Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.

Cancers of the same tissue-type but in anatomically distinct locations exhibit different molecular dependencies for tumorigenesis. Proximal and distal colon cancers exemplify such characteristics, with BRAFV600E predominantly occurring in proximal colon cancers along with increased DNA methylation phenotype. Using mouse colon organoids, here we show that proximal and distal colon stem cells have distinct transcriptional programs that regulate stemness and differentiation. We identify that the homeobox transcription factor, CDX2, which is silenced by DNA methylation in proximal colon cancers, is a key mediator of the differential transcriptional programs. Cdx2-mediated proximal colon-specific transcriptional program concurrently is tumor suppressive, and Cdx2 loss sufficiently creates permissive state for BRAFV600E-driven transformation. Human proximal colon cancers with CDX2 downregulation showed similar transcriptional program as in mouse proximal organoids with Cdx2 loss. Developmental transcription factors, such as CDX2, are thus critical in maintaining tissue-location specific transcriptional programs that create tissue-type origin specific dependencies for tumor development.

The molecular mechanism underlying dermatomyositis related interstitial lung disease: evidence from bioinformatic analysis and in vivo validation.

Background: Dermatomyositis (DM) is an autoimmune and inflammatory disease that can affect the lungs, causing interstitial lung diseases (ILD). However, the exact pathophysiological mechanisms underlying DM-ILD are unknown. Idiopathic pulmonary fibrosis (IPF) belongs to the broader spectrum of ILD and evidence shows that common pathologic pathways might lie between IPF and DM-ILD. Methods: We retrieved gene expression profiles of DM and IPF from the Gene Expression Omnibus (GEO) and utilized weighted gene co-expression network analysis (WGCNA) to reveal their co-expression modules. We then performed a differentially expressed gene (DEG) analysis to identify common DEGs. Enrichment analyses were employed to uncover the hidden biological pathways. Additionally, we conducted protein-protein interaction (PPI) networks analysis, cluster analysis, and successfully found the hub genes, whose levels were further validated in DM-ILD patients. We also examined the relationship between hub genes and immune cell abundance in DM and IPF. Finally, we conducted a common transcription factors (TFs)-genes network by NetworkAnalyst. Results: WGCNA revealed 258 intersecting genes, while DEG analysis identified 66 shared genes in DM and IPF. All of these genes were closely related to extracellular matrix and structure, cell-substrate adhesion, and collagen metabolism. Four hub genes (POSTN, THBS2, COL6A1, and LOXL1) were derived through intersecting the top 30 genes of the WGCNA and DEG sets. They were validated as active transcripts and showed diagnostic values for DM and IPF. However, ssGSEA revealed distinct infiltration patterns in DM and IPF. These four genes all showed a positive correlation with immune cells abundance in DM, but not in IPF. Finally, we identified one possible key transcription factor, MYC, that interact with all four hub genes. Conclusion: Through bioinformatics analysis, we identified common hub genes and shared molecular pathways underlying DM and IPF, which provides valuable insights into the intricate mechanisms of these diseases and offers potential targets for diagnostic and therapeutic interventions.

Primary or metastatic branchial cleft carcinoma?: a case report.

The brachial cleft carcinoma is an extremely rare head and neck facial malignancy, and there is some disagreement about its differential diagnosis. In this paper, we report a 63-year-old male patient who had a mass on the left side of the neck and diagnosed as the brachial cleft carcinoma by intraoperative biopsy pathology. However, this patient was diagnosed with the carcinoma of the left soft palate more than 20 days after surgery and esophageal cancer 2 years later, and was treated accordingly. Therefore, it is hard to confirm whether the branchial cleft carcinoma is primary or metastatic. In fact, the diagnostic criteria for primary squamous cell carcinoma of branchial cleft cysts are very rigorous. Confirmation of the diagnosis is based on pathological examination of the branchial cleft cyst epithelium lined with squamous cells, meanwhile, a thorough examination should also be performed to exclude the presence of other primary cancers.

