Structure-based development of novel substrate-type G9a inhibitors as epigenetic modulators for sickle cell disease treatment.

The discovery and development of structurally distinct lysine methyltransferase G9a inhibitors have been the subject of intense research in epigenetics. Structure-based optimization was conducted, starting with the previously reported seed compound 7a and lead to the identification of a highly potent G9a inhibitor, compound 7i (IC50 = 0.024 µM). X-ray crystallography for the ligand-protein interaction and kinetics study, along with surface plasmon resonance (SPR) analysis, revealed that compound 7i interacts with G9a in a unique binding mode. In addition, compound 7i caused attenuation of cellular H3K9me2 levels and induction of γ-globin mRNA expression in HUDEP-2 cells in a dose-dependent manner.

One-year sac regression is associated with freedom from fatal adverse events after endovascular aneurysm repair.

OBJECTIVE: Although the predictors of long-term prognosis after endovascular aneurysm repair (EVAR) have been investigated, several reports have suggested that early sac shrinkage (ESS) is associated with superior long-term prognosis. However, it was not clear whether ESS was associated with aneurysm-related mortality. The aim of this study was to define fatal adverse events and to examine their association with ESS. METHODS: All consecutive patients who underwent EVAR for an abdominal aortic aneurysm at Nagoya University Hospital between June 2007 and August 2018 were identified. We defined ESS as an aneurysm diameter decrease of 10 mm or more at 1 year after EVAR, and we defined fatal adverse events as aneurysm-related death, aneurysm sac rupture, open conversion, secondary type Ia endoleak, or secondary type IIIa/b endoleak. Then, we evaluated the association between ESS and fatal adverse events and identified predictors of ESS. RESULTS: During the study period, 553 patients were identified and included. Fatal adverse events occurred in 42 patients (7.6%), and the details of the fatal adverse events were as follows: 13 aneurysm-related deaths, 17 aneurysm sac ruptures, 14 open conversions, 13 type Ia endoleaks, and 6 type III endoleaks. ESS occurred in 146 patients (26.4%). Kaplan-Meier curves showed that the ESS group had a significantly lower incidence of fatal adverse events (P < .001). Multivariate analysis showed that there were significant differences in terms of 5 or more preoperatively patent lumbar arteries (odds ratio [OR], 0.67; P = .049; 95% confidence interval [CI], 0.45-1.00), chronic kidney disease (OR, 0.49; P < .01; 95% CI, 0.29-0.84), and Zenith endograft use (OR, 1.76; P < .01; 95% CI, 1.16-2.67). Furthermore, the percentage of cases that achieved an aneurysm diameter of less than 40 mm was significantly higher in the ESS group (76.0% vs 15.5%; P < .01). The use of Zenith endografts showed a significantly higher rate of aneurysm disappearance than the use of Endurant endografts (P < .01) and Excluder endografts (P < .01). In addition, it was found that ESS was more likely to occur with the use of Zenith endografts, even when propensity score matching was performed for the neck morphology. CONCLUSIONS: ESS was associated with a lower rate of life-threatening adverse events after EVAR. The use of Zenith endografts was a predictor of ESS and was associated with increased rates of long-term sac shrinkage and aneurysm disappearance compared with the Endurant and Excluder endografts. Using the predictors of ESS identified in this study, we may be able to expand the indications for EVAR to patients with a longer life expectancy.

The Association Between the D-dimer Level at 1 Year After EVAR and Sac Diameter Change in Patients With Persistent Type 2 Endoleak.

