A gene-environment-induced epigenetic program initiates tumorigenesis.

Tissue damage increases the risk of cancer through poorly understood mechanisms1. In mouse models of pancreatic cancer, pancreatitis associated with tissue injury collaborates with activating mutations in the Kras oncogene to markedly accelerate the formation of early neoplastic lesions and, ultimately, adenocarcinoma2,3. Here, by integrating genomics, single-cell chromatin assays and spatiotemporally controlled functional perturbations in autochthonous mouse models, we show that the combination of Kras mutation and tissue damage promotes a unique chromatin state in the pancreatic epithelium that distinguishes neoplastic transformation from normal regeneration and is selected for throughout malignant evolution. This cancer-associated epigenetic state emerges within 48 hours of pancreatic injury, and involves an 'acinar-to-neoplasia' chromatin switch that contributes to the early dysregulation of genes that define human pancreatic cancer. Among the factors that are most rapidly activated after tissue damage in the pre-malignant pancreatic epithelium is the alarmin cytokine interleukin 33, which recapitulates the effects of injury in cooperating with mutant Kras to unleash the epigenetic remodelling program of early neoplasia and neoplastic transformation. Collectively, our study demonstrates how gene-environment interactions can rapidly produce gene-regulatory programs that dictate early neoplastic commitment, and provides a molecular framework for understanding the interplay between genetic and environmental cues in the initiation of cancer.

Cardiopulmonary Resuscitation Without Aortic Valve Compression Increases the Chances of Return of Spontaneous Circulation in Out-of-Hospital Cardiac Arrest: A Prospective Observational Cohort Study.

OBJECTIVES: Following current cardiopulmonary resuscitation (CPR) guidelines, which recommend chest compressions at "the center of the chest," ~50% of patients experiencing out-of-hospital cardiac arrest (OHCA) undergo aortic valve (AV) compression, obstructing blood flow. We used resuscitative transesophageal echocardiography (TEE) to elucidate the impact of uncompressed vs. compressed AV on outcomes of adult patients experiencing OHCA. DESIGN: Prospective observational cohort study. SETTING: Single center. PATIENTS: This study included adult OHCA patients undergoing resuscitative TEE in the emergency department. Patients were categorized into AV uncompressed or AV compressed groups based on TEE findings. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: The primary outcome was sustained return of spontaneous circulation (ROSC). The secondary outcomes included end-tidal co2 (Etco2) during CPR, any ROSC, survival to ICU and hospital discharge, post-resuscitation withdrawal, and favorable neurologic outcomes at discharge. Additional analyses on intra-arrest arterial blood pressure (ABP) were also conducted. The sample size was pre-estimated at 37 patients/group. From October 2020 to January 2023, 76 patients were enrolled, 39 and 37 in the AV uncompressed and AV compressed groups, respectively. Intergroup baseline characteristics were similar. Compared with the AV compressed group, the AV uncompressed group had a higher probability of sustained ROSC (53.8% vs. 24.3%; adjusted odds ratio [aOR], 4.72; p = 0.010), any ROSC (56.4% vs. 32.4%; aOR, 3.30; p = 0.033), and survival to ICU (33.3% vs. 8.1%; aOR, 6.74; p = 0.010), and recorded higher initial diastolic ABP (33.4 vs. 11.5 mm Hg; p = 0.002) and a larger proportion achieving diastolic ABP greater than 20 mm Hg during CPR (93.8% vs. 33.3%; p < 0.001). The Etco2, post-resuscitation withdrawal, and survival to discharge revealed no significant intergroup differences. No patients were discharged with favorable neurologic outcomes. Uncompressed AV seemed critical for sustained ROSC across all subgroups. CONCLUSIONS: Absence of AV compression during OHCA resuscitation is associated with an increased chance of ROSC and survival to ICU. However, its effect on long-term outcomes remains unclear.

Cul3-KLHL20 Ubiquitin Ligase Governs the Turnover of ULK1 and VPS34 Complexes to Control Autophagy Termination.

