The Relationship Between Fracture and Mortality in a Chinese Maintenance Hemodialysis Patients Cohort.

Background: Patients on maintenance hemodialysis have an increased risk of fracture. However, the relationship between fracture and poor prognosis is not clear. Methods: A total of 182 maintenance hemodialysis patients were enrolled in the study. The relationship between fracture and poor prognosis (cardiovascular events, stroke, malignancy and 5-year all-cause mortality) were analyzed. Results: 21 of 182 patients had a history of fracture at the time of enrollment. 26 patients had a new fracture after enrollment. A total of 57 fractures occurred in 47 patients, the most common fracture site was the rib. Patients with fracture group had a higher proportion of elderly and female, higher serum phosphorus and B-type natriuretic peptide and lower hemoglobin, albumin, and potassium compared with those without fracture. Age (OR=3.809, 95% CI: 1.064-8.966, p=0.038), hemoglobin (OR=0.961, 95% CI: 0.925-0.997, p=0.035), and serum phosphorus (OR=3.325, 95% CI:1.104-10.019, p=0.033) were the independent risk factors of new fractures in MHD patients. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture (p<0.05). But there was no significant difference in the incidence of acute myocardial infarction or stroke. Conclusion: 25.8% of maintenance hemodialysis patients had at least one fracture, with rib fractures accounting for the highest proportion. Age, hemoglobin and serum phosphorus were the independent risk factors of new fractures. The incidence of malignancy and 5-year all-cause mortality in patients with fracture was higher than those without fracture, but there was no significant difference in the incidence of acute myocardial infarction and stroke.

To determine the incidence of fractures in hemodialysis patients, we conducted this single center, prospective observational study. 182 patients were enrolled. We also recorded the 5-year incidence of acute myocardial infarction(AMI), stroke, malignancy, and mortality. Our results showed that the incidence of fracture in hemodialysis patients was 25.8%. The most common fracture site was the rib. There were significant statistical differences in age, gender, hemoglobin, serum albumin, B-type natriuretic peptide, potassium and phosphorus between patients with and without fractures. Logistic regression analysis suggested that advanced age, anaemia and hyperphosphatemia were independent risk factors for new fractures in hemodialysis patients. We followed 182 patients for 5 years and recorded the incidence of stroke, AMI and malignancy. The rates of AMI and stroke did not differ significantly between the two groups. However, the incidence of malignancy in patients with fractures is significantly higher than that in patients without fractures. In our study, a total of 74 patients died, including 24 deaths in the fracture group and 50 deaths in the non-fracture group. The main causes of death in 74 cases were cardiovascular events. Our study provides some insight into the association between fractures and poor outcomes in hemodialysis patients.

Dual-energy CT quantitative parameters to evaluate occult peritoneal metastasis in advanced gastric cancer preoperatively.

PURPOSE: To explore whether dual-energy CT (DECT) quantitative parameters could provide analytic value for the diagnosis of patients with occult peritoneal metastasis (OPM) in advanced gastric cancer preoperatively. MATERIALS AND METHODS: This retrospective study included 219 patients with advanced gastric cancer and DECT scans. The patient's clinical data and DECT related iodine concentration (IC) parameters and effective atomic number (Zeff) were collated and analyzed among noun-peritoneal metastasis (NPM), OPM and radiologically peritoneal metastasis (RPM) groups. The predictive performance of the DECT parameters was compared with that of the conventional CT features and clinical characteristics through evaluating area under curve of the precision-recall (AUC-PR), F1 score, balanced accuracy, sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV). RESULTS: Borrmann IV type diagnosed on CT and serum tumor indicator CA125 index were statistically different between the NPM and OPM groups. DECT parameters included IC, normalized IC (NIC), and Zeff of PM group were lower than the NPM group. The DECT predictive nomogram combined three independent DECT parameters produced a better diagnostic performance than the conventional CT feature Borrmann IV type and serum CA125 index in AUC-PR with 0.884 vs 0.368 vs 0.189, but similar to the combined indicator which was based on the DECT parameters, the conventional CT feature, and serum CA125 index in AUC-PR with 0.884 vs 0.918. CONCLUSION: The lower quantitative NIC, IC ratio, and Zeff on DECT was associated with peritoneal metastasis in advanced gastric cancer and was promising to identify patients with OPM noninvasively.