PURPOSE: Recent studies suggested that continuous clotting renewal in thrombi plays a central role in sac enlargement after endovascular aneurysm repair (EVAR). We reviewed patients with persistent type 2 endoleak (T2EL) to estimate the impact of D-dimer level on sac enlargement. METHODS: A retrospective review of elective EVAR for infrarenal abdominal aortic aneurysm performed between June 2007 and February 2020. Persistent T2EL was defined as T2EL confirmed at both the 6 and 12 month contrast-enhanced computed tomography (CECT) follow-ups. "Isolated" T2EL was defined as T2EL without other types of endoleak within 12 months. Patients with >2 year follow-up, persistent isolated T2ELs, and D-dimer level data at 1 year (DD1Y) were included. Patients with any reintervention within 12 months were excluded. The association between DD1Y and aneurysm enlargement (AnE), defined as a ≥5 mm diameter increase, within 5 years was analyzed. Among 761 conventional EVAR, 515 patients had >2 years of follow-up. Thirty-three patients with any reintervention within 12 months and 127 patients without CECT at either 6 or 12 months were excluded. Among 131 patients with persistent isolated T2ELs, 74 patients with DD1Y data were enrolled. During a 37 month median follow-up [25-60, IQR], 24 AnEs were observed. In the AnE patients, the median DD1Y was significantly higher than that in the other patients (12.30 [6.88-21.90] vs 7.62 [4.41-13.00], P=0.024). ROC curve analysis indicated that the optimal cutoff point of DD1Y for AnE was 5.5 µg/mL (AUC=0.681). In univariate analysis, angulated neck, occlusion of the inferior mesenteric artery, and DD1Y≥5.5 µg/mL were significantly associated with AnE (P= 0.037, 0.038, and 0.010). Cox regression analysis revealed that DD1Y≥5.5 µg/mL was correlated with AnE (P=0.042, HR [95% CI] 4.520 [1.056-19.349]). CONCLUSION: A 1 year higher D-dimer level can potentially predict AnE within 5 years in persistent T2EL patients. AnE was considered improbable when the D-dimer level was low enough. CLINICAL IMPACT: The present study suggests that a 1-year higher D-dimer level could potentially predict aneurysm expansion within 5 years in patients with persistent type 2 endoleak (T2EL). On the other hand, aneurysm expansion was considered unlikely if the D-dimer level was low enough.As there are many patients with T2EL who require regular follow-up, any predictor of future aneurysm expansion could be of great help in conserving medical resources. In patients with a low likelihood of future expansion, we might consider delaying follow-up, similar to patients with sac shrinkage.

Factors Associated With Spontaneous Sac Shrinkage in Patients With Persistent Type 2 Endoleaks After EVAR.

PURPOSE: Despite controversy surrounding the management of type 2 endoleaks (T2ELs) after endovascular aortic aneurysm repair (EVAR), the current European guidelines recommend reintervention for T2ELs when the aneurysm expands by ≥10 mm. Meanwhile, sac shrinkage ≥10 mm can be considered low risk for failure even with T2ELs, and the guidelines suggest less frequent follow-up delayed until 5 years after EVAR. This study reviewed patients with persistent T2ELs to identify predictors of spontaneous sac shrinkage (SpS) within 5 years. METHODS: A retrospective review of elective EVAR for infrarenal aortic aneurysms between June 2007 and December 2017. Patients with >1 year follow-up and persistent T2ELs, defined as T2ELs confirmed at both the 6 and 12 month follow-up with contrast-enhanced computed tomography (CT), were included. Any reintervention or type 1 or 3 endoleaks within 12 months were excluded. SpS was defined as a ≥10 mm reduction in diameter without any reintervention. Aneurysm enlargement (AnE) was defined as a ≥5 mm increase in diameter. Factors associated with SpS within 5 years were analyzed. The clinical outcomes were reviewed. RESULTS: Among 726 patients, 162 patients had persistent isolated T2ELs. After excluding 21 patients, 141 patients were enrolled. During a median follow-up of 43 months (interquartile range [IQR], 26-60), 28 SpS and 39 AnE were observed, and 31 reinterventions were performed. The cumulative rates of SpS were 14.2%±2.9% and 25.6%±5.1% at 1 and 5 years. Cox regression analysis revealed that the presence of ≥6 patent lumbar arteries had a significant negative correlation with SpS (p=0.036). During further follow-up after SpS, 2 reinterventions for type 1a and 3b endoleaks were required at 49 and 45 months. CONCLUSIONS: Patients with fewer patent lumbar arteries were likely to experience SpS within 5 years, even in the presence of persistent T2ELs. Follow-up imaging studies were advisable earlier than 5 years, even after SpS.

Epicardial adipose tissue volume is associated with abdominal aortic aneurysm expansion.