Autophagy, a cellular self-eating mechanism, is important for maintaining cell survival and tissue homeostasis in various stressed conditions. Although the molecular mechanism of autophagy induction has been well studied, how cells terminate autophagy process remains elusive. Here, we show that ULK1, a serine/threonine kinase critical for autophagy initiation, is a substrate of the Cul3-KLHL20 ubiquitin ligase. Upon autophagy induction, ULK1 autophosphorylation facilitates its recruitment to KLHL20 for ubiquitination and proteolysis. This autophagy-stimulated, KLHL20-dependent ULK1 degradation restrains the amplitude and duration of autophagy. Additionally, KLHL20 governs the degradation of ATG13, VPS34, Beclin-1, and ATG14 in prolonged starvation through a direct or indirect mechanism. Impairment of KLHL20-mediated regulation of autophagy dynamics potentiates starvation-induced cell death and aggravates diabetes-associated muscle atrophy. Our study identifies a key role of KLHL20 in autophagy termination by controlling autophagy-dependent turnover of ULK1 and VPS34 complex subunits and reveals the pathophysiological functions of this autophagy termination mechanism.

Influence of the Door-to-ECG Time on the Prognosis of Patients with Acute Coronary Syndrome.

Background: The rapid acquisition of an electrocardiogram (ECG) plays a crucial role in the diagnosis and management decisions in patients with acute coronary syndrome (ACS). Objectives: We determined the time-to-ECG acquisition, identified factors associated with timely acquisition, and evaluated the influence of time-to-ECG on in-hospital mortality. Methods: We measured the door-to-ECG time for 903 of 2140 patients in the emergency department of Far Eastern Memorial Hospital with a diagnosis of ACS from January 1, 2016 to December 31, 2018, via a retrospective chart review. The primary outcome was in-hospital mortality. Outcome analysis of mortality was conducted using multivariable logistic regression. The secondary outcome was to determine which factors influenced whether or not a patient received an ECG within 10 min. The analysis was conducted using multiple logistic regression. Results: The median time-to-ECG was 5 min (interquartile range: 4-11 min) in all patients. In multivariable logistic regression analysis, we found that older age and more severe heart-broken index were significantly related to timely ECG acquisition. In-hospital mortality was higher in those in whom ECG was performed after more than 10 min. However, in the multivariable logistic regression analysis, it did not have a significant positive correlation with ECG acquisition time. Conclusions: Timely ECG acquisition owing to the triage protocol at our institution, the heart-broken index, led to early PCI and thus better outcomes for the ACS patients in this study. The implementation of a protocol-driven timely evaluation of patients with ACS and prompt PCI are important.

Speckle reduction using deformable mirrors with diffusers in a laser pico-projector.

We propose a design for speckle reduction in a laser pico-projector adopting diffusers and deformable mirrors. This research focuses on speckle noise suppression by changing the angle of divergence of the diffuser. Moreover, the speckle contrast value can be further reduced by the addition of a deformable mirror. The speckle reduction ability obtained using diffusers with different divergence angles is compared. Three types of diffuser designs are compared in the experiments. For Type 1 which uses a circular symmetric diffuser the speckle contrast value can be decreased to 0.0264. For Type 2, the speckle contrast value can be reduced to 0.0267 because of the inclusion of an elliptical distribution diffuser. With Type 3 which includes a combination of the circular distribution diffuser and elliptical distribution diffuser, the speckle contrast value can be reduced to 0.0236. For all three types, the speckle contrast value is lower than 0.05. Under this speckle value, the speckle phenomenon is invisible to the human eye.

Establishment of 2D Crystal Heterostructures by Sulfurization of Sequential Transition Metal Depositions: Preparation, Characterization, and Selective Growth.

A nine-layer WS2/MoS2 heterostructure is established on a sapphire substrate after sequential growth of large-area and uniform five- and four-layer MoS2 and WS2 films by using sulfurization of predeposited 1.0 nm molybdenum (Mo) and tungsten (W), respectively. By using the results obtained from the ultraviolet photoelectron spectroscopy and the absorption spectrum measurements of the standalone MoS2 and WS2 samples, a type-II band alignment is predicated for the WS2/MoS2 heterostructure. Increasing drain currents and enhanced field-effect mobility value of the transistor fabricated on the heterostructure suggested that a channel with higher electron concentration compared with the standalone MoS2 transistor channel is obtained with electron injection from WS2 to MoS2 under thermal equilibrium. Selective 2D crystal growth with (I) blank sapphire substrate, (II) standalone MoS2, (III) WS2/MoS2 heterostructure, and (IV) standalone WS2 was demonstrated on a single sapphire substrate. The results have revealed the potential of this growth technique for practical applications.