Postoperative elevated cardiac troponin levels predict all-cause mortality and major adverse cardiovascular events following noncardiac surgery: A dose-response meta-analysis of prospective studies.

STUDY OBJECTIVE: To perform a dose-response meta-analysis for the association between postoperative myocardial injury (PMI) in noncardiac surgery and the risk of all-cause mortality or major adverse cardiovascular event (MACE). DESIGN: Dose-response meta-analysis of prospective studies with weighted (WL) or generalized (GL) linear and restricted cubic spline (RCS) regression. SETTING: Teaching hospitals. PATIENTS: Adult patients undergoing noncardiac surgery. INTERVENTIONS: No. MEASUREMENTS: The primary outcome was all-cause mortality. The secondary outcome was MACE. MAIN RESULTS: 29 studies (53,518 patients) were included. The overall incidence of PMI was 26.0% (95% CI 21.0% to 32.0%). Compared to those without PMI, patients with PMI had an increased risk of all-cause mortality at short- (<12 months) (cardiac troponin[cTn]I: unadj OR 1.71,95%CI 1.22 to 2.41, P < 0.001; cTnT: unadj OR 2.33,95%CI 2.07 to 2.63, P < 0.001), and long-term (≥ 12 months) (cTnI: unadj OR 1.80, 95%CI 1.63 to 1.99; cTnT: unadj OR 1.47,95%CI 1.33 to 1.62) (All P < 0.001) follow-up. For MACE, the group with elevated values was associated with an increased risk (cTnI: unadj OR 1.98, 95% CI 1.13 to 3.47, P = 0.018; cTnT: unadj OR 2.29, 95% CI 1.88 to 2.79, P < 0.001). Dose-response analysis showed positive associations between PMI (per 1× upper reference limit[URL] increment) and all-cause mortality both at short- (unadj OR) (WL, OR 1.09, 95% CI 1.09 to 1.10; GL, OR 1.06, 95% CI 1.06 to 1.07; RCS in the range of 1-2× URL, OR = 2.43, 95%CI 2.25 to 2.62) and long-term follow-up (unadj HR) (WL, OR 1.16, 95% CI 1.14 to 1.17; GL, OR 1.15, 95% CI 1.13 to 1.16; RCS in the range of 1-2.75× URL, OR = 1.23, 95%CI 1.13 to 1.33), and MACE at longest follow-up (unadj OR) (WL: OR 1.53, 95% CI 1.49 to 1.57; GL: OR 1.46, 95% CI 1.42 to 1.50; RCS in the range of 1-2 x URL, OR = 3.10, 95%CI 2.51 to 3.81) (All P < 0.001). For mild cTn increase below URL, the risk of mortality increased with every increment of 0.25xURL (WL, OR 1.03, 95% CI 1.02 to 1.03; GL, OR 1.05, 95% CI 1.03 to 1.07; RCS in the range of 0-0.5 URL, OR = 9.41, 95% CI 7.41 to 11.95) (All P < 0.001). CONCLUSIONS: This study shows positive WL or GL and RCS dose-response relationships between PMI and all-cause mortality at short (< 12 mons)- and long-term (≥ 12 mons) follow-up, and MACE at longest follow-up. For mild cTn increase below URL, the risk of mortality also increases even with every increment of 0.25× URL.

Oxymatrine boosts hematopoietic regeneration by modulating MAPK/ERK phosphorylation after irradiation-induced hematopoietic injury.