BACKGROUND: The epicardial adipose tissue volume (EATV) is associated with cardiovascular diseases such as coronary artery disease. However, no information is available regarding the relationship between the EATV and abdominal aortic aneurysm (AAA) expansion. In the present study, we evaluated the association between the EATV and AAA growth and sought to identify the predictors of AAA expansion. METHODS: Between June 2009 and December 2019, 906 patients had undergone endovascular or open repair of AAAs at our institution. Patients with previous cardiac surgery, previous ascending thoracic aortic surgery, a ruptured AAA, an infected AAA, an inflammatory AAA, a saccular aneurysm, a solitary iliac aneurysm, or reintervention after treatment of the AAA were excluded. A total of 237 patients with at least two preoperative computed tomography (CT) scans performed >180 days apart were included in the present study. The EATV within the pericardium was retrospectively quantified from the preoperative non-contrast-enhanced CT images using a three-dimensional workstation. The EATV index was defined as the EATV divided by the body surface area. The AAA expansion rate was defined as an increase in the AAA diameter annually, and the patients were divided into the slow-expansion group (expansion rate, <5 mm/y) and the fast-expansion group (expansion rate, ≥5 mm/y). The correlation between the expansion rate and the EATV index was analyzed, and the cutoff value for the EATV index was determined using a receiver operating characteristics curve. Multivariate analysis was used to assess the predictors of the AAA expansion rate. RESULTS: The expansion rate of AAA correlated positively with the EATV index (R = 0.237; P < .001). The initial aneurysm diameter (P < .001) and EATV index (P = .009) differed significantly between the two groups. The cutoff for the EATV index was 60.3 cm3/m2 (area under the curve, 0.658; 95% confidence interval [CI], 0.568-0.749; sensitivity, 1.000; specificity, 0.309). Multivariate analysis revealed that the initial aneurysm diameter and an EATV index of >60.3 cm3/m2 were significantly associated with the AAA expansion rate. CONCLUSIONS: The results of the present study have demonstrated that the EATV index is associated with AAA expansion.

Severe Tortuosity of the Distal Descending Thoracic Aorta Affects the Accuracy of Distal Deployment During a Thoracic Endovascular Aortic Repair.

PURPOSE: An accurate distal deployment is essential for successful thoracic endovascular aortic repair (TEVAR) of a paradiaphragmatic aortic aneurysm. This study aimed to investigate the anatomical and intraoperative factors that affect the accuracy of distal deployment during TEVAR. METHODS: We conducted a retrospective review of preoperative and postoperative computed tomography scans of 426 patients undergoing TEVAR at our institution between October 2008 and May 2021, of which the stent-graft was attempted to be deployed just above the celiac axis or the superior mesenteric artery in 56 patients. Based on the anatomical factors related to the malposition (deployed >10 mm away from the target vessel) and the greater curve to the straight-line ratio (G/S ratio), the patients were categorized as severe tortuosity (n=21) and mild tortuosity (n=35) groups to compare the operative and clinical outcomes. RESULT: Stent-graft malpositioning occurred in 21 cases. Among all anatomical variables, only the G/S ratio was significantly larger in the malpositioned cases (p=0.049). A cutoff G/S ratio value of 1.15 was determined using the receiver operating curve analysis. In the severe tortuosity group, the distal end of the stent-graft was significantly farther (median: 10.0 [interquartile range (IQR): 2.5-19.5] mm vs 3.0 [0-8.0] mm; p=0.015) from the target vessel, and the tilt angle of the stent-graft's distal edge was larger (median: 21.4 [IQR: 15.8-24.5] vs 9.5 [5.5-12.5] degree; p<0.01) than that in the mild tortuosity group. Both groups were comparable for the incidence of a primary type Ib endoleak (p=0.454), a secondary type Ib endoleak (p=1.0), and the rate of distal reintervention (p=0.276). CONCLUSION: Severe tortuosity in the distal descending thoracic aorta is associated with a malpositioned and tilted distal end of the stent-graft. CLINICAL IMPACT: Thoracic endovascular aortic repair (TEVAR) for paradiaphragmatic thoracic aortic aneurysms requires accurate distal landing. In this paper, a retrospective CT analysis revealed that the greater curve to the straight-line ratio (G/S ratio) was associated to affects the malposition of the stent graft, defined as being deployed more than 10 mm away from the target vessel. Further, a comparative analysis based on the G/S ratio demonstrated that severe aortic tortuosity was associated with a more distal and tilted deployment of the stent graft.

Selective Inhibitor Design for Kinase Homologs Using Multiobjective Monte Carlo Tree Search.