1.1-µm InAs/GaAs quantum-dot light-emitting transistors grown by molecular beam epitaxy.

In this Letter, we report the enhanced radiative recombination output from an AlGaAs/GaAs heterojunction bipolar transistor with InAs quantum dots embedded in the base region to form a quantum-dot light-emitting transistor (QDLET) grown by molecular beam epitaxy systems. For the device with a 100 µm×100 µm emitter area, we demonstrate the dual output characteristics with an electrical output and an optical output when the device is operating in the common-emitter configuration. The quantum-dot light-emitting transistor exhibits a base recombination radiation in the near-infrared spectral range with a dominant peak at λ of 1100 nm.

Somatic mouse models of gastric cancer reveal genotype-specific features of metastatic disease.

Metastatic gastric carcinoma is a highly lethal cancer that responds poorly to conventional and molecularly targeted therapies. Despite its clinical relevance, the mechanisms underlying the behavior and therapeutic response of this disease are poorly understood owing, in part, to a paucity of tractable models. Here we developed methods to somatically introduce different oncogenic lesions directly into the murine gastric epithelium. Genotypic configurations observed in patients produced metastatic gastric cancers that recapitulated the histological, molecular and clinical features of all nonviral molecular subtypes of the human disease. Applying this platform to both wild-type and immunodeficient mice revealed previously unappreciated links between the genotype, organotropism and immune surveillance of metastatic cells, which produced distinct patterns of metastasis that were mirrored in patients. Our results establish a highly portable platform for generating autochthonous cancer models with flexible genotypes and host backgrounds, which can unravel mechanisms of gastric tumorigenesis or test new therapeutic concepts.

Effect of resuscitative endovascular balloon occlusion of the aorta in nontraumatic out-of-hospital cardiac arrest: a multinational, multicenter, randomized, controlled trial.

BACKGROUND: Out-of-hospital cardiac arrest (OHCA) is a significant public health issue worldwide and is associated with low survival rates and poor neurological outcomes. The generation of optimal coronary perfusion pressure (CPP) via high-quality chest compressions is a key factor in enhancing survival rates. However, it is often challenging to provide adequate CPP in real-world cardiopulmonary resuscitation (CPR) scenarios. Based on animal studies and human trials on improving CPP in patients with nontraumatic OHCA, resuscitative endovascular balloon occlusion of the aorta (REBOA) is a promising technique in these cases. This study aims to investigate the benefits of REBOA adjunct to CPR compared with conventional CPR for the clinical management of nontraumatic OHCA. METHODS: This is a parallel-group, randomized, controlled, multinational trial that will be conducted at two urban academic tertiary hospitals in Korea and Taiwan. Patients aged 20-80 years presenting with witnessed OHCA will be enrolled in this study. Eligible participants must fulfill the inclusion criteria, and written informed consent should be collected from their legal representatives. Patients will be randomly assigned to the intervention (REBOA-CPR) or control (conventional CPR) group. The intervention group will receive REBOA and standard advanced cardiovascular life support (ACLS). Meanwhile, the control group will receive ACLS based on the 2020 American Heart Association guidelines. The primary outcome is the return of spontaneous circulation (ROSC). The secondary outcomes include sustained ROSC, survival to admission, survival to discharge, neurological outcome, and hemodynamic changes. DISCUSSION: Our upcoming trial can provide essential evidence regarding the efficacy of REBOA, a mechanical method for enhancing CPP, in OHCA resuscitation. Our study aims to determine whether REBOA can improve treatment strategies for patients with nontraumatic OHCA based on clinical outcomes, thereby potentially providing valuable insights and guiding further advancements in this critical public health area. TRIAL REGISTRATION: ClinicalTrials.gov NCT06031623. Registered on September 9, 2023.

Senescence Rewires Microenvironment Sensing to Facilitate Antitumor Immunity.