Hematopoietic toxicity due to ionizing radiation (IR) is a leading cause of death in nuclear incidents, occupational hazards, and cancer therapy. Oxymatrine (OM), an extract originating from the root of Sophora flavescens (Kushen), possesses extensive pharmacological properties. In this study, we demonstrate that OM treatment accelerates hematological recovery and increases the survival rate of mice subjected to irradiation. This outcome is accompanied by an increase in functional hematopoietic stem cells (HSCs), resulting in enhanced hematopoietic reconstitution abilities. Mechanistically, we observed significant activation of the MAPK signaling pathway, accelerated cellular proliferation, and decreased cell apoptosis. Notably, we identified marked increases in the cell cycle transcriptional regulator Cyclin D1 (Ccnd1) and the anti-apoptotic protein BCL2 in HSCs after OM treatment. Further investigation revealed that the expression of Ccnd1 transcript and BCL2 levels were reversed upon specific inhibition of ERK1/2 phosphorylation, effectively negating the rescuing effect of OM. Moreover, we determined that targeted inhibition of ERK1/2 activation significantly counteracted the regenerative effect of OM on human HSCs. Taken together, our results suggest a crucial role for OM in hematopoietic reconstitution following IR via MAPK signaling pathway-mediated mechanisms, providing theoretical support for innovative therapeutic applications of OM in addressing IR-induced injuries in humans.

Transcription factor Nkx2-3 maintains the self-renewal of hematopoietic stem cells by regulating mitophagy.

Hematopoietic stem cells (HSCs) reside at the top of the hematopoietic hierarchy, exhibiting a unique capacity to self-renew and differentiate into all blood cells throughout the lifetime. However, how to prevent HSC exhaustion during long-term hematopoietic output is not fully understood. Here, we show that the homeobox transcription factor Nkx2-3 is required for HSC self-renewal by preserving metabolic fitness. We found that Nkx2-3 is preferentially expressed in HSCs with excessive regenerative potential. Mice with conditional deletion of Nkx2-3 displayed a reduced HSC pool and long-term repopulating capacity as well as increased sensitivity to irradiation and 5-flurouracil treatment due to impaired HSC quiescence. In contrast, overexpression of Nkx2-3 improved HSC function both in vitro and in vivo. Furthermore, mechanistic studies revealed that Nkx2-3 can directly control the transcription of the critical mitophagy regulator ULK1, which is essential for sustaining metabolic homeostasis in HSCs by clearing activated mitochondria. More importantly, a similar regulatory role of NKX2-3 was observed in human cord blood-derived HSCs. In conclusion, our data demonstrate an important role of the Nkx2-3/ULK1/mitophagy axis in regulating the self-renewal of HSCs, therefore providing a promising strategy to improve the function of HSCs in the clinic.

Tespa1 facilitates hematopoietic and leukemic stem cell maintenance by restricting c-Myc degradation.

Hematopoietic stem cells (HSCs) and leukemia stem cells (LSCs) have robust self-renewal potential, which is responsible for sustaining normal and malignant hematopoiesis, respectively. Although considerable efforts have been made to explore the regulation of HSC and LSC maintenance, the underlying molecular mechanism remains obscure. Here, we observe that the expression of thymocyte-expressed, positive selection-associated 1 (Tespa1) is markedly increased in HSCs after stresses exposure. Of note, deletion of Tespa1 results in short-term expansion but long-term exhaustion of HSCs in mice under stress conditions due to impaired quiescence. Mechanistically, Tespa1 can interact with CSN subunit 6 (CSN6), a subunit of COP9 signalosome, to prevent ubiquitination-mediated degradation of c-Myc protein in HSCs. As a consequence, forcing c-Myc expression improves the functional defect of Tespa1-null HSCs. On the other hand, Tespa1 is identified to be highly enriched in human acute myeloid leukemia (AML) cells and is essential for AML cell growth. Furthermore, using MLL-AF9-induced AML model, we find that Tespa1 deficiency suppresses leukemogenesis and LSC maintenance. In summary, our findings reveal the important role of Tespa1 in promoting HSC and LSC maintenance and therefore provide new insights on the feasibility of hematopoietic regeneration and AML treatment.

