The N-Degron Pathway Mediates ER-phagy.

The endoplasmic reticulum (ER) is susceptible to wear-and-tear and proteotoxic stress, necessitating its turnover. Here, we show that the N-degron pathway mediates ER-phagy. This autophagic degradation initiates when the transmembrane E3 ligase TRIM13 (also known as RFP2) is ubiquitinated via the lysine 63 (K63) linkage. K63-ubiquitinated TRIM13 recruits p62 (also known as sequestosome-1), whose complex undergoes oligomerization. The oligomerization is induced when the ZZ domain of p62 is bound by the N-terminal arginine (Nt-Arg) of arginylated substrates. Upon activation by the Nt-Arg, oligomerized TRIM13-p62 complexes are separated along with the ER compartments and targeted to autophagosomes, leading to lysosomal degradation. When protein aggregates accumulate within the ER lumen, degradation-resistant autophagic cargoes are co-segregated by ER membranes for lysosomal degradation. We developed synthetic ligands to the p62 ZZ domain that enhance ER-phagy for ER protein quality control and alleviate ER stresses. Our results elucidate the biochemical mechanisms and pharmaceutical means that regulate ER homeostasis.

Increased PTCHD4 expression via m6A modification of PTCHD4 mRNA promotes senescent cell survival.

RNA modifications, including N6-methyladenosine (m6A), critically modulate protein expression programs in a range of cellular processes. Although the transcriptomes of cells undergoing senescence are strongly regulated, the landscape and impact of m6A modifications during senescence are poorly understood. Here, we report a robust m6A modification of PTCHD4 mRNA, encoding Patched Domain-Containing Protein 4, in senescent cells. The METTL3/METTL14 complex was found to incorporate the m6A modification on PTCHD4 mRNA; addition of m6A rendered PTCHD4 mRNA more stable and increased PTCHD4 production. MeRIP RT-qPCR and eCLIP analyses were used to map this m6A modification to the last exon of PTCHD4 mRNA. Further investigation identified IGF2BP1, but not other m6A readers, as responsible for the stabilization and increased abundance of m6A-modified PTCHD4 mRNA. Silencing PTCHD4, a transmembrane protein, enhanced growth arrest and DNA damage in pre-senescent cells and sensitized them to senolysis and apoptosis. Our results indicate that m6A modification of PTCHD4 mRNA increases the production of PTCHD4, a protein associated with senescent cell survival, supporting the notion that regulating m6A modification on specific mRNAs could be exploited to eliminate senescent cells for therapeutic benefit.

Surfaceome analysis of extracellular vesicles from senescent cells uncovers uptake repressor DPP4.

Senescent cells are beneficial for repairing acute tissue damage, but they are harmful when they accumulate in tissues, as occurs with advancing age. Senescence-associated extracellular vesicles (S-EVs) can mediate cell-to-cell communication and export intracellular content to the microenvironment of aging tissues. Here, we studied the uptake of EVs from senescent cells (S-EVs) and proliferating cells (P-EVs) and found that P-EVs were readily taken up by proliferating cells (fibroblasts and cervical cancer cells) while S-EVs were not. We thus investigated the surface proteome (surfaceome) of P-EVs relative to S-EVs derived from cells that had reached senescence via replicative exhaustion, exposure to ionizing radiation, or treatment with etoposide. We found that relative to P-EVs, S-EVs from all senescence models were enriched in proteins DPP4, ANXA1, ANXA6, S10AB, AT1A1, and EPHB2. Among them, DPP4 was found to selectively prevent uptake by proliferating cells, as ectopic overexpression of DPP4 in HeLa cells rendered DPP4-expressing EVs that were no longer taken up by other proliferating cells. We propose that DPP4 on the surface of S-EVs makes these EVs refractory to internalization by proliferating cells, advancing our knowledge of the impact of senescent cells in aging-associated processes.

Neutral or detrimental effects of TREM2 agonist antibodies in preclinical models of Alzheimer's Disease and Multiple Sclerosis.