Designing highly selective molecules for a drug target protein is a challenging task in drug discovery. This task can be regarded as a multiobjective problem that simultaneously satisfies criteria for various objectives, such as selectivity for a target protein, pharmacokinetic endpoints, and drug-like indices. Recent breakthroughs in artificial intelligence have accelerated the development of molecular structure generation methods, and various researchers have applied them to computational drug designs and successfully proposed promising drug candidates. However, designing efficient selective inhibitors with releasing activities against various homologs of a target protein remains a difficult issue. In this study, we developed a de novo structure generator based on reinforcement learning that is capable of simultaneously optimizing multiobjective problems. Our structure generator successfully proposed selective inhibitors for tyrosine kinases while optimizing 18 objectives consisting of inhibitory activities against 9 tyrosine kinases, 3 pharmacokinetics endpoints, and 6 other important properties. These results show that our structure generator and optimization strategy for selective inhibitors will contribute to the further development of practical structure generators for drug designs.

Impact of Serum Zinc Level and Oral Zinc Supplementation on Clinical Outcomes in Patients Undergoing Infrainguinal Bypass for Chronic Limb-Threatening Ischemia.

BACKGROUND: Zinc (Zn) has been reported to play an important role in wound healing (WH). Nevertheless, the effect of Zn in chronic limb-threatening ischemia (CLTI) patients is unclear. This study investigated the effect of Zn on the clinical outcomes of CLTI patients undergoing bypass surgery.Methods and Results: This study reviewed 111 consecutive patients who underwent an infrainguinal bypass from 2012 to 2020. Patients with Zn deficiency (serum Zn level <60 µg/dL) received oral Zn supplementation and maintained a normal level until WH. This study aimed to explore: (1) the effect of Zn deficiency; and (2) Zn supplementation in Zn-deficient patients on the clinical outcomes of this cohort. Patients with Zn deficiency, Zn supplementation, and no Zn supplementation despite Zn deficiency accounted for 48, 21, and 42 patients, respectively. (1) Zn deficiency was associated with WH (HR, 0.47; 95% CI, 0.29-0.78: P=0.003), major adverse limb events (MALE) (HR, 2.53; 95% CI, 1.26-5.09: P=0.009), and major amputation or death (HR, 3.17; 95% CI, 1.51-6.63: P=0.002). (2) Zn supplementation was positively related to WH (HR, 2.30; 95% CI, 1.21-4.34: P=0.011). This result was confirmed using propensity score matching (HR, 2.24; 95% CI, 1.02-4.87: P=0.043). CONCLUSIONS: The current study revealed that Zn level was associated with clinical outcomes in CLTI patients after bypass surgery. Oral Zn supplementation could improve WH in these patients.

New Morphological Factor for Predicting Late Proximal Type I Endoleak after Endovascular Aneurysm Repair.

BACKGROUND: Although we have witnessed several cases of late proximal type I endoleak (T1AEL) after endovascular aneurysm repair (EVAR), most patients did not have "hostile neck" preoperatively. We hypothesized that the distance between the lowest renal artery and the neck angulation point and neck length are the 2 most important factors for maintaining long-term proximal sealing. This study evaluated "neck hostility," which is the product of the distance to the angulation point and the neck length, as a preoperative morphological risk factor for the development of late T1AEL after EVAR. METHODS: A retrospective review of a prospectively assembled database was performed for all patients who had undergone EVAR at a single institution from June 2007 to May 2017. Patient demographics and preoperative imaging data were collected, and Cox regression analysis was performed to identify the risk factors for late T1AEL. RESULTS: Of the 655 patients who underwent EVAR during the study period, 115 were excluded due to complex EVAR (n = 14), primary indications for iliac aneurysms (n = 86), primary T1AEL (n = 3), or other reasons (n = 15). Of the remaining 537 patients, twelve patients (2.2%) developed late T1AEL a median of 3.2 (interquartile range [IQR]; 3.0, 5.4) years after EVAR. Receiver operating characteristic (ROC) curve analysis revealed a neck hostility cutoff value of 8. Cox regression analysis revealed that a neck hostility value ≤8 and conical neck anatomy were risk factors for the development of late T1AEL after EVAR. Well-known hostile neck factors such as short neck, severe angulated neck, and severe calcification/thrombus in the proximal neck were not significantly different. CONCLUSIONS: The present study demonstrated a correlation between late T1AEL and the product of the angulation distance and the neck length. This factor may be useful for predicting poor late proximal outcomes after EVAR.

Predictors of infrapopliteal vein bypass graft revision in patients with chronic limb-threatening ischemia.