Melanocortin/MC5R axis regulates the proliferation of hematopoietic stem cells in mice after ionizing radiation injury.

Hematopoietic stem cells (HSCs) possess great self-renewal and multidirectional differentiation abilities, which contribute to the continuous generation of various blood cells. Although many intrinsic and extrinsic factors have been found to maintain HSC homeostasis, the precise regulation of hematopoiesis under stress conditions is poorly understood. In this study, we show that melanocortin receptor 5 (MC5R) is abundantly expressed in hematopoietic stem progenitor cells (HSPCs). Using an MC5R knockout mouse model, we observed that it is not essential for steady-state hematopoiesis. Interestingly, the levels of α-melanocyte stimulating hormone (α-MSH), an important subtype of melanocortin, were elevated in the serum and bone marrow, and the expression of MC5R was upregulated in HSPCs from mice after irradiation. MC5R deficiency aggravates irradiation-induced myelosuppression because of impaired proliferation and reconstitution of HSCs. Further investigation revealed that the melanocortin/MC5R axis regulates the proliferation of HSCs by activating the PI3K/AKT and MAPK pathways. More importantly, α-MSH treatment can significantly accelerate hematopoietic recovery in irradiated mice. In conclusion, our data demonstrate that the melanocortin/MC5R axis plays a crucial role in regulating HSC proliferation under stress, thus providing a promising strategy to promote hematopoietic regeneration when suffering from injury.

High-Dose Tranexamic Acid in Patients Underwent Surgical Repair of Aortic Dissection Might Reduce Postoperative Blood Loss: A Cohort Analysis.

Introduction: While tranexamic acid (TXA) is widely used in patients with acute type A aortic dissection (ATAAD) who undergo surgical repair to reduce blood loss and transfusion requirement, the optimal dosage of TXA is unknown in these patients. Materials and Methods: This was a retrospective cohort study that compared high-dose (>50 mg/kg) and low-dose TXA (≤50 mg/kg) in patients with ATAAD who underwent surgical repair. Propensity score matching (PSM) was performed between the two groups and results were analyzed in matched cases. The primary outcome was postoperative blood loss within 3 days after surgery. The secondary outcomes were total blood loss after surgery and perioperative blood transfusion, and safety outcomes were also assessed. Results: Through medical record screening, 529 patients were identified. After PSM, 196 patients in the high-dose group and 196 patients in the low-dose group were matched and included in the final analysis. Postoperative blood loss in 3 days after surgery was 940 mL (710-1,010 mL) in the low-dose group and 695 mL (620-860 mL) in the high-dose group. The difference was statistically significant (P < 0.001). Total postoperative blood loss was also statistically less in the high-dose group compared to the low-dose group (1,890 mL (1,410-2,100 mL) vs. 2,040 mL (1,460-2,320 mL), P = 0.032). No difference was found between the two groups in transfusion and safety outcomes. Conclusion: In ATAAD patients who underwent surgical repair, high-dose TXA significantly reduced postoperative blood loss compared to low-dose TXA, while no difference in transfusion or adverse events was found.

Physiological Mechanism of Exogenous 5-Aminolevulinic Acid Improved the Tolerance of Chinese Cabbage (Brassica pekinensis L.) to Cadmium Stress.

