Relative band power in assessing temporary neurological dysfunction post- type A aortic dissection surgery: a prospective study.

Temporary neurological dysfunction (TND), a common complication following surgical repair of Type A Aortic Dissection (TAAD), is closely associated with increased mortality and long-term cognitive impairment. Currently, effective treatment options for TND remain elusive. Therefore, we sought to investigate the potential of postoperative relative band power (RBP) in predicting the occurrence of postoperative TND, with the aim of identifying high-risk patients prior to the onset of TND. We conducted a prospective observational study between February and December 2022, involving 165 patients who underwent surgical repair for TAAD at our institution. Bedside Quantitative electroencephalography (QEEG) was utilized to monitor the post-operative brain electrical activity of each participant, recording changes in RBP (RBP Delta, RBP Theta, RBP Beta and RBP Alpha), and analyzing their correlation with TND. Univariate and multivariate analyses were employed to identify independent risk factors for TND. Subsequently, line graphs were generated to estimate the incidence of TND. The primary outcome of interest was the development of TND, while secondary outcomes included intensive care unit (ICU) admission and length of hospital stay. A total of 165 patients were included in the study, among whom 68 (41.2%) experienced TND. To further investigate the independent risk factors for postoperative TND, we conducted both univariate and multivariate logistic regression analyses on all variables. In the univariate regression analysis, we identified age (Odds Ratio [OR], 1.025; 95% CI, 1.002-1.049), age ≥ 60 years (OR, 2.588; 95% CI, 1.250-5.475), hemopericardium (OR, 2.767; 95% CI, 1.150-7.009), cardiopulmonary bypass (CPB) (OR, 1.007; 95% CI, 1.001-1.014), RBP Delta (OR, 1.047; 95% CI, 1.020-1.077), RBP Alpha (OR, 0.853; 95% CI, 0.794-0.907), and Beta (OR, 0.755; 95% CI, 0.649-0.855) as independent risk factors for postoperative TND. Further multivariate regression analyses, we discovered that CPB time ≥ 180 min (OR, 1.021; 95% CI, 1.011-1.032), RBP Delta (OR, 1.168; 95% CI, 1.105-1.245), and RBP Theta (OR, 1.227; 95% CI, 1.135-1.342) emerged as independent risk factors. TND patients had significantly longer ICU stays (p < 0.001), and hospital stays (p = 0.002). We obtained the simplest predictive model for TND, consisting of three variables (CPB time ≥ 180 min, RBP Delta, RBP Theta, upon which we constructed column charts. The areas under the receiver operating characteristic (AUROC) were 0.821 (0.755, 0.887). Our study demonstrates that postoperative RBP monitoring can detect changes in brain function in patients with TAAD during the perioperative period, providing clinicians with an effective predictive method that can help improve postoperative TND in TAAD patients. These findings have important implications for improving clinical care in this population.Trial registration ChiCTR2200055980. Registered 30th Jan. 2022. This trial was registered before the first participant was enrolled.

Diameter and dissection of the abdominal aorta and the risk of distal aortic reoperation after surgery for type A aortic dissection.

BACKGROUND: Surgery for Stanford type A aortic dissection (TAAD) is associated with an increased risk of late aortic reoperations due to degeneration of the dissected aorta. METHODS: The subjects of this analysis were 990 TAAD patients who survived surgery for acute TAAD and had complete data on the diameter and dissection status of all aortic segments. RESULTS: After a mean follow-up of 4.2 ± 3.6 years, 60 patients underwent 85 distal aortic reoperations. Ten-year cumulative incidence of distal aortic reoperation was 9.6%. Multivariable competing risk analysis showed that the maximum preoperative diameter of the abdominal aorta (SHR 1.041, 95%CI 1.008-1.075), abdominal aorta dissection (SHR 2.133, 95%CI 1.156-3.937) and genetic syndromes (SHR 2.840, 95%CI 1.001-8.060) were independent predictors of distal aortic reoperation. Patients with a maximum diameter of the abdominal aorta >30 mm and/or abdominal aortic dissection had a cumulative incidence of 10-year distal aortic reoperation of 12.0% compared to 5.7% in those without these risk factors (adjusted SHR 2.076, 95%CI 1.062-4.060). CONCLUSION: TAAD patients with genetic syndromes, and increased size and dissection of the abdominal aorta have an increased the risk of distal aortic reoperations. A policy of extensive surgical or hybrid primary aortic repair, completion endovascular procedures for aortic remodeling and tight surveillance may be justified in these patients. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT04831073.