Human genetics and preclinical studies have identified key contributions of TREM2 to several neurodegenerative conditions, inspiring efforts to modulate TREM2 therapeutically. Here, we characterize the activities of three TREM2 agonist antibodies in multiple mixed-sex mouse models of Alzheimer's Disease (AD) pathology and remyelination. Receptor activation and downstream signaling are explored in vitro, and active dose ranges are determined in vivo based on pharmacodynamic responses from microglia. For mice bearing amyloid-ß (Aß) pathology (PS2APP) or combined Aß and tau pathology (TauPS2APP), chronic TREM2 agonist antibody treatment had limited impact on microglia engagement with pathology, overall pathology burden, or downstream neuronal damage. For mice with demyelinating injuries triggered acutely with lysolecithin, TREM2 agonist antibodies unexpectedly disrupted injury resolution. Likewise, TREM2 agonist antibodies limited myelin recovery for mice experiencing chronic demyelination from cuprizone. We highlight the contributions of dose timing and frequency across models. These results introduce important considerations for future TREM2-targeting approaches.Significance Statement Multiple TREM2 agonist antibodies are investigated in mouse models of Alzheimer's Disease and Multiple Sclerosis. Despite agonism in culture models and after acute dosing in mice, antibodies do not show benefit in overall AD pathology and worsen recovery after demyelination.

miR-616-3p alleviates inflammatory response by targeting C-X-C motif chemokine ligand 5.

C/EBP homologous protein (CHOP) is a key regulator in ER stress-mediated signaling pathway via PERK-dependent unfolded protein response. It has been known that microRNA-616 (miR-616) is produced from the intron of the human DDIT3 gene encoding CHOP and increased by ER stress. However, the role of miR-616 and its targets are not fully addressed yet. Here we try to identify a novel target of miR-616 in human lung epithelial cells. Microarray analysis showed that CXCL5 is the most downregulated gene by miR-616 overexpression in A549 cells. We also found that CXCL5 mRNA and protein levels were significantly reduced by miR-616 mimic in the presence or absence of TNFα, while anti-miR-616 enhanced CXCL5 expression. In addition, miR-616-3p targeting sequence in 3'UTR of CXCL5 was confirmed by luciferase reporter assay suggesting that miR-616-3p directly binds to 3'UTR of CXCL5 and inhibits CXCL5 expression. Finally, we confirmed that conditioned medium from A549 cells treated with TNFα or Streptococcus pneumoniae lysates increased intra-alveolar neutrophil infiltration in a mouse model of pulmonary inflammation, while this induction was significantly reduced in a conditioned medium from cells transfected with miR-616-3p. These results suggest that miR-616-3p can alleviate CXCL5-induced pulmonary inflammatory response via targeting 3'UTR of CXCL5 gene.

Circulating miRNA-4701-3p as a predictive biomarker of cardiovascular disease which induces angiogenesis by inhibition of TOB2.

Angiogenesis is mainly regulated by the delivery of VEGF-dependent signaling to cells. However, the angiogenesis mechanism regulated by VEGF-induced miRNA is still not understood. After VEGF treatment in HUVECs, we screened the changed miRNAs through small-RNA sequencing and found VEGF-induced miR-4701-3p. Furthermore, the GFP reporter gene was used to reveal that TOB2 expression was regulated by miR-4701-3p, and it was found that TOB2 and miR-4701-3p modulation could cause angiogenesis in an in-vitro angiogenic assay. Through the luciferase assay, it was confirmed that the activation of the angiogenic transcription factor MEF2 was regulated by the suppression and overexpression of TOB2 and miR-4701-3p. As a result, MEF2 downstream gene mRNAs that induce angiogenic function were regulated. We used the NCBI GEO datasets to reveal that the expression of TOB2 and MEF2 was significantly changed in cardiovascular disease. Finally, it was confirmed that the expression of circulating miR-4701-3p in the blood of myocardial infarction patients was remarkably increased. In patients with myocardial infarction, circulating miR-4701-3p was increased regardless of age, BMI, and sex, and showed high AUC levels in specificity and sensitivity analysis (AUROC) (AUC = 0.8451, 95 % CI 0.78-0.90). Our data showed TOB2-mediated modulation of MEF2 and its angiogenesis by VEGF-induced miR-4701-3p in vascular endothelial cells. In addition, through bioinformatics analysis using GEO data, changes in TOB2 and MEF2 were revealed in cardiovascular disease. We suggest that circulating miR-4701-3p has high potential as a biomarker for myocardial infarction.