Cellular senescence involves a stable cell-cycle arrest coupled to a secretory program that, in some instances, stimulates the immune clearance of senescent cells. Using an immune-competent liver cancer model in which senescence triggers CD8 T cell-mediated tumor rejection, we show that senescence also remodels the cell-surface proteome to alter how tumor cells sense environmental factors, as exemplified by type II interferon (IFNγ). Compared with proliferating cells, senescent cells upregulate the IFNγ receptor, become hypersensitized to microenvironmental IFNγ, and more robustly induce the antigen-presenting machinery-effects also recapitulated in human tumor cells undergoing therapy-induced senescence. Disruption of IFNγ sensing in senescent cells blunts their immune-mediated clearance without disabling the senescence state or its characteristic secretory program. Our results demonstrate that senescent cells have an enhanced ability to both send and receive environmental signals and imply that each process is required for their effective immune surveillance. SIGNIFICANCE: Our work uncovers an interplay between tissue remodeling and tissue-sensing programs that can be engaged by senescence in advanced cancers to render tumor cells more visible to the adaptive immune system. This new facet of senescence establishes reciprocal heterotypic signaling interactions that can be induced therapeutically to enhance antitumor immunity. See related article by Marin et al., p. 410. This article is highlighted in the In This Issue feature, p. 247.

Epigenetic plasticity cooperates with cell-cell interactions to direct pancreatic tumorigenesis.

The response to tumor-initiating inflammatory and genetic insults can vary among morphologically indistinguishable cells, suggesting as yet uncharacterized roles for epigenetic plasticity during early neoplasia. To investigate the origins and impact of such plasticity, we performed single-cell analyses on normal, inflamed, premalignant, and malignant tissues in autochthonous models of pancreatic cancer. We reproducibly identified heterogeneous cell states that are primed for diverse, late-emerging neoplastic fates and linked these to chromatin remodeling at cell-cell communication loci. Using an inference approach, we revealed signaling gene modules and tissue-level cross-talk, including a neoplasia-driving feedback loop between discrete epithelial and immune cell populations that was functionally validated in mice. Our results uncover a neoplasia-specific tissue-remodeling program that may be exploited for pancreatic cancer interception.

A multicenter cohort study on the association between prehospital immobilization and functional outcome of patients following spinal injury in Asia.

Prehospital spinal immobilization is a widely used procedure in the emergency medical service (EMS) system worldwide, while the incidence of patients with spinal injury (SI) is relatively low, and unnecessary prehospital spinal immobilization is associated with patient complications. This study aimed to determine the association between prehospital spine immobilization and favorable functional outcomes at hospital discharge among trauma patients with SI. We conducted a retrospective cohort study using the Pan-Asia Trauma Outcomes Study (PATOS) registry data from January 1, 2016, to November 30, 2018. A total of 759 patients with SI were enrolled from 43,752 trauma patients in the PATOS registry during the study period. The subjects had a median age of 58 years (Q1-Q3, 41-72), and 438 (57.7%) patients had prehospital spine immobilization. Overall, prehospital spinal immobilization was not associated with favorable functional outcomes at discharge in multivariable logistic regression (aOR 1.06; 95% CI 0.62-1.81, p = 0.826). However, in the subgroup of cervical SI, prehospital spinal immobilization was associated with favorable functional outcomes at discharge (aOR 3.14; 95% CI 1.04-9.50; p = 0.043). Therefore, we suggest that paramedics should be more careful when determining the presence of a cervical SI and should apply full spine immobilization if possible.

Influence of advanced life support response time on out-of-hospital cardiac arrest patient outcomes in Taipei.

