KLF4, and LMYC, in human somatic cells improves the quality of reprogramming to both primed and naive pluripotency. H1FOO-DD expression was associated with altered chromatin accessibility around pluripotency genes and with suppression of the innate immune response. Notably, H1FOO-DD generates naive induced pluripotent stem cells with lower variation in transcriptome and methylome among clones and a more uniform and superior differentiation potency. Furthermore, we elucidated that upregulation of FKBP1A, driven by these five factors, plays a key role in H1FOO-DD-mediated reprogramming.