Transcriptome analysis reveals organ-specific effects of 2-deoxyglucose treatment in healthy mice.

OBJECTIVE: Glycolytic inhibition via 2-deoxy-D-glucose (2DG) has potential therapeutic benefits for a range of diseases, including cancer, epilepsy, systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA), and COVID-19, but the systemic effects of 2DG on gene function across different tissues are unclear. METHODS: This study analyzed the transcriptional profiles of nine tissues from C57BL/6J mice treated with 2DG to understand how it modulates pathways systemically. Principal component analysis (PCA), weighted gene co-network analysis (WGCNA), analysis of variance, and pathway analysis were all performed to identify modules altered by 2DG treatment. RESULTS: PCA revealed that samples clustered predominantly by tissue, suggesting that 2DG affects each tissue uniquely. Unsupervised clustering and WGCNA revealed six distinct tissue-specific modules significantly affected by 2DG, each with unique key pathways and genes. 2DG predominantly affected mitochondrial metabolism in the heart, while in the small intestine, it affected immunological pathways. CONCLUSIONS: These findings suggest that 2DG has a systemic impact that varies across organs, potentially affecting multiple pathways and functions. The study provides insights into the potential therapeutic benefits of 2DG across different diseases and highlights the importance of understanding its systemic effects for future research and clinical applications.

Lesion of NPY Receptor-expressing Neurons in Perifornical Lateral Hypothalamus Attenuates Glucoprivic Feeding.

Glucoprivic feeding is one of several counterregulatory responses (CRRs) that facilitates restoration of euglycemia following acute glucose deficit (glucoprivation). Our previous work established that glucoprivic feeding requires ventrolateral medullary (VLM) catecholamine (CA) neurons that coexpress neuropeptide Y (NPY). However, the connections by which VLM CA/NPY neurons trigger increased feeding are uncertain. We have previously shown that glucoprivation, induced by an anti-glycolygic agent 2-deoxy-D-glucose (2DG), activates perifornical lateral hypothalamus (PeFLH) neurons and that expression of NPY in the VLM CA/NPY neurons is required for glucoprivic feeding. We therefore hypothesized that glucoprivic feeding and possibly other CRRs require NPY-sensitive PeFLH neurons. To test this, we used the ribosomal toxin conjugate NPY-saporin (NPY-SAP) to selectively lesion NPY receptor-expressing neurons in the PeFLH of male rats. We found that NPY-SAP destroyed a significant number of PeFLH neurons, including those expressing orexin, but not those expressing melanin-concentrating hormone. The PeFLH NPY-SAP lesions attenuated 2DG-induced feeding but did not affect 2DG-induced increase in locomotor activity, sympathoadrenal hyperglycemia, or corticosterone release. The 2DG-induced feeding response was also significantly attenuated in NPY-SAP-treated female rats. Interestingly, PeFLH NPY-SAP lesioned male rats had reduced body weights and decreased dark cycle feeding, but this effect was not seen in female rats. We conclude that a NPY projection to the PeFLH is necessary for glucoprivic feeding, but not locomotor activity, hyperglycemia, or corticosterone release, in both male and female rats.

Is a severe preoperative condition a contraindication for aortic valve-sparing reimplantation in type A aortic dissection?

BACKGROUND: Type A aortic dissection (TAAD) surgical management is still under debate. The purpose of this study was to demonstrate the feasibility and safety of the aortic valve-sparing root reconstruction (AVSR) procedure in 92 consecutive patients operated for TAAD, even when preoperative condition was severe (malperfusion, shock or both). METHODS: Our hospital database was reviewed to identify all patients who underwent an AVSR procedure for TAAD over 14 years. From May 2000 to June 2014, 92 consecutive patients were studied regarding to their preoperative condition. RESULTS: Age (61±13 years) and logistic Euroscore (23.4±15.3%) as well as cross-clamping (113±39 min), cardiopulmonary bypass (142±49 min) and circulatory arrest (22±13 min) times were collected. Hospital mortality was 16.3%. Mean follow-up was complete for a mean period of 27.6 months. One patient had early reoperation for aortic insufficiency. Actuarial survival at 1 year was 82.5%. The analysis of each group showed comparable mortality and morbidity in between patients. CONCLUSIONS: Based upon our experience in the management of TAAD, a reimplantation procedure could be performed regardless preoperative malperfusion or shock, with an acceptable postoperative over mortality or morbidity. A word of caution should be brought to patients over 70 years old.