The 5-aminolevulinic acid (ALA), a new type of plant growth regulator, can relieve the toxicity of cadmium (Cd) to plants. However, its mechanism has not been thoroughly studied. In the study, the roles of ALA have been investigated in the tolerance of Chinese cabbage (Brassica pekinensis L.) seedlings to Cd stress. The results showed that Cd significantly reduced the biomass and the length of the primary root of seedlings but increased the malondialdehyde (MDA) and the hydrogen peroxide (H2O2) contents. These can be effectively mitigated through the application of ALA. The ALA can further induce the activities of antioxidant enzymes in the ascorbate-glutathione (AsA-GSH) cycle under Cd stress, which resulted in high levels of both GSH and AsA. Under ALA + Cd treatment, the seedlings showed a higher chlorophyll content and photosynthetic performance in comparison with Cd treatment alone. Microscopic analysis results confirmed that ALA can protect the cell structure of shoots and roots, i.e., stabilizing the morphological structure of chloroplasts in leaf mesophyll cells. The qRT-PCR results further reported that ALA downregulated the expressions of Cd absorption and transport-related genes in shoots (HMA2 and HMA4) and roots (IRT1, IRT2, Nramp1, and Nramp3), which resulted in the low Cd content in the shoots and roots of cabbage seedlings. Taken together, the exogenous application of ALA alleviates Cd stress through maintaining redox homeostasis, protecting the photosynthetic system, and regulating the expression of Cd transport-related genes in Chinese cabbage seedlings.

Corrigendum: Moderate and Deep Hypothermic Circulatory Arrest Have Comparable Effects on Severe Systemic Inflammatory Response Syndrome After Total Aortic Arch Replacement in Patients With Type A Aortic Dissection.

[This corrects the article DOI: 10.3389/fsurg.2021.758854.].

CDK19 regulates the proliferation of hematopoietic stem cells and acute myeloid leukemia cells by suppressing p53-mediated transcription of p21.

The cell cycle progression of hematopoietic stem cells (HSCs) and acute myeloid leukemia (AML) cells is precisely controlled by multiple regulatory factors. However, the underlying mechanisms are not fully understood. Here, we find that cyclin-dependent kinase 19 (CDK19), not its paralogue CDK8, is relatively enriched in mouse HSCs, and its expression is more significantly increased than CDK8 after proliferative stresses. Furthermore, SenexinB (a CDK8/19 inhibitor) treatment impairs the proliferation and self-renewal ability of HSCs. Moreover, overexpression of CDK19 promotes HSC function better than CDK8 overexpression. Using CDK19 knockout mice, we observe that CDK19-/- HSCs exhibit similar phenotypes to those of cells treated with SenexinB. Interestingly, the p53 signaling pathway is significantly activated in HSCs lacking CDK19 expression. Further investigations show that CDK19 can interact with p53 to inhibit p53-mediated transcription of p21 in HSCs and treatment with a specific p53 inhibitor (PFTß) partially rescues the defects of CDK19-null HSCs. Importantly, SenexinB treatment markedly inhibits the proliferation of AML cells. Collectively, our findings indicate that CDK19 is involved in regulating HSC and AML cell proliferation via the p53-p21 pathway, revealing a new mechanism underlying cell cycle regulation in normal and malignant hematopoietic cells.

Srebf1c preserves hematopoietic stem cell function and survival as a switch of mitochondrial metabolism.

Mitochondria are fundamental but complex determinants for hematopoietic stem cell (HSC) maintenance. However, the factors involved in the regulation of mitochondrial metabolism in HSCs and the underlying mechanisms have not been fully elucidated. Here, we identify sterol regulatory element binding factor-1c (Srebf1c) as a key factor in maintaining HSC biology under both steady-state and stress conditions. Srebf1c knockout (Srebf1c-/-) mice display increased phenotypic HSCs and less HSC quiescence. In addition, Srebf1c deletion compromises the function and survival of HSCs in competitive transplantation or following chemotherapy and irradiation. Mechanistically, SREBF1c restrains the excessive activation of mammalian target of rapamycin (mTOR) signaling and mitochondrial metabolism in HSCs by regulating the expression of tuberous sclerosis complex 1 (Tsc1). Our study demonstrates that Srebf1c plays an important role in regulating HSC fate via the TSC1-mTOR-mitochondria axis.

CD63 acts as a functional marker in maintaining hematopoietic stem cell quiescence through supporting TGFß signaling in mice.