Role of oxygen reserve index monitoring in patients undergoing robot-assisted radical prostatectomy: a retrospective study.

PURPOSE: Robot-assisted radical prostatectomy (RARP) is a common surgical procedure for the treatment of prostate cancer. Although beneficial, it can lead to intraoperative hypoxia due to high-pressure pneumoperitoneum and Trendelenburg position. This study explored the use of oxygen reserve index (ORi) to monitor and predict hypoxia during RARP. METHODS: A retrospective analysis was conducted on 329 patients who underwent RARP at the Seoul National University Bundang Hospital between July 2021 and March 2023. Various pre- and intraoperative variables were collected, including ORi values. The relationship between ORi values and hypoxia occurrence was assessed using receiver operating characteristic curves and logistic regression analysis. RESULTS: Intraoperative hypoxia occurred in 18.8% of the patients. The receiver operating characteristic curve showed a satisfactory area under the curve of 0.762, with the ideal ORi cut-off value for predicting hypoxia set at 0.16. Sensitivity and specificity were 64.5% and 75.7%, respectively. An ORi value of < 0.16 and a higher body mass index were identified as independent risk factors of hypoxia during RARP. CONCLUSIONS: ORi monitoring provides a non-invasive approach to predict intraoperative hypoxia during RARP, enabling early management. Additionally, the significant relationship between a higher body mass index and hypoxia underscores the importance of individualized patient assessment.

Percutaneous insertion of long-covered biliary stents in patients with malignant duodenobiliary stricture.

OBJECTIVE: To investigate the technical feasibility, safety, and efficacy of a long-covered biliary stent in patients with malignant duodenobiliary stricture. METHODS: This retrospective study enrolled 57 consecutive patients (34 men, 23 women; mean age, 64 years; range, 32-85 years) who presented with malignant duodenobiliary stricture between February 2019 and November 2020. All patients were treated with a long (18 or 23 cm)-covered biliary stent. RESULTS: The biliary stent deployment was technically successful in all 57 patients. The overall adverse event rate was 17.5% (10 of 57 patients). Successful internal drainage was achieved in 55 (96.5%) of 57 patients. The median patient survival and stent patency times were 99 days (95% confidence interval [CI], 58-140 days) and 73 days (95% CI, 60-86 days), respectively. Fourteen (25.5%) of the fifty-five patients presented with biliary stent dysfunction due to sludge (n = 11), tumor overgrowth (n = 1), collapse of the long biliary stent by a subsequently inserted additional duodenal stent (n = 1), or rapidly progressed duodenal cancer (n = 1). A univariate Cox proportional hazards model did not reveal any independent predictor of biliary stent patency. CONCLUSIONS: Percutaneous insertion of a subsequent biliary stent was technically feasible after duodenal stent insertion. Percutaneous insertion of a long-covered biliary stent was safe and effective in patients with malignant duodenobiliary stricture. CLINICAL RELEVANCE STATEMENT: In patients with malignant duodenobiliary stricture, percutaneous insertion of a long-covered biliary stent was safe and effective regardless of duodenal stent placement. KEY POINTS: • Percutaneous insertion of long-covered biliary stents in patients with malignant duodenobiliary stricture is a safe and effective procedure. • Biliary stent deployment was technically successful in all 57 patients and successful internal drainage was achieved in 55 (96.5%) of 57 patients. • The median patient survival and stent patency times were 99 days and 73 days, respectively, after placement of a long-covered biliary stent in patients with duodenobiliary stricture.