Classification of the Urgency of the Procedure and Outcome of Acute Type A Aortic Dissection.

Surgery for type A aortic dissection (TAAD) is associated with a high risk of early mortality. The prognostic impact of a new classification of the urgency of the procedure was evaluated in this multicenter cohort study. Data on consecutive patients who underwent surgery for acute TAAD were retrospectively collected in the multicenter, retrospective European Registry of TAAD (ERTAAD). The rates of in-hospital mortality of 3,902 consecutive patients increased along with the ERTAAD procedure urgency grades: urgent procedure 10.0%, emergency procedure grade 1 13.3%, emergency procedure grade 2 22.1%, salvage procedure grade 1 45.6%, and salvage procedure grade 2 57.1% (p <0.0001). Preoperative arterial lactate correlated with the urgency grades. Inclusion of the ERTAAD procedure urgency classification significantly improved the area under the receiver operating characteristics curves of the regression model and the integrated discrimination indexes and the net reclassification indexes. The risk of postoperative stroke/global brain ischemia, mesenteric ischemia, lower limb ischemia, dialysis, and acute heart failure increased along with the urgency grades. In conclusion, the urgency of surgical repair of acute TAAD, which seems to have a significant impact on the risk of in-hospital mortality, may be useful to improve the stratification of the operative risk of these critically ill patients. This study showed that salvage surgery for TAAD is justified because half of the patients may survive to discharge.

NIR-II imaging-guided precise photodynamic therapy for augmenting tumor-starvation therapy by glucose metabolism reprogramming interference.

Metabolic reprogramming is a mechanism by which cancer cells alter their metabolic patterns to promote cell proliferation and growth, thereby enabling their resistance to external stress. 2-Deoxy-D-glucose (2DG) can eliminate their energy source by inhibiting glucose glycolysis, leading to cancer cell death through starvation. However, a compensatory increase in mitochondrial metabolism inhibits its efficacy. Herein, we propose a synergistic approach that combines photodynamic therapy (PDT) with starvation therapy to address this challenge. To monitor the nanodrugs and determine the optimal triggering time for precise tumor therapy, a multifunctional nano-platform comprising lanthanide-doped nanoparticle (LnNP) cores was constructed and combined with mesoporous silicon shells loaded with 2DG and photosensitizer chlorin e6 (Ce6) in the mesopore channels. Under 980 nm near-infrared light excitation, the downshifted 1550 nm fluorescence signal in the second near-infrared (NIR-II, 1000-1700 nm) window from the LnNPs was used to monitor the accumulation of nanomaterials in tumors. Furthermore, upconverted 650 nm light excited the Ce6 to generate singlet oxygen for PDT, which damaged mitochondrial function and enhanced the efficacy of 2DG by inhibiting hexokinase 2 and lactate dehydrogenase A expressions. As a result, glucose metabolism reprogramming was inhibited and the efficiency of starvation therapy was significantly enhanced. Overall, the proposed NIR-II bioimaging-guided PDT-augmented starvation therapy, which simultaneously inhibited glycolysis and mitochondria, facilitated the effects of a cancer theranostic system.

Risk factors for prolonged postoperative ICU stay in the patients with Stanford type A aortic dissection.