Hematopoietic stem cell (HSC) fate is tightly controlled by various regulators, whereas the underlying mechanism has not been fully uncovered due to the high heterogeneity of these populations. In this study, we identify tetraspanin CD63 as a novel functional marker of HSCs in mice. We show that CD63 is unevenly expressed on the cell surface in HSC populations. Importantly, HSCs with high CD63 expression (CD63hi) are more quiescent and have more robust self-renewal and myeloid differentiation abilities than those with negative/low CD63 expression (CD63-/lo). On the other hand, using CD63 knockout mice, we find that loss of CD63 leads to reduced HSC numbers in the bone marrow. In addition, CD63-deficient HSCs exhibit impaired quiescence and long-term repopulating capacity, accompanied by increased sensitivity to irradiation and 5-fluorouracil treatment. Further investigations demonstrate that CD63 is required to sustain TGFß signaling activity through its interaction with TGFß receptors I and II, thereby playing an important role in regulating the quiescence of HSCs. Collectively, our data not only reveal a previously unrecognized role of CD63 but also provide us with new insights into HSC heterogeneity.

Moderate and Deep Hypothermic Circulatory Arrest Have Comparable Effects on Severe Systemic Inflammatory Response Syndrome After Total Aortic Arch Replacement in Patients With Type A Aortic Dissection.

Background: The objective of this study was to compare the incidence of severe systemic inflammatory response syndrome (sSIRS) after total aortic arch replacement between patients who underwent moderate hypothermic circulatory arrest (MHCA) and those who underwent deep hypothermic circulatory arrest (DHCA). Methods: At Fuwai Hospital, 600 patients who underwent total aortic arch replacement with MHCA or DHCA from January 2013 to December 2016 were consecutively enrolled and divided into DHCA (14.1-20.0°C) and MHCA (20.1-28.0°C) groups. Preliminary statistical analysis revealed that some baseline indicators differed between the two groups; therefore, propensity score matching (PSM) was used to balance the covariates. Post-operative sSIRS as the primary outcome was compared between the groups both before and after PSM. Results: A total of 275 (45.8%) patients underwent MHCA, and 325 (54.2%) patients underwent DHCA. After PSM analysis, a total of 191 matched pairs were obtained. The overall incidence of sSIRS was 27.3%. There was no significant difference in post-operative sSIRS between the MHCA group and the DHCA group in either the overall cohort or the PSM cohort (no-PSM: P = 0.188; PSM: P = 0.416); however, post-operative sSIRS was increased by ~4% in the DHCA group compared with the MHCA group in both the no-PSM and PSM cohorts (no-PSM: 29.5 vs. 24.7%; PSM: 29.3 vs. 25.1%). Both before and after PSM, the rates of gastrointestinal hemorrhage and pulmonary infection and post-operative length of stay were significantly increased in the DHCA group compared with the MHCA group (P < 0.05), and the remaining secondary outcomes were not significantly different between the groups. Conclusions: MHCA and DHCA are associated with comparable incidences of sSIRS in patients following total aortic arch replacement for type A aortic dissection. However, the MHCA group had a shorter cardiopulmonary bypass time, a shorter post-operative length of stay and lower pulmonary infection and gastrointestinal hemorrhage rates than the DHCA group. We cautiously recommend the use of MHCA for most total arch replacements in patients with type A aortic dissection.

The salutary effect of peritoneal dialysis catheters on enhanced recovery among high-risk pediatric patients undergoing the left coronary transfer procedure: a cohort study.