Effect of glycotoxicity and lipotoxicity on carbohydrate antigen 19 - 9 in the patients with diabetes.

OBJECTIVES: In comparison to the subjects without diabetes, a greater concentration of serum carbohydrate antigen 19 - 9 (CA 19 - 9) was observed in the subjects with diabetes. Nevertheless, since the occurrence of abnormal CA 19 - 9 is not widespread among the whole diabetic population, this phenomenon has not attracted enough attention. The prevalence of abnormal CA 19 - 9 in hospitalized patients with diabetes was the focus of our research. METHOD: A total of 385 subjects with diabetes and 200 controls were enrolled and all had been tested the CA19-9 levels. Cases of cancers were excluded through examination and followup for 1 year. RESULTS: We found that the rate of patients with abnormal CA19-9 level was 8.3%. The rate of patients with abnormal CA19-9 level was 14.0% in the HbA1c ≥ 9% group, and 3.0% in the HbA1c < 9% group, 2.5% in the control group. There was no significant difference in the HbA1c < 9% group and the control group. A significant correlation between serum CA19-9 and both HbA1c and total cholesterol was observed, yet no difference in CRP level was observed between subjects with normal CA19-9 level and subjects with abnormal CA19-9 level. However, a significant difference in fasting C-peptide levels was observed between the two groups, p = 0.039. CONCLUSION: The percentage of patients with diabetes exhibiting elevated CA19-9 level is 14% in the HbA1c ≥ 9% diabetic patients, much higher than expected. The underlying mechanism may be related to islet injury caused by glycotoxicity and lipotoxicity. STRENGTHS AND LIMITATIONS OF THE STUDY: We studied the rate of hospitalized diabetic patients with elevated CA 19 - 9 which were characterized with poorly controlled blood glucose. We found that the elevation of CA 19 - 9 was unexpectedly high in diabetic inpatients without development to cancer. The limitation of this study is that the underlying mechanism is not sufficiently studied.

Computed tomography radiogenomics: A potential tool for prediction of molecular subtypes in gastric stromal tumor.

BACKGROUND: Preoperative knowledge of mutational status of gastrointestinal stromal tumors (GISTs) is essential to guide the individualized precision therapy. AIM: To develop a combined model that integrates clinical and contrast-enhanced computed tomography (CE-CT) features to predict gastric GISTs with specific genetic mutations, namely KIT exon 11 mutations or KIT exon 11 codons 557-558 deletions. METHODS: A total of 231 GIST patients with definitive genetic phenotypes were divided into a training dataset and a validation dataset in a 7:3 ratio. The models were constructed using selected clinical features, conventional CT features, and radiomics features extracted from abdominal CE-CT images. Three models were developed: ModelCT sign, modelCT sign + rad, and model CTsign + rad + clinic. The diagnostic performance of these models was evaluated using receiver operating characteristic (ROC) curve analysis and the Delong test. RESULTS: The ROC analyses revealed that in the training cohort, the area under the curve (AUC) values for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic for predicting KIT exon 11 mutation were 0.743, 0.818, and 0.915, respectively. In the validation cohort, the AUC values for the same models were 0.670, 0.781, and 0.811, respectively. For predicting KIT exon 11 codons 557-558 deletions, the AUC values in the training cohort were 0.667, 0.842, and 0.720 for modelCT sign, modelCT sign + rad, and modelCT sign + rad + clinic, respectively. In the validation cohort, the AUC values for the same models were 0.610, 0.782, and 0.795, respectively. Based on the decision curve analysis, it was determined that the modelCT sign + rad + clinic had clinical significance and utility. CONCLUSION: Our findings demonstrate that the combined modelCT sign + rad + clinic effectively distinguishes GISTs with KIT exon 11 mutation and KIT exon 11 codons 557-558 deletions. This combined model has the potential to be valuable in assessing the genotype of GISTs.