OBJECTIVE: To investigate the independent risk factors for postoperative prolonged ICU stay in patients with Stanford type A aortic dissection (TAAD) and assess the clinical outcomes of prolonged ICU stay. METHOD: The clinical data of 100 patients with TAAD admitted to the Department of Cardiovascular Surgery, First Affiliated Hospital of Anhui Medical University from December 2018 to September 2022 were retrospectively collected and analyzed. Patients were divided into two groups, based on the postoperative ICU stay (7 days as the threshold), regular ICU stay group (< 7 days) and prolonged ICU stay group (≥ 7 days). First, preoperative and intraoperative materials were collected for univariate analysis. Then, the significant variables after univariate analysis were analyzed using logistic regression, and the final independent risk factors for prolonged ICU stay were determined. Meanwhile, the postoperative clinical outcomes were analyzed with the aim of assessing the clinical outcomes due to prolonged ICU stay. RESULTS: There were 65 and 35 patients in the regular ICU stay group and the prolonged ICU stay group, respectively. In accordance with the result of univariate analysis in the two groups, emergency surgery (χ2 = 13.598; P < 0.001), preoperative urea nitrogen (t = 3.006; P = 0.004), cardiopulmonary bypass (CPB) time (t = 2.671; P = 0.001) and surgery time (t = 2.630; P = 0.010) were significant. All significant variates were analyzed through logistic regression, and it was found that emergency surgery (OR = 0.192; 95% CI: 0.065-0.561), preoperative urea nitrogen (OR = 0.775; 95% CI: 0.634-0.947) and cardiopulmonary time (OR = 0.988; 95% CI: 0.979-0.998) were independent risk factors for prolonged postoperative ICU stay. The Receiver Operating Characteristic (ROC) curves of these three factors were also effective in predicting postoperative prolonged ICU stay (Emergency surgery, AUC = 0.308, 95% CI: 0.201-0.415; Preoperative urea nitrogen, AUC = 0.288, 95% CI: 0.185-0.392; cardiopulmonary time, AUC = 0.340, 95% CI: 0.223-0.457). Moreover, compared with a single factor, the predictive value of combined factors was more significant (AUC = 0.810, 95% CI: 0.722-0.897). For the comparison of postoperative data in the two groups,, compared with the regular ICU stay group, the incidence of adverse events in the prolonged ICU stay group increased significantly, including limb disability of limbs (χ2 = 22.182; P < 0.001), severe organ injury (χ2 = 23.077; P < 0.001), tracheotomy (χ2 = 17.582; P < 0.001), reintubation (χ2 = 28.020; P < 0.001), 72 h tracheal extubation after surgery (χ2 = 29.335; P < 0.001), 12 h consciousness recovery after surgery (χ2 = 18.445; P < 0.001), ICU re-entering (χ2 = 9.496; P = 0.002) and irregular discharging (χ2 = 24.969; P < 0.001). CONCLUSION: Emergency surgery, preoperative urea nitrogen, and CPB time are risk factors for postoperative prolonged ICU stay after TAAD surgery. Furthermore, prolonged ICU stay is associated with worse clinical outcomes. Hence, a reasonable strategy should be adopted proactively focusing on the risk factors to shorten ICU stays and improve clinical outcomes.

Versican accumulation drives Nos2 induction and aortic disease in Marfan syndrome via Akt activation.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening condition associated with Marfan syndrome (MFS), a disease caused by fibrillin-1 gene mutations. While various conditions causing TAAD exhibit aortic accumulation of the proteoglycans versican (Vcan) and aggrecan (Acan), it is unclear whether these ECM proteins are involved in aortic disease. Here, we find that Vcan, but not Acan, accumulated in Fbn1C1041G/+ aortas, a mouse model of MFS. Vcan haploinsufficiency protected MFS mice against aortic dilation, and its silencing reverted aortic disease by reducing Nos2 protein expression. Our results suggest that Acan is not an essential contributor to MFS aortopathy. We further demonstrate that Vcan triggers Akt activation and that pharmacological Akt pathway inhibition rapidly regresses aortic dilation and Nos2 expression in MFS mice. Analysis of aortic tissue from MFS human patients revealed accumulation of VCAN and elevated pAKT-S473 staining. Together, these findings reveal that Vcan plays a causative role in MFS aortic disease in vivo by inducing Nos2 via Akt activation and identify Akt signaling pathway components as candidate therapeutic targets.

Nerve growth factor (Ngf) gene-driven semaphorin 3a (Sema3a) expression exacerbates thoracic aortic aneurysm dissection in mice.