BACKGROUND: Evidence for peritoneal dialysis catheter (PDC) usage in pediatric patients undergoing surgery for deteriorating cardiac dysfunction is lacking. This investigation explored factors associated with PDC usage and its effectiveness in children with anomalous origin of the left coronary artery from the pulmonary artery (ALCAPA). METHODS: Eighty-four children undergoing left coronary artery transfer were retrospectively recruited. The primary endpoint was the postoperative ratio of the general ward/[intensive care unit (ICU)] length of stay. Univariable and multivariable analyses were fitted to assess factors related most strongly to PDC and the ratio of general ward/ICU length of stay. RESULTS: Of the 84 patients, 17 (20.2%) underwent postoperative PDC placement. Patients with extreme cardiac dysfunction [left ventricular ejection fraction (LVEF) ≤25%] were much more likely to require a PDC (OR, 9.88; 95% CI, 2.13-45.76; P = 0.003). Moreover, univariate analysis indicated that concomitant mitral repair significantly decreased the likelihood of PDC placement (OR, 0.25; 95% CI, 0.07-0.85; P = 0.026). In those with cardiac dysfunction (LVEF ≤50%), PDC use was associated with a reduced ratio of ward/ICU length of stay (B, - 1.62; 95% CI, - 2.77- -0.46; P = 0.008), as was age ≤ 12 months (B, - 1.57; 95% CI, - 2.88- -0.26; P = 0.02). At the 1-year follow-up, cardiac improvement was significantly greater in patients with PDC usage than in those without it (P <  0.001), and the number of mitral recoveries was comparable between the groups (64.2% vs. 53.3%, P = 0.434). CONCLUSION: In cohorts with ALCAPA, PDC placement following surgery may be necessary for patients with extreme cardiac compromise, while concomitant mitral repair can probably reduce their usage rate. PDC is beneficial in conferring an improvement in cardiac and mitral performance. Importantly, after patients are transferred from the ICU, recovery efficiency in the general ward can be enhanced by PDC placement, and hospital discharge can therefore be achieved early, especially for patients younger than 12 months or with LVEF ≤50%.

Low postoperative blood platelet count may be a risk factor for 3-year mortality in patients with acute type A aortic dissection.

BACKGROUND: Mortality and complications remain high after acute type A aortic dissection (ATAAD) open surgery and are associated with coagulation dysfunction. Platelets play an important role in the process of coagulation. This study explored the relationship between postoperative platelet counts and 3-year mortality after operation in patients with ATAAD undergoing open aortic repair surgery. METHODS: Patients with ATAAD who underwent Total Arch Replacement and Frozen Elephant Trunk in Fuwai Hospital from 2011 to 2015 were selected for this study. The perioperative data were collected and sorted through the electronic clinical case system. Multivariate Logistic regression was used to analyze the risk factors for death within three years after surgery. RESULTS: A total of 495 patients were included in the analysis. After correction for confounding factors, decreased postoperative platelet count remained an independent factor that was associated with lower mortality (OR = 0.918, 95% CI 0.853-0.988, P = 0.023). CONCLUSIONS: The study indicated that decreased postoperative platelet count may lead to increased 3-year mortality, in patients with ATAAD who underwent open aortic repair surgery.

Grape seed proanthocyanidin extract ameliorates ionizing radiation-induced hematopoietic stem progenitor cell injury by regulating Foxo1 in mice.

Ionizing radiation (IR)-induced excessive reactive oxygen species (ROS) is an important contributor of the injury of hematopoietic system. Grape seed proanthocyanidin extract (GSPE) is a new type of antioxidant, whereas whether it could ameliorate IR-induced hematopoietic injury remains unclear. Here, we show that GSPE treatment improves the survival of irradiated mice and alleviates IR-induced myelosuppression. Meanwhile, the hematopoietic reconstituting ability of hematopoietic stem cells (HSCs) in mice following irradiation exposure is significantly increased after GSPE treatment. Furthermore, GSPE treatment can reduce IR-induced ROS production and relieve DNA damage and apoptosis in hematopoietic stem progenitor cells (HSPCs). Interestingly, we find that a critical antioxidant-associated gene fokhead box transcription factor O1 (Foxo1) is significantly decreased in HSPCs after irradiation. Consistently, hematopoietic specific deletion of Foxo1 increases the radiosensitivity of mice. Further investigations reveal that GSPE treatment specifically upregulates the expression of Foxo1, as well as its target genes superoxide dismutase 1 (SOD1), superoxide dismutase 2 (SOD2) and catalase (CAT). Importantly, Foxo1 deficiency largely abolishes the radioprotection of GSPE on HSPCs. Collectively, our data demonstrate that GSPE plays an important role in ameliorating IR-induced HSPC injury via the Foxo1-mediated pathway. Therefore, GSPE may be used as a promising radioprotective agent.