Prognostic Implications of N-Terminal Pro-B-Type Natriuretic Peptide in Patients With Non-ST-Elevation Myocardial Infarction.

BACKGROUND: Limited data exist regarding the prognostic implications of N-terminal pro-B-type natriuretic peptide (NT-proBNP) in patients with non-ST-elevation myocardial infarction (NSTEMI) who undergo percutaneous coronary intervention (PCI).Methods and Results: Of 13,104 patients in the nationwide Korea Acute Myocardial Infarction Registry-National Institutes of Health, 3,083 patients with NSTEMI who underwent PCI were included in the present study. The primary endpoint was major adverse cardiovascular events (MACE) at 3 years, a composite of all-cause death, recurrent myocardial infarction, unplanned repeat revascularization, and admission for heart failure. NT-proBNP was measured at the time of initial presentation for the management of NSTEMI, and patients were divided into a low (<700 pg/mL; n=1,813) and high (≥700 pg/mL; n=1,270) NT-proBNP group. The high NT-proBNP group had a significantly higher risk of MACE, driven primarily by a higher risk of cardiac death or admission for heart failure. These results were consistent after confounder adjustment by propensity score matching and inverse probability weighting analysis. CONCLUSIONS: In patients with NSTEMI who underwent PCI, an initial elevated NT-proBNP concentration was associated with higher risk of MACE at 3 years, driven primarily by higher risks of cardiac death or admission for heart failure. These results suggest that the initial NT-proBNP concentration may have a clinically significant prognostic value in NSTEMI patients undergoing PCI.

Analysis of PM2.5 inorganic and organic constituents to resolve contributing sources in Seoul, South Korea and Beijing, China and their possible associations with cytokine IL-8.

China and South Korea are the most polluted countries in East Asia due to significant urbanization and extensive industrial activities. As neighboring countries, collaborative management plans to maximize public health in both countries can be helpful in reducing transboundary air pollution. To support such planning, PM2.5 inorganic and organic species were determined in simultaneously collected PM2.5 integrated filters. The resulting data were used as inputs to positive matrix factorization, which identified nine sources at the ambient air monitoring sites in both sites. Secondary nitrate, secondary sulfate/oil combustion, soil, mobile, incinerator, biomass burning, and secondary organic carbon (SOC) were found to be sources at both sampling sites. Industry I and II were only identified in Seoul, whereas combustion and road dust sources were only identified in Beijing. A subset of samples was selected for exposure assessment. The expression levels of IL-8 were significantly higher in Beijing (167.7 pg/mL) than in Seoul (72.7 pg/mL). The associations between the PM2.5 chemical constituents and its contributing sources with PM2.5-induced inflammatory cytokine (interleukin-8, IL-8) levels in human bronchial epithelial cells were investigated. For Seoul, the soil followed by the secondary nitrate and the biomass burning showed increase with IL-8 production. However, for the Beijing, the secondary nitrate exhibited the highest association with IL-8 production and SOC and biomass burning showed modest increase with IL-8. As one of the highest contributing sources in both cities, secondary nitrate showed an association with IL-8 production. The soil source having the strongest association with IL-8 production was found only for Seoul, whereas SOC showed a modest association only for Beijing. This study can provide the scientific basis for identifying the sources to be prioritized for control to provide effective mitigation of particulate air pollution in each city and thereby improve public health.

Effect of COVID-19 response work experience on turnover intention among employees of dedicated COVID-19 hospitals in Seoul.