Thoracic aortic aneurysm and dissection (TAAD) is a life-threatening disease and currently there is no pharmacological therapy. Sympathetic nerve overactivity plays an important role in the development of TAAD. Sympathetic innervation is mainly controlled by nerve growth factor (NGF, a key neural chemoattractant) and semaphoring 3A (Sema3A, a key neural chemorepellent), while the roles of these two factors in aortic sympathetic innervation and especially TAAD are unknown. We hypothesized that genetically manipulating the NGF/Sema3A ratio by the Ngf -driven Sema3a expression approach may reduce aortic sympathetic nerve innervation and mitigate TAAD progression. A mouse strain of Ngf gene-driven Sema3a expression (namely NgfSema3a/Sema3a mouse) was established by inserting the 2A-Sema3A expression frame to the Ngf terminating codon using CRISPR/Cas9 technology. TAAD was induced by ß-aminopropionitrile monofumarate (BAPN) both in NgfSema3a/Sema3a mice and wild type (WT) littermates. Contrary to our expectation, the BAPN-induced TAAD was severer in NgfSema3a/Sema3a mice than in wild-type (WT) mice. In addition, NgfSema3a/Sema3a mice showed higher aortic sympathetic innervation, inflammation and extracellular matrix degradation than the WT mice after BAPN treatment. The aortic vascular smooth muscle cells isolated from NgfSema3a/Sema3a mice and pretreated with BAPN in vivo for two weeks showed stronger capabilities of proliferation and migration than that from the WT mice. We conclude that the strategy of Ngf -driven Sema3a expression cannot suppress but worsens the BAPN-induced TAAD. By investigating the aortic phenotype of NgfSema3a/Sema3a mouse strain, we unexpectedly find a path to exacerbate BAPN-induced TAAD which might be useful in future TAAD studies.

2-Deoxyglucose and hydroxychloroquine HPLC-MS-MS analytical methods and pharmacokinetic interactions after oral co-administration in male rats.

Our previous work has shown a synergistic tumoricidal efficacy of combining the hexokinase (HK) inhibitor 2-deoxyglucose (2-DG) and the autophagy inhibitor chloroquine (CQ) through intraperitoneal injections on HK2-addicted prostate cancers in animal models. The pharmacokinetic (PK) behaviors of these oral drugs after simultaneous oral administration have not been reported. We developed high-performance liquid chromatography-tandem mass spectrometry (HPLC-MS-MS) analytical methods for 2-DG and the clinically favored drug hydroxychloroquine (HCQ) for sera samples. Using a jugular vein-cannulated male rat model with serial blood collection before and after a single gavage dose of each drug alone or in combination, we examined their PK metrics for drug-drug interactions. The data demonstrated a rapid and complete separation of 2-DG from common monosaccharides by HPLC-MS-MS multi-reaction monitoring. Application of the HPLC-MS-MS 2-DG and HCQ methods to sera samples of nine rats showed a peak time (Tmax ) for 2-DG of 0.5 h after 2-DG alone or with HCQ and identical post-peak half-life of approximately 1 h. With a seemingly bi-modal time course for HCQ, the Tmax for HCQ alone (1.2 h) was faster than that for the combination (2 h; p = .017). After combination dosing, the peak concentration (Cmax ) and area under the curve (AUC0-4h ) of 2-DG were decreased by 53.8% (p = .0004) and 53.7% (p = .0001), whereas AUC0-8h for HCQ was decreased by 30.8% (p = .0279) from the respective single dosing. Without changing the mean residence time (MRT0-∞ ) of each drug, the combination affected the apparent volume of distribution (Vd ) and clearance (CL) of 2-DG, and CL for HCQ without affecting its Vd . We observed significant negative PK interactions, probably at the intestinal absorption level, between 2-DG and HCQ taken simultaneously by mouth. Future optimization efforts are warranted for their combination regimen for clinical translation.

Outcomes of two-stage type II hybrid aortic arch repair in elderly patients with acute type A aortic dissection.