Deep learning-accelerated T2WI: image quality, efficiency, and staging performance against BLADE T2WI for gastric cancer.

PURPOSE: The purpose of our study is to investigate image quality, efficiency, and diagnostic performance of a deep learning-accelerated single-shot breath-hold (DLSB) against BLADE for T2-weighted MR imaging (T2WI) for gastric cancer (GC). METHODS: 112 patients with GCs undergoing gastric MRI were prospectively enrolled between Aug 2022 and Dec 2022. Axial DLSB-T2WI and BLADE-T2WI of stomach were scanned with same spatial resolution. Three radiologists independently evaluated the image qualities using a 5-scale Likert scales (IQS) in terms of lesion delineation, gastric wall boundary conspicuity, and overall image quality. Signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) were calculated in measurable lesions. T staging was conducted based on the results of both sequences for GC patients with gastrectomy. Pairwise comparisons between DLSB-T2WI and BLADE-T2WI were performed using the Wilcoxon signed-rank test, paired t-test, and chi-squared test. Kendall's W, Fleiss' Kappa, and intraclass correlation coefficient values were used to determine inter-reader reliability. RESULTS: Against BLADE, DLSB reduced total acquisition time of T2WI from 495 min (mean 4:42 per patient) to 33.6 min (18 s per patient), with better overall image quality that produced 9.43-fold, 8.00-fold, and 18.31-fold IQS upgrading against BALDE, respectively, in three readers. In 69 measurable lesions, DLSB-T2WI had higher mean SNR and higher CNR than BLADE-T2WI. Among 71 patients with gastrectomy, DLSB-T2WI resulted in comparable accuracy to BLADE-T2WI in staging GCs (P > 0.05). CONCLUSIONS: DLSB-T2WI demonstrated shorter acquisition time, better image quality, and comparable staging accuracy, which could be an alternative to BLADE-T2WI for gastric cancer imaging.

Utility of Combined Use of Imaging Features From Abdominopelvic CT and CA 125 to Identify Presence of CT Occult Peritoneal Metastases in Advanced Gastric Cancer.

OBJECTIVE: The purpose of this study is to identify the presence of occult peritoneal metastasis (OPM) in patients with advanced gastric cancer (AGC) by using clinical characteristics and abdominopelvic computed tomography (CT) features. METHODS: This retrospective study included 66 patients with OPM and 111 patients without peritoneal metastasis (non-PM [NPM]) who underwent preoperative contrast-enhanced CT between January 2020 and December 2021. Occult PMs means PMs that are missed by CT but later diagnosed by laparoscopy or laparotomy. Patients with NPM means patients have neither PM nor other distant metastases, indicating there is no evidence of distant metastases in patients with AGC. Patients' clinical characteristics and CT features such as tumor marker, Borrmann IV, enhancement patterns, and pelvic ascites were observed by 2 experienced radiologists. Computed tomography features and clinical characteristics were combined to construct an indicator for identifying the presence of OPM in patients with AGC based on a logistic regression model. Receiver operating characteristic curves and the area under the receiver operating characteristic curve (AUC) were generated to assess the diagnostic performance of the combined indicator. RESULTS: Four independent predictors (Borrmann IV, pelvic ascites, carbohydrate antigen 125, and normalized arterial CT value) differed significantly between OPM and NPM and performed outstandingly in distinguishing patients with OPM from those without PM (AUC = 0.643-0.696). The combined indicator showed a higher AUC value than the independent risk factors (0.820 vs 0.643-0.696). CONCLUSIONS: The combined indicator based on abdominopelvic CT features and carbohydrate antigen 125 may assist clinicians in identifying the presence of CT OPMs in patients with AGC.

New Analogues of Amides and Quinolinones Produced by Streptomyces sp. YIM S01983.