BACKGROUND: According to previous studies, stress and job burnout among medical personnel increased during the COVID-19 pandemic. This study analyzed the effect of the experience of COVID-19 response work on the intention of municipal hospital staffs to leave their workplaces during the pandemic. METHODS: The 3556 employees who had worked for more than 1 year at one of the eight Seoul Municipal Hospitals that either provided inpatient treatment for quarantined COVID-19 patients or operated as screening clinics were taken as the study population. In total, 1227 employees completed a web or mobile survey between October 21 and November 18, 2020. A chi-squared test was performed to confirm the difference in the distribution of turnover intention depending on whether the employees performed COVID-19 response tasks. Multiple logistic regression analyses were performed to determine the factors that affected the intention to leave. RESULTS: Of the 1227 respondents, 761 (62.0%) were frontline workers who were the first line of response to COVID-19. Experience with COVID-19 response tasks (OR = 1.59, p = 0.003) was significantly associated with the intention to leave. Additionally, the probability of turnover intention was significantly higher among workers aged 20-29 years (OR = 2.11, p = 0.038) and 40-49 years (OR = 1.57, p = 0.048), unmarried individuals (OR = 1.66, p = 0.005), doctors (OR = 2.41, p = 0.010), nurses (OR = 1.59, p = 0.036), and technical staff members (OR = 2.22, p = 0.009). High turnover intention was found among those who experienced high levels of burnout (OR = 2.03, p < 0.001) and those working in non-directly managed municipal hospitals (OR = 1.87, p = 0.018). CONCLUSION: Employees directly involved in COVID-19 response work displayed higher turnover intention. Various personal, job, and organizational factors significantly influenced employees' intentions to leave their positions in dedicated COVID-19 hospitals. These findings suggest the necessity of introducing management programs to aid workers who have experienced sudden changes in their duties and loss of autonomy while performing COVID-19 response tasks.

Comparison of Volatile Anesthetics Versus Propofol on Postoperative Cognitive Function After Cardiac Surgery: A Systematic Review and Meta-analysis.

OBJECTIVE: To compare the effects of volatile anesthetics and propofol on neurocognitive function after cardiac surgery. DESIGN: A systematic review and meta-analysis of randomized controlled trials. SETTING: A literature search of PubMed, EMBASE, CENTRAL, CINAHL, Scopus, and Web of Science databases was conducted. PARTICIPANTS: A total of 10 randomized controlled trials comparing volatile anesthetics and propofol in cardiac surgery were included in the study. INTERVENTIONS: The standardized mean difference and risk ratio were calculated to estimate pooled effect sizes. MEASUREMENTS AND MAIN RESULTS: The primary outcome was the postoperative neurocognitive function score, and the secondary outcome was the incidence of delirium after cardiac surgery. The analysis did not show significant differences in postoperative neurocognitive function scores (standardized mean difference -0.06, 95% CI -0.81-0.69; p = 0.879). The incidences of delirium (risk ratio 1.10, 95% CI 0.81-1.50) between the volatile anesthetics and propofol groups were not significant (p = 0.533). CONCLUSIONS: Unlike noncardiac surgery, there are no differences between volatile anesthetics and propofol regarding postoperative neurocognitive dysfunction after cardiac surgery.

The N-terminal cysteine is a dual sensor of oxygen and oxidative stress.