PURPOSE: Surgical revascularization is the standard treatment for chronic limb-threatening ischemia (CLTI). However, some patients may require reintervention. The Global Anatomic Staging System (GLASS), which evaluates the complexity of infrainguinal lesions, was proposed. This study aimed to identify predictors for graft revision and evaluate whether GLASS impacts vein graft revision. METHODS: Between 2011 and 2018, CLTI patients who underwent de novo infrapopliteal bypass using autogenous veins were retrospectively analyzed. To assess anatomic complexity with GLASS, femoropopliteal, infrapopliteal, and inframalleolar/pedal (IM) disease grades were determined. The outcomes of patients with or without graft revision were compared. Cox regression analysis was performed. RESULTS: Thirty-six of the 80 patients underwent reintervention for graft revision. Compared to the non-graft revision group, the graft revision group exhibited significantly higher rates of GLASS stage III (66% vs 81%, p = 0.046) and grade P2 IM disease (25% vs 58%, p = 0.009). Multivariate analysis revealed that IM grade P2 (hazard ratio [HR], 3.35; 95% confidence interval [CI], 1.66-6.75; p = 0.001) and spliced vein grafts (HR, 3.18; 95% CI, 1.43-7.06; p = 0.005) were significantly associated with graft revision. CONCLUSIONS: This study demonstrated that IM grade P2 and spliced vein grafts were predictors of graft revision. The GLASS stratification of IM disease grade may be useful in optimizing treatment for CLTI.

Low-density vulnerable thrombus/plaque volume on preoperative computed tomography predicts for spinal cord ischemia after endovascular repair for thoracic aortic aneurysm.

BACKGROUND: Similar to open surgical repair, thoracic endovascular aortic repair (TEVAR) carries a risk of spinal cord ischemia (SCI). However, the generally lower incidence of SCI after TEVAR compared with that after open surgical repair, despite the inability to preserve the intercostal arteries, indicates different pathophysiologic mechanisms with the two procedures. We hypothesized that a microembolism from an aortic mural thrombus is the main cause of SCI. Thus, we evaluated the association between the density of a mural thrombus in the descending thoracic aorta and the development of SCI. METHODS: A retrospective review of a prospectively assembled database was performed for all patients who had undergone surgery at a single institution from October 2008 to December 2018. Patient demographics and procedure-related variables were collected. The volume and Hounsfield unit (HU) value of mural thrombi in the whole descending thoracic aorta were estimated on preoperative computed tomography using a three-dimensional workstation. Logistic regression analysis was performed to identify the risk factors for SCI development. RESULTS: Of the 367 patients who had undergone TEVAR during the study period, 155 were excluded because of previous arch surgery (n = 59), previous descending thoracic aortic surgery (n = 6), previous TEVAR (n = 6), unavailability of optimal preoperative computed tomography data (n = 17), double-barreled dissection (n = 40), and other reasons. The mean ± standard deviation age of the remaining 212 patients was 75.8 ± 6.4 years, and 42 (19.8%) were women. Of the 212 patients, 14 (6.6%) developed SCI after TEVAR. The low mean density of the mural thrombus, total thrombus volume, low-density (≥-100 HU but <30 HU) thrombus volume, intermediate-density (≥30 HU but <150 HU) thrombus volume, treatment length, urgent surgery, and baseline dialysis differed significantly between patients with and without SCI. Although subsequent multivariate analysis could not be performed owing to the small number of SCI events, vulnerable low-density thrombus/plaque was a stronger predictor among the aneurysm-related factors of SCI after TEVAR on univariate analysis. Well-known risk factors, such as distal coverage between T8 and L1, left subclavian artery coverage, previous abdominal aortic surgery, and prophylactic spinal drainage, did not show significant differences. CONCLUSIONS: The results from the present study have demonstrated that among aneurysm-related factors, a lower density mural thrombus/plaque in the descending thoracic aorta is a predictor of SCI development after TEVAR. These results suggest that microembolism is one of the important mechanisms of SCI after TEVAR, which might change the prophylactic strategy.

Novel bicyclic pyrazoles as potent ALK2 (R206H) inhibitors for the treatment of fibrodysplasia ossificans progressiva.