Streptomide (1), a new amide analogue, streptomynone (2), a new quinolinone, and ten known compounds including three aliphatic acids (3-5), two amides (6-7), four cyclic dipeptides (8-11), and an adenosine (12) were isolated from the fermentation broth of Streptomyces sp. YIM S01983 isolated from a sediment sample collected in Bendong Village, Huadong Town, Chuxiong, China. Their structures were determined by analysis of the 1D/2D-NMR and HR-ESI-MS spectra. Compound 12 presented weak antimicrobial activities against Candida albicans and Aligenes faecalis (MIC=64 µg/mL). Compounds 7 and 12 showed weak cytotoxic activity against MHCC97H.

Role of protein degradation systems in colorectal cancer.

Protein degradation is essential for maintaining protein homeostasis. The ubiquitin‒proteasome system (UPS) and autophagy-lysosome system are the two primary pathways responsible for protein degradation and directly related to cell survival. In malignant tumors, the UPS plays a critical role in managing the excessive protein load caused by cancer cells hyperproliferation. In this review, we provide a comprehensive overview of the dual roles played by the UPS and autolysosome system in colorectal cancer (CRC), elucidating their impact on the initiation and progression of this disease while also highlighting their compensatory relationship. Simultaneously targeting both protein degradation pathways offers new promise for enhancing treatment efficacy against CRC. Additionally, apoptosis is closely linked to ubiquitination and autophagy, and caspases degrade proteins. A thorough comprehension of the interplay between various protein degradation pathways is highly important for clarifying the mechanism underlying the onset and progression of CRC.

Validation of the IMPEDE VTE score for prediction of venous thromboembolism in Chinese patients with multiple myeloma: A single-center retrospective cohort study.

Multiple myeloma (MM) significantly increases the risk of venous thromboembolism (VTE) within 6 months of treatment initiation. The IMPEDE VTE score is a VTE risk prediction model which is recently incorporated into the National Comprehensive Cancer Network (NCCN) guidelines, but it lacks validation among Asians, including Chinese MM patients. We performed a retrospective chart review of 405 Chinese with newly diagnosed MM who started therapy at Beijing Jishuitan Hospital between April 2013 to October 2022. The 6-month cumulative incidence of VTE was 3.8 % (95 % CI:1.6-7.6), 8.6 % (95 % CI: 5.3-21.9) and 40.5 % (95 % CI: 24.9-55.7) in the low-, intermediate- and high-risk groups (P < 0.001), respectively. The C-statistic of the IMPEDE VTE scores for predicting VTE within 6 months of treatment initiation was 0.74 (95 % CI: 0.65-0.83). Of note, in this single-center cohort study, we propose that the anticoagulant LMWH may be more effective than the antiplatelet aspirin in potentially preventing VTE in newly diagnosed MM patients. Our findings suggest that the IMPEDE VTE score is a valid evidence-based risk stratification tool in Chinese patients with newly diagnosed MM.

Reconstruction of the Large Frontal Sinus Defect With the Small Supporting Bone Pieces in Neurosurgical Anterior Skull Base Surgery.

BACKGROUND: Large defects of frontal sinus (FS) might be difficult to manage effectively. Mismanagement of the large defects could lead to serious postoperative complications in anterior skull base surgery. This study introduces a simple and reliable method applying small supporting bone pieces to cover or insert into large FS defects, then the large defect of FS was transformed into the small defects which was sealed by bone wax successfully. METHODS: Eleven patients underwent anterior skull base surgery for lesions or aneurysms, with the reconstruction of large FS defects by small supporting bone pieces. During craniotomy, mild violations of the FS mucosa were spared and sterilized, while severe violations required mucosal removal. Small supporting bone pieces were obtained from the inner plate of the bone flap and carefully covered or inserted into the large defects. The large defects were transformed into some small ones, which could be sealed effectively by bone wax. Demographic, intraoperative, and postoperative complication data were collected. RESULTS: Four patients had severe mucosal violations requiring removal, while 7 had mild violations sparing the mucosa. All underwent effective reconstruction with small supporting bone pieces. Median follow-up was 6 months. All cases showed effective FS morphology reconstruction, with no FS-related complications. CONCLUSIONS: Applying the small supporting bone pieces for large FS defect reconstruction can restore the FS morphology, preserve physiological function, and avoid postoperative complications.