Cellular homeostasis requires the sensing of and adaptation to intracellular oxygen (O2) and reactive oxygen species (ROS). The Arg/N-degron pathway targets proteins that bear destabilizing N-terminal residues for degradation by the proteasome or via autophagy. Under normoxic conditions, the N-terminal Cys (Nt-Cys) residues of specific substrates can be oxidized by dioxygenases such as plant cysteine oxidases and cysteamine (2-aminoethanethiol) dioxygenases and arginylated by ATE1 R-transferases to generate Arg-CysO2(H) (R-CO2). Proteins bearing the R-CO2 N-degron are targeted via Lys48 (K48)-linked ubiquitylation by UBR1/UBR2 N-recognins for proteasomal degradation. During acute hypoxia, such proteins are partially stabilized, owing to decreased Nt-Cys oxidation. Here, we show that if hypoxia is prolonged, the Nt-Cys of regulatory proteins can be chemically oxidized by ROS to generate Arg-CysO3(H) (R-CO3), a lysosomal N-degron. The resulting R-CO3 is bound by KCMF1, a N-recognin that induces K63-linked ubiquitylation, followed by K27-linked ubiquitylation by the noncanonical N-recognin UBR4. Autophagic targeting of Cys/N-degron substrates is mediated by the autophagic N-recognin p62/SQTSM-1/Sequestosome-1 through recognition of K27/K63-linked ubiquitin (Ub) chains. This Cys/N-degron-dependent reprogramming in the proteolytic flux is important for cellular homeostasis under both chronic hypoxia and oxidative stress. A small-compound ligand of p62 is cytoprotective under oxidative stress through its ability to accelerate proteolytic flux of K27/K63-ubiquitylated Cys/N-degron substrates. Our results suggest that the Nt-Cys of conditional Cys/N-degron substrates acts as an acceptor of O2 to maintain both O2 and ROS homeostasis and modulates half-lives of substrates through either the proteasome or lysosome by reprogramming of their Ub codes.

Sinonasal seromucinous hamartoma: a single institution case series combined with a narrative review of the literature.

PURPOSE: This study aimed to investigate the clinical and histopathological characteristics of sinonasal seromucinous hamartomas (SHs). METHODS: Eight patients with sinonasal SH and treated at a tertiary hospital between November 2005 and September 2023 were included. Additionally, a systematic review of published articles was conducted, analyzing 48 cases of SH described in the literature. RESULTS: Among the eight patients treated at our institution, tumors originated from the posterior nasal cavity in four patients and middle turbinate and middle meatus were the primary origin in two patients each. Coexistence of inflammatory nasal polyps (NPs) was observed in four cases. Histopathologically, four patients exhibited focal respiratory epithelial adenomatoid hamartoma (REAH) features, and low-grade dysplasia was found in one patient. A combined analysis with previous literature revealed that 46.3% of all cases originated in the anterior nasal cavity. The proportions of cases accompanied by NPs and those with focal REAH features were 20.5% and 39.1%, respectively. Additionally, the frequencies of cases exhibiting dysplastic features (5.4%) and recurrence (2.1%) were low. Remarkably, tumors originating from the anterior region tended to have a higher frequency of dysplasia than those originating from the posterior region, although this difference was not statistically significant (p = 0.0996). CONCLUSION: Patients with sinonasal SH showed favorable treatment outcomes following surgical resection. Focal REAH features and accompanying NPs were frequently observed. A substantial proportion of cases originate in the anterior nasal cavity, and these tumors may exhibit a high tendency for dysplasia.

Y-Box Binding Protein 1: Unraveling the Multifaceted Role in Cancer Development and Therapeutic Potential.

Y-box binding protein 1 (YBX1), a member of the Cold Shock Domain protein family, is overexpressed in various human cancers and is recognized as an oncogenic gene associated with poor prognosis. YBX1's functional diversity arises from its capacity to interact with a broad range of DNA and RNA molecules, implicating its involvement in diverse cellular processes. Independent investigations have unveiled specific facets of YBX1's contribution to cancer development. This comprehensive review elucidates YBX1's multifaceted role in cancer across cancer hallmarks, both in cancer cell itself and the tumor microenvironment. Based on this, we proposed YBX1 as a potential target for cancer treatment. Notably, ongoing clinical trials addressing YBX1 as a target in breast cancer and lung cancer have showcased its promise for cancer therapy. The ramp up in in vitro research on targeting YBX1 compounds also underscores its growing appeal. Moreover, the emerging role of YBX1 as a neural input is also proposed where the high level of YBX1 was strongly associated with nerve cancer and neurodegenerative diseases. This review also summarized the up-to-date advanced research on the involvement of YBX1 in pancreatic cancer.

Del-1 Plays a Protective Role against COPD Development by Inhibiting Inflammation and Apoptosis.