Acute type A aortic dissection (a-TAAD) is a severe disease characterized by high mortality, which can be fatal in elderly patients. The objective of this study was to investigate the safety and efficacy of two-stage type II hybrid aortic arch repair (HAR) in elderly patients with acute type A aortic dissection (a-TAAD). This was a single-center, retrospective study involving 119 patients with a-TAAD, including 82 males and 37 females, aged 22-81 years old. Eighty-eight patients underwent total aortic arch replacement (TAR) with frozen elephant trunk (FET) implantation (TAR with FET group) and 31 patients underwent two-stage type II HAR (HAR group). Propensity score matching was applied to adjust for preoperative data, and match 25 pairs. The preoperative, perioperative, postoperative and follow-up data were recorded. Fifteen patients died during the perioperative period; 13 cases were in the TAR with FET group and 2 cases were in the HAR group. The age, body mass index, cerebral infarction, renal insufficiency were significantly higher, and the 24-h fluid drainage, the incidence of acute liver injury, acute kidney injury and pulmonary infection were lower in the HAR group (all P < 0.05). Moreover, the mechanical ventilation time, intensive care unit time, hospital stay time were shorter in the HAR group (all P < 0.05). The follow-up period ranged from 12 to 54 months, with 7 deaths (9.3%) in the TAR with FET group and 2 deaths (6.9%) in the HAR group. The true lumen of the aortic arch and the middle descending thoracic aorta were larger and the false lumen thrombosis rates of the middle descending thoracic aorta and renal artery level were higher in the HAR group (all P < 0.05). Two-stage type II HAR is a safe and effective method for the treatment of elderly patients with a-TAAD. It may be a good choice for elderly patients with a-TAAD and comorbidities.

Activation of the alternative complement pathway modulates inflammation in thoracic aortic aneurysm/dissection.

Thoracic aortic aneurysm/dissection (TAAD) is a lethal vascular disease, and several pathological factors participate in aortic medial degeneration. We previously discovered that the complement C3a-C3aR axis in smooth muscle cells promotes the development of thoracic aortic dissection (TAD) through regulation of matrix metalloproteinase 2. However, discerning the specific complement pathway that is activated and elucidating how inflammation of the aortic wall is initiated remain unknown. We ascertained that the plasma levels of C3a and C5a were significantly elevated in patients with TAD and that the levels of C3a, C4a, and C5a were higher in acute TAD than in chronic TAD. We also confirmed the activation of the complement in a TAD mouse model. Subsequently, knocking out Cfb (Cfb) or C4 in mice with TAD revealed that the alternative pathway and Cfb played a significant role in the TAD process. Activation of the alternative pathway led to generation of the anaphylatoxins C3a and C5a, and knocking out their receptors reduced the recruitment of inflammatory cells to the aortic wall. Moreover, we used serum from wild-type mice or recombinant mice Cfb as an exogenous source of Cfb to treat Cfb KO mice and observed that it exacerbated the onset and rupture of TAD. Finally, we knocked out Cfb in the FBN1C1041G/+ Marfan-syndrome mice and showed that the occurrence of TAA was reduced. In summary, the alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.NEW & NOTEWORTHY The alternative complement pathway promoted the development of TAAD by recruiting infiltrating inflammatory cells. Targeting the alternative pathway may thus constitute a strategy for preventing the development of TAAD.

Comparison of 4 mortality scores for surgical repair of type A aortic dissection: a multicentre external validation.

OBJECTIVES: In the last decades, 4 different scores for the prediction of mortality following surgery for type A acute aortic dissection (TAAD) were proposed. We aimed to validate these scores in a large external multicentre cohort. METHODS: We retrospectively analysed patients who underwent surgery for TAAD between 2000 and 2020. Patients were enrolled from 10 centres from 2 European countries. Outcomes were the early (30-day and/or in-hospital) and 1-year mortality. Discrimination, calibration and observed/expected (O/E) ratio were evaluated. RESULTS: A total of 1895 patients (31.7% females, mean age 63.72 ± 12.8 years) were included in the study. Thirty-day mortality and in-hospital mortality were 21.7% (n = 412) and 22.5% (n = 427) respectively. The German Registry of Acute Aortic Dissection Type A (GERAADA) score shows to have the best discrimination [area under the curve (AUC) 0.671 and 0.672] in predicting as well the early and the 1-year mortality, followed by the International Registry of Acute Aortic Dissection (IRAD) model 1 (AUC 0.658 and 0.672), the Centofanti (AUC 0.645 and 0.66) and the UK aortic score (AUC 0.549 and 0.563). According to Hosmer-Lemeshow and Brier tests, the IRAD model I and GERAADA, respectively, were well calibrated for the early mortality, while the GERAADA and Centofanti for the 1-year mortality. The O/E analysis showed a marked underestimation for patients labelled as low-risk for UK aortic score and IRAD model I for both outcomes. CONCLUSIONS: The GERAADA score showed the best performance in comparison with other scores. However, none of them achieved together a fair discrimination and a good calibration for predicting either the early or the 1-year mortality.