Contrast-enhanced ultrasound of polyp malignant transformation with multiple metastases in a patient with Peutz-Jeghers syndrome.

Multi-systemic metastasis in patients with Peutz-Jeghers syndrome (PJS) is very rare, and there are nearly no relevant imaging reports, especially in contrast-enhanced ultrasound (CEUS). We present here a 40-year-old male patient who underwent several partial small bowel resections and endoscopic polypectomy for intestinal polyps. After reviewing the patient's clinical diagnosis and treatment process, CEUS with sulfur hexafluoride microbubbles (SonoVue, Bracco, Milan, Italy) in the liver and gastrointestinal tract was performed. We imaged multiple abnormal masses with sonographic features consistent with malignancies. Combined with other imaging examinations and 18 gauge core-needle puncture biopsy of liver masses, multiple metastases outside the gastrointestinal tract were considered. This case report suggests CEUS may be an easy, effective, and supplementary method for evaluating PJS patients with suspected multi-systemic malignant lesions including the gastrointestinal tract.

Deep learning-based target tracking with X-ray images for radiotherapy: a narrative review.

Background and Objective: As one of the main treatment modalities, radiotherapy (RT) (also known as radiation therapy) plays an increasingly important role in the treatment of cancer. RT could benefit greatly from the accurate localization of the gross tumor volume and circumambient organs at risk (OARs). Modern linear accelerators (LINACs) are typically equipped with either gantry-mounted or room-mounted X-ray imaging systems, which provide possibilities for marker-less tracking with two-dimensional (2D) kV X-ray images. However, due to organ overlapping and poor soft tissue contrast, it is challenging to track the target directly and precisely with 2D kV X-ray images. With the flourishing development of deep learning in the field of image processing, it is possible to achieve real-time marker-less tracking of targets with 2D kV X-ray images in RT using advanced deep-learning frameworks. This article sought to review the current development of deep learning-based target tracking with 2D kV X-ray images and discuss the existing limitations and potential solutions. Finally, it also discusses some common challenges and potential future developments. Methods: Manual searches of the Web of Science, and PubMed, and Google Scholar were carried out to retrieve English-language articles. The keywords used in the searches included "radiotherapy, radiation therapy, motion tracking, target tracking, motion estimation, motion monitoring, X-ray images, digitally reconstructed radiographs, deep learning, convolutional neural network, and deep neural network". Only articles that met the predetermined eligibility criteria were included in the review. Ultimately, 23 articles published between March 2019 and December 2023 were included in the review. Key Content and Findings: In this article, we narratively reviewed deep learning-based target tracking with 2D kV X-ray images in RT. The existing limitations, common challenges, possible solutions, and future directions of deep learning-based target tracking were also discussed. The use of deep learning-based methods has been shown to be feasible in marker-less target tracking and real-time motion management. However, it is still quite challenging to directly locate tumor and OARs in real-time with 2D kV X-ray images, and more technical and clinical efforts are needed. Conclusions: Deep learning-based target tracking with 2D kV X-ray images is a promising method in motion management during RT. It has the potential to track the target in real time, recognize motion, reduce the extended margin, and better spare the normal tissue. However, it still has many issues that demand prompt attention, and further development before it can be put into clinical practice.

Mechanism for leaching of fluoride ions from carbon dross generated in high-temperature and low-lithium aluminum electrolytic systems.