Mutant activin receptor-like kinase-2 (ALK2) is associated with the pathogenesis of fibrodysplasia ossificans progressiva, making it an attractive target for therapeutic intervention. We synthesized a new series of bicyclic pyrazoles and evaluated their mutant ALK2 enzyme inhibitory activities, leading to the identification of 8 as the most potent inhibitor. This compound showed moderate microsomal metabolic stability and human ether-a-go-go related gene (hERG) safety. In C2C12 cells carrying mutant ALK2 (R206H), 8 efficiently inhibited the bone morphogenetic protein (BMP)-induced alkaline phosphatase activity.

FMODB: The World's First Database of Quantum Mechanical Calculations for Biomacromolecules Based on the Fragment Molecular Orbital Method.

We developed the world's first web-based public database for the storage, management, and sharing of fragment molecular orbital (FMO) calculation data sets describing the complex interactions between biomacromolecules, named FMO Database (https://drugdesign.riken.jp/FMODB/). Each entry in the database contains relevant background information on how the data was compiled as well as the total energy of each molecular system and interfragment interaction energy (IFIE) and pair interaction energy decomposition analysis (PIEDA) values. Currently, the database contains more than 13 600 FMO calculation data sets, and a comprehensive search function implemented at the front-end. The procedure for selecting target proteins, preprocessing the experimental structures, construction of the database, and details of the database front-end were described. Then, we demonstrated a use of the FMODB by comparing IFIE value distributions of hydrogen bond, ion-pair, and XH/π interactions obtained by FMO method to those by molecular mechanics approach. From the comparison, the statistical analysis of the data provided standard reference values for the three types of interactions that will be useful for determining whether each interaction in a given system is relatively strong or weak compared to the interactions contained within the data in the FMODB. In the final part, we demonstrate the use of the database to examine the contribution of halogen atoms to the binding affinity between human cathepsin L and its inhibitors. We found that the electrostatic term derived by PIEDA greatly correlated with the binding affinities of the halogen containing cathepsin L inhibitors, indicating the importance of QM calculation for quantitative analysis of halogen interactions. Thus, the FMO calculation data in FMODB will be useful for conducting statistical analyses to drug discovery, for conducting molecular recognition studies in structural biology, and for other studies involving quantum mechanics-based interactions.

Endovascular Aneurysm Repair Compared With Open Repair Does Not Improve Survival in Octogenarians.

BACKGROUND: Not every elderly person is frail, and whether it would be beneficial to perform endovascular aneurysm repair (EVAR) solely because a patient is older is unclear. This study aimed to compare the results of EVAR and open surgical repair (OSR) in elderly individuals.Methods and Results:From May 1998 to March 2021, 828 EVAR patients and 886 OSR patients with abdominal aortic aneurysm (AAA) were reviewed. Patients aged ≥80 years were included among them. After propensity score matching by age, sex, and American Society of Anesthesiologists (ASA) classification, the outcomes were compared between patients who underwent EVAR and OSR. The study cohort was composed of 351 EVAR patients and 90 OSR patients. The groups had similar comorbidities, except that EVAR patients were significantly older and had higher ASA classifications. After propensity score matching, 79 pairs of patients were selected. The 30-day mortality (0 vs. 1.2%) and aneurysm-related death (ARD) rates during follow up (2.3% vs. 2.3%, respectively) were similar between the groups. Kaplan-Meier curves revealed that estimated overall survival and freedom from ARD were also similar. CONCLUSIONS: This study suggests that EVAR cannot improve survival outcomes compared with OSR if applied solely because a patient is aged ≥80 years. Not only age but also other risk factors and quality of life after surgery need to be further studied.

Time-to-Event Analysis of the Impact of Endovascular Aortic Aneurysm Repair on Chronic Renal Decline.