Risk Factors for Prolonged Mechanical Ventilation After Pulmonary Endarterectomy: 7 Years' Experience From an Experienced Hospital in China.

Background: Prolonged mechanical ventilation (PMV) is common after cardiothoracic surgery, whereas the mechanical ventilation strategy after pulmonary endarterectomy (PEA) has not yet been reported. We aim to identify the incidence and risk factors for PMV and the relationship between PMV and short-term outcomes. Methods: We studied a retrospective cohort of 171 who undergoing PEA surgery from 2014 to 2020. Cox regression with restricted cubic splines was performed to identify the cutoff value for PMV. The Least absolute shrinkage and selection operator regression and logistic regressions were applied to identify risk factors for PMV. The impacts of PMV on the short-term outcomes were evaluated. Results: PMV was defined as the duration of mechanical ventilation exceeding 48 h. Independent risk factors for PMV included female sex (OR 2.911; 95% CI 1.303-6.501; P = 0.009), prolonged deep hypothermic circulatory arrest (DHCA) time (OR 1.027; 95% CI 1.002-1.053; P = 0.036), increased postoperative blood product use (OR 3.542; 95% CI 1.203-10.423; P = 0.022), elevated postoperative total bilirubin levels (OR 1.021; 95% CI 1.007-1.034; P = 0.002), increased preoperative pulmonary artery pressure (PAP) (OR 1.031; 95% CI 1.014-1.048; P < 0.001) and elongated postoperative right ventricular anteroposterior dimension (RVAD) (OR 1.119; 95% CI 1.026-1.221; P = 0.011). Patients with PMV had longer intensive care unit stays, higher incidences of postoperative complications, and higher in-hospital medical expenses. Conclusions: Female sex, prolonged DHCA time, increased postoperative blood product use, elevated postoperative total bilirubin levels, increased preoperative PAP, and elongated postoperative RVAD were independent risk factors for PMV. Identification of risk factors associated with PMV in patients undergoing PEA may facilitate timely diagnosis and re-intervention for some of these modifiable factors to decrease ventilation time and improve patient outcomes.

Using Machine Learning to Predict Postoperative Liver Dysfunction After Aortic Arch Surgery.

OBJECTIVES: The study compared machine-learning models with traditional logistic regression to predicting liver outcomes after aortic arch surgery. DESIGN: Retrospective review from January 2013 to May 2017. SETTING: Fuwai Hospital. PARTICIPANTS: The study comprised 672 consecutive patients who had undergone aortic arch surgery. MEASUREMENTS AND MAIN RESULTS: Three machine-learning methods were compared with logistic regression with regard to the prediction of postoperative liver dysfunction (PLD) after aortic arch surgery. The perioperative characteristics, including the patients' baseline medical condition and intraoperative data, were analyzed. The performance of the models was assessed using the area under the receiver operating characteristic curve. Naïve Bayes had the best discriminative ability for the prediction of PLD (area under the receiver operating characteristic curve = 0.77) compared with random forest (0.76), support vector machine (0.73), and logistic regression (0.72). The primary endpoint of PLD was observed in 185 patients (27.5%). The cardiopulmonary bypass time, long surgery time, long aortic clamp time, high preoperative bilirubin value, and low rectal temperature were strongly associated with the development of PLD after aortic arch surgery. CONCLUSION: The machine-learning method of naïve Bayes predicts PLD after aortic arch surgery significantly better than traditional logistic regression.