Carbon dross, a hazardous solid waste generated during aluminum electrolysis, contains large amounts of soluble fluoride ions for the main components of the electrolyte (such as Na3AlF6 and NaF). Response surface methodology (RSM) was used to investigate the mechanism for fluoride ion leaching from carbon dross via water leaching, acid leaching and alkali leaching, and the kinetic and thermodynamic principles of the leaching process were revealed. The RSM predicted the optimum conditions of water leaching, alkali leaching and acid leaching, and the conditions are as follows: temperature, 50 °C; shaking speed, 213 r·min-1; particle size, 0.075 mm; shaking speed, 194 r·min-1; liquid-solid ratio, 12.6 mg·L-1; sodium hydroxide concentration, 1.53 mol·L-1; liquid-solid ratio, 25.0 mg·L-1; sulfuric acid concentration, 2.00 mol·L-1; and temperature, 60 °C，and actual results which were almost consistent with the predicted results were gained. The fluoride ions in the alkaline and acid leaching solutions were mainly the dissociation products of fluorides such as Na3AlF6, Na5Al3F14 and CaF2, as indicated by thermodynamics calculations. In particular, the fluoride compounds dissolved in alkali solution were Na3AlF6, Na5Al3F14, AlF3, ZrF4, K3AlF6, while the acid solution could dissolve only Na3AlF6 and CaF2. The leaching kinetics experiments showed that the leaching rate fit the unreacted shrinking core model [1-2/3α-(1-α)2/3 =kt] and that the leaching process was controlled by internal diffusion. This study provides theoretical guidance for the removal of soluble fluoride ions from carbon dross and will also assist in the separation of electrolytes from carbon dross. ENVIRONMENTAL IMPLICATION: Carbon dross, a hazardous waste generated during the aluminum electrolysis production process, contains a large amount of soluble fluoride. Improper storage will lead the fluoride ions pollution in soil, surface water or groundwater under the direct contact between carbon dross and rainfall, snow or surface runoff. The influence of wind will cause carbon dross dust to pollute further areas. With the human body long-term contact with fluoride ion contaminated soil or water, human health will be seriously harmed.

Deep learning based ultrasound analysis facilitates precise distinction between parotid pleomorphic adenoma and Warthin tumor.

Background: Pleomorphic adenoma (PA), often with the benign-like imaging appearances similar to Warthin tumor (WT), however, is a potentially malignant tumor with a high recurrence rate. It is worse that pathological fine-needle aspiration cytology (FNAC) is difficult to distinguish PA and WT for inexperienced pathologists. This study employed deep learning (DL) technology, which effectively utilized ultrasound images, to provide a reliable approach for discriminating PA from WT. Methods: 488 surgically confirmed patients, including 266 with PA and 222 with WT, were enrolled in this study. Two experienced ultrasound physicians independently evaluated all images to differentiate between PA and WT. The diagnostic performance of preoperative FNAC was also evaluated. During the DL study, all ultrasound images were randomly divided into training (70%), validation (20%), and test (10%) sets. Furthermore, ultrasound images that could not be diagnosed by FNAC were also randomly allocated to training (60%), validation (20%), and test (20%) sets. Five DL models were developed to classify ultrasound images as PA or WT. The robustness of these models was assessed using five-fold cross-validation. The Gradient-weighted Class Activation Mapping (Grad-CAM) technique was employed to visualize the region of interest in the DL models. Results: In Grad-CAM analysis, the DL models accurately identified the mass as the region of interest. The area under the receiver operating characteristic curve (AUROC) of the two ultrasound physicians were 0.351 and 0.598, and FNAC achieved an AUROC of only 0.721. Meanwhile, for DL models, the AUROC value for discriminating between PA and WT in the test set was from 0.828 to 0.908. ResNet50 demonstrated the optimal performance with an AUROC of 0.908, an accuracy of 0.833, a sensitivity of 0.736, and a specificity of 0.904. In the test set of cases that FNAC failed to provide a diagnosis, DenseNet121 demonstrated the optimal performance with an AUROC of 0.897, an accuracy of 0.806, a sensitivity of 0.789, and a specificity of 0.824. Conclusion: For the discrimination of PA and WT, DL models are superior to ultrasound and FNAC, thereby facilitating surgeons in making informed decisions regarding the most appropriate surgical approach.

Angle Kappa is Not Correlated with Patient-Reported Outcomes After Multifocal Lens Implantation.