BACKGROUND: Although randomized studies have revealed the long-term outcomes of the endovascular repair (ER) of abdominal aortic aneurysm (AAA) compared to open repair (OR), there is controversy surrounding chronic renal decline (CRD) after ER. This study reviewed our propensity-matched cohorts of ER and OR to compare CRD rates using a time-to-event analysis. The ER groups undergoing suprarenal (SR) or infrarenal (IR) proximal fixation were also compared with the OR group. METHODS: This retrospective review of infrarenal AAA repair was conducted from June 2007-December 2017. Patients with ≥1 year of follow-up were included. Cases of supra/pararenal AAAs, infectious AAAs, rupture, or severe chronic kidney disease (CKD) (estimated glomerular filtration rate (eGFR) <15 mL/min/1.73 m2 or dependence on renal replacement therapy) were excluded. CRD was defined as eGFR decline of >20% or de novo hemodialysis during follow-up. Patients treated with ER (ER group) and OR (OR group) were propensity-score matched for age, sex, comorbidities, ejection fraction, respiratory function, and baseline eGFR. Kaplan-Meier analysis compared the freedom from CRD rates of the matched cohorts (mER and mOR groups). Patients treated with SR and IR fixation devices (SR and IR groups) were also separately matched to the OR group, followed by analysis. RESULTS: In total, 1087 patients underwent elective AAA repair. Among them, 944 (512 ER and 432 OR) were enrolled. The ER group was older than the OR group (median age 79 vs 71; P<0.001). The ER group had significantly lower baseline eGFR and more comorbidities than the OR group. Among 187 propensity-score matched pairs (187 mER and 187 mOS patients), background characteristics, including age and baseline eGFR, were comparable, but median renal function follow-up was significantly longer in the mER group than in the mOR group (48 vs 26 months; P<0.001). CRD was observed in 57 patients in the mER group and 30 patients in the mOR group. Kaplan-Meier analysis of the freedom from CRD showed no significant difference between the matched groups (P=0.268); however, in the later follow-up of >4 years, CRD was more common in the mER group. The matched analyses between the OR group and specific fixation groups, comprising 102 OR-SR and 73 OR-IR pairs, demonstrated no significant differences in CRD. CONCLUSIONS: Compared to OR, there was no significant impact of ER on CRD at up to 4 years, supporting the safety of ER in terms of the mid-term renal outcome of our present clinical practice.

Clinical Comparison between Early and Late Spontaneous Sac Shrinkage after Endovascular Aortic Aneurysm Repair.

BACKGROUND: Early spontaneous shrinkage (ESS) of abdominal aortic aneurysm (AAA) within 1 year after endovascular aortic aneurysm repair (EVAR) could be a predictor of durable success. However, late spontaneous shrinkage (LSS) during longer follow-up has not been well addressed. We compared late complications of ESS and LSS. METHODS: Our series of elective EVAR for infrarenal AAA from June 2007 to December 2017 was reviewed. Patients with ≥1 year of follow-up with computed tomography (CT) studies were included. Patients with any reintervention within 1 year were excluded. Spontaneous shrinkage (SpS) was defined as a diameter reduction ≥10 mm without any reintervention. ESS was defined as SpS within 1 year, and LSS was defined as SpS occurring after 1 year of follow-up. Aneurysms that became larger than the original size after SpS were defined as re-expansion. Late complications (re-expansion, reintervention, and aneurysm-related death) and related factors were compared between ESS and LSS. RESULTS: A total of 495 patients were enrolled. Median follow-up was 43 months [24-67, interquartile range (IQR)]. Among patients, 126 ESS and 55 LSS occurred. The cumulative rates of SpS were 25.7±2.0%, 37.4±2.4%, and 47.3±3.7% at 1, 3, and 7 years, respectively. There was 1 re-expansion and 6 reinterventions during further follow-up after SpS. The rates of freedom from late complications at 5 years were not significantly different between ESS (89.2±4.0%) and LSS (95.8±4.1%) (P = 0.465). Regression analysis revealed that the Zenith device was significantly related to ESS compared to the Excluder (P = 0.006) and Endurant (P = 0.040) . More than 6 preoperative patent lumbar arteries negatively correlated with ESS (P = 0.023). However, these factors had no significant impact on LSS. CONCLUSIONS: The rates of late complications after SpS were comparable between ESS and LSS. Patients with delayed sac shrinkage with a reduction in diameter ≥10 mm should expect the same durable success as patients with quick shrinkage.

Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei.