Establishment of bone-targeted nano-platform and the study of its combination with 2-deoxy-d-glucose enhanced photodynamic therapy to inhibit bone metastasis.

At present, simple anti-tumor drugs are ineffective at targeting bone tissue and are not purposed to treat patients with bone metastasis. In this study, zoledronic acid (ZOL) demonstrated excellent bone-targeting properties as a bone-targeting ligand. The metal-organic framework (MOF) known as ZIF-90 was modified with ZOL to construct a bone-targeting-based drug delivery system. Chlorin e6 (Ce6) was loaded in the bone-targeted drug delivery system and combined with 2-deoxy-D-glucose (2-DG), which successfully treated bone tumors when enhanced photodynamic therapy was applied. The Ce6@ZIF-PEG-ZOL (Ce6@ZPZ) nanoparticles were observed to have uniform morphology, a particle size of approximately 210 nm, and a potential of approximately -30.4 mV. The results of the bone-targeting experiments showed that Ce6@ZPZ exhibited a superior bone-targeted effect when compared to Ce6@ZIF-90-PEG. The Ce6@ZPZ solution was subjected to 660 nm irradiation and the resulting production of reactive oxygen species increased over time, which could be further increased when Ce6@ZPZ was used in combination with 2-DG. Their combination had a stronger inhibitory capacity against tumor cells than either 2-DG or Ce6@ZPZ alone, increasing the rate of tumor cell apoptosis. The apoptosis rate caused by HGC-27 was 61.56% when 2-DG was combined with Ce6@ZPZ. In vivo results also showed that Ce6@ZPZ combined with 2-DG maximally inhibited tumor growth and prolonged mice survival compared to the other experimental groups. Therefore, the combination of PDT and glycolytic inhibitors serves as a potential option for the treatment of cancer.

2-Deoxy-D-glucose ameliorates inflammation and fibrosis in a silicosis mouse model by inhibiting hypoxia-inducible factor-1α in alveolar macrophages.

Inhaling silica causes the occupational illness silicosis, which mostly results in the gradual fibrosis of lung tissue. Previous research has demonstrated that hypoxia-inducible factor-1α (HIF-1α) and glycolysis-related genes are up-regulated in silicosis. The role of 2-deoxy-D-glucose (2-DG) as an inhibitor of glycolysis in silicosis mouse models and its molecular mechanisms remain unclear. Therefore, we used 2-DG to observe its effect on pulmonary inflammation and fibrosis in a silicosis mouse model. Furthermore, in vitro cell experiments were conducted to explore the specific mechanisms of HIF-1α. Our study found that 2-DG down-regulated HIF-1α levels in alveolar macrophages induced by silica exposure and reduced the interleukin-1ß (IL-1ß) level in pulmonary inflammation. Additionally, 2-DG reduced silica-induced pulmonary fibrosis. From these findings, we hypothesize that 2-DG reduced glucose transporter 1 (GLUT1) expression by inhibiting glycolysis, which inhibits the expression of HIF-1α and ultimately reduces transcription of the inflammatory cytokine, IL-1ß, thus alleviating lung damage. Therefore, we elucidated the important regulatory role of HIF-1α in an experimental silicosis model and the potential defense mechanisms of 2-DG. These results provide a possible effective strategy for 2-DG in the treatment of silicosis.

Aortic dissection in a young male with persistent ductus arteriosus and a novel variant in MYLK.

Pathogenic variants in several genes involved in the function or regulation of smooth muscle cells (SMC) are known to predispose to congenital heart disease and thoracic aortic aneurysm and dissection (TAAD). Variants in MYLK are primarily known to predispose to TAAD, but a growing body of evidence points toward MYLK also playing an essential role in the regulation of SMC contraction outside the aorta. In this case report, we present a patient with co-occurrence of persistent ductus arteriosus (PDA) and thoracic aortic dissection. Genetic analyses revealed a novel splice acceptor variant (c.3986-1G > A) in MYLK, which segregated with disease in the family. RNA-analyses on fibroblasts showed that the variant induced skipping of exon 24, which resulted in an in-frame deletion of 101 amino acids. These findings suggest that MYLK-associated disease could include a broader phenotypic spectrum than isolated TAAD, including PDA and obstructive pulmonary disease. Genetic analyses could be considered in families with TAAD and PDA or obstructive pulmonary disease.