Purpose: To examine the effect of preoperative angle kappa on patient-reported outcomes after multifocal lens placement during cataract surgery and determine if it is an effective measure for preoperative patients screening for multifocal lens placement. Setting: Private refractive surgery clinics. Design: Retrospective cohort study. Methods: All patients undergoing bilateral cataract or refractive lens exchange surgery with a target of emmetropia between 2013 and 2017 at Optical Express (Glasgow, UK) with multifocal lens placement for whom preoperative angle kappa measurement and a postoperative month 1 patient-reported outcomes measures were available were included. Results: A total of 1368 patients were identified. Median preoperative angle kappa was 0.41mm with an interquartile range of 0.30mm to 0.53mm. Preoperative angle kappa did not have a significant association with patient-reported satisfaction with vision (correlation coefficient 0.15, 95% confidence interval -0.081 to 0.39, P = 0.20) nor with patient-reported photic phenomena (P > 0.09 for all comparisons). A receiver-operator characteristic analysis did not yield a viable cutoff predictive of patient-reported satisfaction. Conclusion: Angle kappa was not predictive of patient-reported satisfaction in this study. This study did not find evidence that it should be used as a screening test for patients considering multifocal intraocular lens placement.

EPC1/2 regulate hematopoietic stem and progenitor cell proliferation by modulating H3 acetylation and DLST.

Enhancers of polycomb 1 (EPC1) and 2 (EPC2) are involved in multiple biological processes as components of histone acetyltransferases/deacetylase complexes and transcriptional cofactors, and their dysfunction was associated with developmental defects and diseases. However, it remains unknown how their dysfunction induces hematopoietic stem and progenitor cell (HSPC) defects. Here, we show that depletion of EPC1/2 significantly reduced the number of hematopoietic stem and progenitor cells (HSPCs) in the aorta-gonad mesonephros and caudal hematopoietic tissue regions by impairing HSPC proliferation, and consistently downregulated the expression of HSPC genes in K562 cells. This study demonstrates the functions of EPC1/2 in regulating histone H3 acetylation, and in regulating DLST (dihydrolipoamide S-succinyltransferase) via H3 acetylation and cooperating with transcription factors serum response factor and FOXR2 together, and in the subsequent HSPC emergence and proliferation. Our results demonstrate the essential roles of EPC1/2 in regulating H3 acetylation, and DLST as a linkage between EPC1 and EPC2 with mitochondria metabolism, in HSPC emergence and proliferation.

Targeting NUPR1-dependent stress granules formation to induce synthetic lethality in KrasG12D-driven tumors.

We find that NUPR1, a stress-associated intrinsically disordered protein, induced droplet formation via liquid-liquid phase separation (LLPS). NUPR1-driven LLPS was crucial for the creation of NUPR1-dependent stress granules (SGs) in pancreatic cancer cells since genetic or pharmacological inhibition by ZZW-115 of NUPR1 activity impeded SGs formation. The KrasG12D mutation induced oncogenic stress, NUPR1 overexpression, and promoted SGs development. Notably, enforced NUPR1 expression induced SGs formation independently of mutated KrasG12D. Mechanistically, KrasG12D expression strengthened sensitivity to NUPR1 inactivation, inducing cell death, activating caspase 3 and releasing LDH. Remarkably, ZZW-115-mediated SG-formation inhibition hampered the development of pancreatic intraepithelial neoplasia (PanINs) in Pdx1-cre;LSL-KrasG12D (KC) mice. ZZW-115-treatment of KC mice triggered caspase 3 activation, DNA fragmentation, and formation of the apoptotic bodies, leading to cell death, specifically in KrasG12D-expressing cells. We further demonstrated that, in developed PanINs, short-term ZZW-115 treatment prevented NUPR1-associated SGs presence. Lastly, a four-week ZZW-115 treatment significantly reduced the number and size of PanINs in KC mice. This study proposes that targeting NUPR1-dependent SGs formation could be a therapeutic approach to induce cell death in KrasG12D-dependent tumors.