African trypanosomiasis, sleeping sickness in humans or nagana in animals, is a potentially fatal neglected tropical disease and a threat to 65 million human lives and 100 million small and large livestock animals in sub-Saharan Africa. Available treatments for this devastating disease are few and have limited efficacy, prompting the search for new drug candidates. Simultaneous inhibition of the trypanosomal glycerol kinase (TGK) and trypanosomal alternative oxidase (TAO) is considered a validated strategy toward the development of new drugs. Our goal is to develop a TGK-specific inhibitor for coadministration with ascofuranone (AF), the most potent TAO inhibitor. Here, we report on the identification of novel compounds with inhibitory potency against TGK. Importantly, one of these compounds (compound 17) and its derivatives (17a and 17b) killed trypanosomes even in the absence of AF. Inhibition kinetics revealed that derivative 17b is a mixed-type and competitive inhibitor for TGK and TAO, respectively. Structural data revealed the molecular basis of this dual inhibitory action, which, in our opinion, will aid in the successful development of a promising drug to treat trypanosomiasis. Although the EC50 of compound 17b against trypanosome cells was 1.77 µM, it had no effect on cultured human cells, even at 50 µM.-Balogun, E. O., Inaoka, D. K., Shiba, T., Tsuge, C., May, B., Sato, T., Kido, Y., Nara, T., Aoki, T., Honma, T., Tanaka, A., Inoue, M., Matsuoka, S., Michels, P. A. M., Watanabe, Y.-I., Moore, A. L., Harada, S., Kita, K. Discovery of trypanocidal coumarins with dual inhibition of both the glycerol kinase and alternative oxidase of Trypanosoma brucei brucei.

ALK2: A Therapeutic Target for Fibrodysplasia Ossificans Progressiva and Diffuse Intrinsic Pontine Glioma.

Fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG) are diseases that typically manifest in childhood and are associated with severely reduced life expectancy. However, there are currently no effective therapies for these diseases, which remain incurable. Activin receptor-like kinase-2 (ALK2), encoded by the ACVR1 gene, is a bone morphogenetic protein (BMP) type-I receptor subtype that plays an important physiological role in the development of bones, muscles, brain, and other organs. Constitutively active mutants of ALK2 have been identified as causative of FOP and involved in the tumorigenesis of DIPG owing to abnormal activation of BMP signaling, and therefore have emerged as promising treatment targets. Here, we describe these two diseases, along with the link to ALK2 signal transduction, and highlight potential ALK2 inhibitors that are under development to offer new hope for patients with FOP and DIPG.

[Verification of Image Reconstruction Method and Collimator Suitable for Quantitative Analysis of Striatum in Dopamine Transporter Scintigraphy].

Specific binding ratio (SBR) is mainly used as a quantitative index of dopamine transporter scintigraphy, although it was reported that standardized uptake value (SUV) is useful for clinical diagnosis in recent years. The aim of this study is to evaluate whether xSPECT is useful for SUV in dopamine transporter scintigraphy. xSPECT is a recently developed, high-resolution image reconstruction technique that transforms single photon emission computed tomography (SPECT) to a computed tomography (CT) coordinate system. Furthermore, low-penetration high-resolution (LPHR), which there has been no previous physical evaluation report was also evaluated. The radioactive concentration of the image with xSPECT is automatically calculated by the periodic sensitivity calibration and one volume sensitivity calibration. In the case of images with conventional reconstruction methods as filtered back projection (FBP) and ordered subset expectation maximization (OSEM), the calibration factor related to the photon count and radioactive concentration was calculated from measuring a cylinder phantom filled with Iodine-123. Radioactive concentrations of the SUV factor were measured by SPECT data acquisition with the striatal phantom in various conditions. Radioactive concentrations with conventional reconstruction methods had a lower value (for example, with FBP it was 7.53 kBq/ml, with OSEM it was 7.22 kBq/ml) compared to the actual measurement value, although that with xSPECT (12.45 kBq/ml) got close to the actual measurement value (14.68 kBq/ml). LPHR showed an approximation to low-energy high-resolution (LEHR) in terms of spatial resolution and scatter fraction estimated from energy windows. The quantitative accuracy of radioactive concentration was the highest under xSPECT.

Bis-Heteroaryl Pyrazoles: Identification of Orally Bioavailable Inhibitors of Activin Receptor-Like Kinase-2 (R206H).

Mutant activin receptor-like kinase-2 (ALK2) was reported to be closely associated with the pathogenesis of fibrodysplasia ossificans progressiva (FOP) and diffuse intrinsic pontine glioma (DIPG), and therefore presents an attractive target for therapeutic intervention. Through in silico virtual screenings and structure-activity relationship studies assisted by X-ray crystallographic analyses, a novel series of bis-heteroaryl pyrazole was identified as potent inhibitors of ALK2 (R206H). Derived from in silico hit compound RK-59638 (6a), compound 18p was identified as a potent inhibitor of ALK2 (R206H) with good aqueous solubility, liver microsomal stability, and oral bioavailability.