2-Deoxy-glucose ameliorates the peritoneal mesothelial and endothelial barrier function perturbation occurring due to Peritoneal Dialysis fluids exposure.

Peritoneal dialysis (PD) and prolonged exposure to PD fluids (PDF) induce peritoneal membrane (PM) fibrosis and hypervascularity, leading to functional PM degeneration. 2-deoxy-glucose (2-DG) has shown potential as PM antifibrotic by inhibiting hyper-glycolysis induced mesothelial-to-mesenchymal transition (MMT). We investigated whether administration of 2-DG with several PDF affects the permeability of mesothelial and endothelial barrier of the PM. The antifibrotic effect of 2-DG was confirmed by the gel contraction assay with embedded mesothelial (MeT-5A) or endothelial (EA.hy926) cells cultured in Dianeal® 2.5 % (CPDF), BicaVera® 2.3 % (BPDF), Balance® 2.3 % (LPDF) with/without 2-DG addition (0.2 mM), and qPCR for αSMA, CDH2 genes. Moreover, 2-DG effect was tested on the permeability of monolayers of mesothelial and endothelial cells by monitoring the transmembrane resistance (RTM), FITC-dextran (10, 70 kDa) diffusion and mRNA expression levels of CLDN-1 to -5, ZO1, SGLT1, and SGLT2 genes. Contractility of MeT-5A cells in CPDF/2-DG was decreased, accompanied by αSMA (0.17 ± 0.03) and CDH2 (2.92 ± 0.29) gene expression fold changes. Changes in αSMA, CDH2 were found in EA.hy926 cells, though αSMA also decreased under LPDF/2-DG incubation (0.42 ± 0.02). Overall, 2-DG mitigated the PDF-induced alterations in mesothelial and endothelial barrier function as shown by RTM, dextran transport and expression levels of the CLDN-1 to -5, ZO1, and SGLT2. Thus, supplementation of PDF with 2-DG not only reduces MMT but also improves functional permeability characteristics of the PM mesothelial and endothelial barrier.

Phenylboronic Acid-Modified Near-Infrared Region II Excitation Donor-Acceptor-Donor Molecule for 2-Deoxy-d-Glucose Improved Starvation/Chemo/Photothermal Combination Therapy.

Synergistic chemotherapy and photothermal therapy (PTT) have emerged as a promising anticancer paradigm to achieve expected therapeutic effects while mitigating side effects. However, the chemo/PTT combination therapy suffers from limited penetration depth, thermoresistance performance of tumor cells, and low drug bioavailability. Herein, multifunctional nanoparticles (BTP/DOX/2DG NPs) coloaded with near-infrared region II (NIR-II) light excitation donor-acceptor-donor (D-A-D) small molecules, doxorubicin (DOX), and 2-deoxy-d-glucose (2-DG) are developed for reinforced starvation/chemo/NIR-II PTT combination therapy. The synthesized phenylboronic acid (PBA)-modified water-soluble D-A-D molecule (BBT-TF-PBA) not only exhibits high binding ability to DOX and 2-DG through donor-acceptor coordination interactions PBA-diol bonds but also serves as a photoactive agent for NIR-II fluorescence imaging, NIR-II photoacoustic imaging, and NIR-II PTT. Under the acidic and oxidizing conditions in the tumor microenvironment, donor-acceptor coordination interactions and PBA-diol bond are decomposed, simultaneously releasing DOX and 2-DG from BTP/DOX/2DG NPs to achieve effective chemotherapy and starvation therapy. 2-DG also effectively inhibits the expression of heat shock protein and further enhances NIR-II PTT and chemotherapy efficiency. In vitro and in vivo experiments demonstrate the combination effect of BTP/DOX/2DG NPs for chemotherapy, NIR-II PTT, and starvation therapy.