Neutrophilic inflammation is a prominent feature of chronic obstructive pulmonary disease (COPD). Developmental endothelial locus-1 (Del-1) has been reported to limit excessive neutrophilic inflammation by inhibiting neutrophil adhesion to the vascular endothelial cells. However, the effects of Del-1 in COPD are not known. We investigated the role of Del-1 in the pathogenesis of COPD. Del-1 protein expression was decreased in the lungs of COPD patients, especially in epithelial cells and alveolar macrophages. In contrast to human lung tissue, Del-1 expression was upregulated in lung tissue from mice treated with cigarette smoke extracts (CSE). Overexpression of Del-1 significantly suppressed IL-8 release and apoptosis in CSE-treated epithelial cells. In contrast, knockdown of Del-1 enhanced IL-8 release and apoptosis. In macrophages, overexpression of Del-1 significantly suppressed inflammatory cytokine release, and knockdown of Del-1 enhanced it. This anti-inflammatory effect was mediated by inhibiting the phosphorylation and acetylation of NF-κB p65. Nuclear factor erythroid 2-related factor 2 (Nrf2) activators, such as quercetin, resveratrol, and sulforaphane, increased Del-1 in both cell types. These results suggest that Del-1, mediated by Nrf2, plays a protective role against the pathogenesis of COPD, at least in part through anti-inflammatory and anti-apoptotic effects.

ER Stress-Activated HSF1 Governs Cancer Cell Resistance to USP7 Inhibitor-Based Chemotherapy through the PERK Pathway.

Ubiquitin-specific protease 7 inhibitors (USP7i) are considered a novel class of anticancer drugs. Cancer cells occasionally become insensitive to anticancer drugs, known as chemoresistance, by acquiring multidrug resistance, resulting in poor clinical outcomes in patients with cancer. However, the chemoresistance of cancer cells to USP7i (P22077 and P5091) and mechanisms to overcome it have not yet been investigated. In the present study, we generated human cancer cells with acquired resistance to USP7i-induced cell death. Gene expression profiling showed that heat stress response (HSR)- and unfolded protein response (UPR)-related genes were largely upregulated in USP7i-resistant cancer cells. Biochemical studies showed that USP7i induced the phosphorylation and activation of heat shock transcription factor 1 (HSF1), mediated by the endoplasmic reticulum (ER) stress protein kinase R-like ER kinase (PERK) signaling pathway. Inhibition of HSF1 and PERK significantly sensitized cancer cells to USP7i-induced cytotoxicity. Our study demonstrated that the ER stress-PERK axis is responsible for chemoresistance to USP7i, and inhibiting PERK is a potential strategy for improving the anticancer efficacy of USP7i.

Unraveling the Role of Ras Homolog Enriched in Brain (Rheb1 and Rheb2): Bridging Neuronal Dynamics and Cancer Pathogenesis through Mechanistic Target of Rapamycin Signaling.

Ras homolog enriched in brain (Rheb1 and Rheb2), small GTPases, play a crucial role in regulating neuronal activity and have gained attention for their implications in cancer development, particularly in breast cancer. This study delves into the intricate connection between the multifaceted functions of Rheb1 in neurons and cancer, with a specific focus on the mTOR pathway. It aims to elucidate Rheb1's involvement in pivotal cellular processes such as proliferation, apoptosis resistance, migration, invasion, metastasis, and inflammatory responses while acknowledging that Rheb2 has not been extensively studied. Despite the recognized associations, a comprehensive understanding of the intricate interplay between Rheb1 and Rheb2 and their roles in both nerve and cancer remains elusive. This review consolidates current knowledge regarding the impact of Rheb1 on cancer hallmarks and explores the potential of Rheb1 as a therapeutic target in cancer treatment. It emphasizes the necessity for a deeper comprehension of the molecular mechanisms underlying Rheb1-mediated oncogenic processes, underscoring the existing gaps in our understanding. Additionally, the review highlights the exploration of Rheb1 inhibitors as a promising avenue for cancer therapy. By shedding light on the complicated roles between Rheb1/Rheb2 and cancer, this study provides valuable insights to the scientific community. These insights are instrumental in guiding the identification of novel targets and advancing the development of effective therapeutic strategies for treating cancer.