BACKGROUND: The association between out-of-hospital cardiac arrest patient survival and advanced life support response time remained controversial. We aimed to test the hypothesis that for adult, non-traumatic, out-of-hospital cardiac arrest patients, a shorter advanced life support response time is associated with a better chance of survival. We analyzed Utstein-based registry data on adult, non-traumatic, out-of-hospital cardiac arrest patients in Taipei from 2011 to 2015. METHODS: Patients without complete data, witnessed by emergency medical technicians, or with response times of ≥ 15 minutes, were excluded. We used logistic regression with an exposure of advanced life support response time. Primary and secondary outcomes were survival to hospital discharge and favorable neurological outcomes (cerebral performance category ≤ 2), respectively. Subgroup analyses were based on presenting rhythms of out-of-hospital cardiac arrest, bystander cardiopulmonary resuscitation, and witness status. RESULTS: A total of 4,278 cases were included in the final analysis. The median advanced life support response time was 9 minutes. For every minute delayed in advanced life support response time, the chance of survival to hospital discharge would reduce by 7% and chance of favorable neurological outcome by 9%. Subgroup analysis showed that a longer advanced life support response time was negatively associated with the chance of survival to hospital discharge among out-of-hospital cardiac arrest patients with shockable rhythm and pulse electrical activity groups. CONCLUSIONS: In non-traumatic, adult, out-of-hospital cardiac arrest patients in Taipei, a longer advanced life support response time was associated with declining odds of survival to hospital discharge and favorable neurologic outcomes, especially in patients presenting with shockable rhythm and pulse electrical activity.

Attenuation of the increase in intraocular pressure with dexmedetomidine: Systematic review with meta-analysis and trial sequential analysis.

STUDY OBJECTIVE: Whether dexmedetomidine effectively attenuates the increase in intraocular pressure (IOP) remains inconclusive. We aim to evaluate the effects of dexmedetomidine on IOP in adult patients undergoing surgery which requires general anesthesia and endotracheal intubation. DESIGN: Systematic review and meta-analysis. INTERVENTIONS: Intravenous administration of dexmedetomidine during surgery. MEASUREMENTS: Intraocular pressure. METHODS: We searched PubMed, Embase, Scopus, Web of Science, Cochrane Library, Google Scholar, Wanfang Data, and China National Knowledge Infrastructure from the inception through April 14, 2020. Randomized control trials which involved adult patients undergoing surgery that required general anesthesia and endotracheal intubation, which compared intravenous administration of dexmedetomidine with placebo regarding the IOP levels, which also provided sufficient information for meta-analysis were considered eligible. MAIN RESULTS: Twenty-nine randomized control trials were included. The IOP levels are significantly lower in patients receiving dexmedetomidine after the administration of dexmedetomidine [mean difference (MD), -2.04 mmHg; 95% confidence interval (CI), -2.40 mmHg to -1.67 mmHg], after the injection of succinylcholine (MD, -3.84 mmHg; 95% CI, -4.80 mmHg to -2.88 mmHg), after endotracheal intubation (MD, -3.64 mmHg; 95% CI, -4.46 mmHg to -2.82 mmHg), after pneumoperitoneum (MD, -3.12 mmHg; 95% CI, -3.93 mmHg to -2.30 mmHg), and after the patients being placed in a steep Trendelenburg position (MD, -4.12 mmHg; 95% CI, -5.39 mmHg to -2.85 mmHg). Trial sequential analyses for these outcomes are conclusive. CONCLUSIONS: Dexmedetomidine effectively attenuates the increase in IOP levels, and should be considered especially for at-risk patients.

Defining the therapeutic selective dependencies for distinct subtypes of PI3K pathway-altered prostate cancers.

Previous studies have suggested that PTEN loss is associated with p110ß signaling dependency, leading to the clinical development of p110ß-selective inhibitors. Here we use a panel pre-clinical models to reveal that PI3K isoform dependency is not governed by loss of PTEN and is impacted by feedback inhibition and concurrent PIK3CA/PIK3CB alterations. Furthermore, while pan-PI3K inhibition in PTEN-deficient tumors is efficacious, upregulation of Insulin Like Growth Factor 1 Receptor (IGF1R) promotes resistance. Importantly, we show that this resistance can be overcome through targeting AKT and we find that AKT inhibitors are superior to pan-PI3K inhibition in the context of PTEN loss. However, in the presence of wild-type PTEN and PIK3CA-activating mutations, p110α-dependent signaling is dominant and selectively inhibiting p110α is therapeutically superior to AKT inhibition. These discoveries reveal a more nuanced understanding of PI3K isoform dependency and unveil novel strategies to selectively target PI3K signaling nodes in a context-specific manner.