Temporary Ureter Occlusion with Simultaneous Urinary Diversion via a Single-Access Route Using a 4-French Balloon Catheter and a Pigtail Nephrostomy Drainage Catheter.

Background and Objectives: This study evaluated the efficacy and safety of temporary ureteral occlusion combined with urinary diversion using a single-access route created by inserting a balloon catheter through a pigtail nephrostomy drainage catheter. With this approach, we aimed to offer an alternative for patients with ureteral leaks who are suboptimal surgical candidates. Materials and Methods: This retrospective study included nine patients (eight of which were bilateral cases and one was unilateral, totaling seventeen cases) who underwent the surgery between September 2023 and March 2024. The method involved gaining percutaneous access to the pelvicalyceal system, inserting a 4-French Fogarty balloon catheter through a pigtail nephrostomy catheter, and inflating the balloon at the proximal or mid-ureter. Results: All 17 cases achieved technical successful with no major complications. The procedure effectively relieved symptoms associated with urinary leakage in most patients. However, the significant deflation of the balloon catheter occurred in five cases (29.4%), with three (17.6%) experiencing complete deflation. In these five cases, the final balloon size was 5.81 mm (range: 0-8.9 mm), confirming a 25.0% decrease in size from pre- to post-procedure. Ureteral occlusion was 28.3 d long on average (range: 8-57 d). All patients experienced symptom relief during temporary ureteral occlusion. Except for two patients lost to follow-up, three patients showed symptom improvement with only PCN and four patients underwent surgical closure of the fistula tract before or after balloon catheter removal. Conclusions: This study confirms that this approach is safe and effective.

Deep Learning for Estimating Lung Capacity on Chest Radiographs Predicts Survival in Idiopathic Pulmonary Fibrosis.

Background Total lung capacity (TLC) has been estimated with use of chest radiographs based on time-consuming methods, such as planimetric techniques and manual measurements. Purpose To develop a deep learning-based, multidimensional model capable of estimating TLC from chest radiographs and demographic variables and validate its technical performance and clinical utility with use of multicenter retrospective data sets. Materials and Methods A deep learning model was pretrained with use of 50 000 consecutive chest CT scans performed between January 2015 and June 2017. The model was fine-tuned on 3523 pairs of posteroanterior chest radiographs and plethysmographic TLC measurements from consecutive patients who underwent pulmonary function testing on the same day. The model was tested with multicenter retrospective data sets from two tertiary care centers and one community hospital, including (a) an external test set 1 (n = 207) and external test set 2 (n = 216) for technical performance and (b) patients with idiopathic pulmonary fibrosis (n = 217) for clinical utility. Technical performance was evaluated with use of various agreement measures, and clinical utility was assessed in terms of the prognostic value for overall survival with use of multivariable Cox regression. Results The mean absolute difference and within-subject SD between observed and estimated TLC were 0.69 L and 0.73 L, respectively, in the external test set 1 (161 men; median age, 70 years [IQR: 61-76 years]) and 0.52 L and 0.53 L in the external test set 2 (113 men; median age, 63 years [IQR: 51-70 years]). In patients with idiopathic pulmonary fibrosis (145 men; median age, 67 years [IQR: 61-73 years]), greater estimated TLC percentage was associated with lower mortality risk (adjusted hazard ratio, 0.97 per percent; 95% CI: 0.95, 0.98; P < .001). Conclusion A fully automatic, deep learning-based model estimated total lung capacity from chest radiographs, and the model predicted survival in idiopathic pulmonary fibrosis. © RSNA, 2022 Online supplemental material is available for this article. See also the editorial by Sorkness in this issue.