Effect of aspirin on cardiovascular events in patients undergoing hemodialysis with hyperphosphatemia: A post hoc analysis of the LANDMARK trial.

INTRODUCTION: The clinical benefits of aspirin in patients undergoing hemodialysis remain unclear. METHODS: The secondary analysis of the LANDMARK trial investigated whether aspirin use was associated with cardiovascular events (CVEs) and all-cause mortality was performed. A total of 2135 patients at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity score matching. RESULTS: The risk of CVEs was comparable between participants with aspirin use at baseline and those without at baseline, between participants with aspirin use during the study period and those without during the study period, and between participants with new aspirin prescription and those without aspirin use during the study period. CONCLUSION: Aspirin use was not significantly associated with a lower risk of CVEs in participants undergoing hemodialysis patients at risk of vascular calcification.

Effect of renin-angiotensin system inhibitors on cardiovascular events in hemodialysis patients with hyperphosphatemia: A post hoc analysis of the LANDMARK trial.

INTRODUCTION: The clinical benefits of renin-angiotensin system inhibitors (RASi) in patients undergoing hemodialysis remain obscure. METHODS: This is a post hoc cohort analysis of the LANDMARK trial investigate whether RASi use was associated with cardiovascular events (CVEs) and all-cause mortality. A total of 2135 patients at risk for vascular calcification were analyzed using a Cox proportional hazards model with propensity-score matching. RESULTS: The risk of CVEs was similar between participants with RASi use at baseline and those without RASi use at baseline and between participants with RASi use during the study period and those without RASi use during the study period. No clinical benefits of RASi use on all-cause mortality were observed. Serum phosphate levels were significantly associated with the effect of RASi on CVEs. CONCLUSIONS: RASi use was not significantly associated with a lower risk of CVEs or all-cause mortality in hemodialysis patients at risk of vascular calcification.

Vepafestinib is a pharmacologically advanced RET-selective inhibitor with high CNS penetration and inhibitory activity against RET solvent front mutations.

RET receptor tyrosine kinase is activated in various cancers (lung, thyroid, colon and pancreatic, among others) through oncogenic fusions or gain-of-function single-nucleotide variants. Small-molecule RET kinase inhibitors became standard-of-care therapy for advanced malignancies driven by RET. The therapeutic benefit of RET inhibitors is limited, however, by acquired mutations in the drug target as well as brain metastasis, presumably due to inadequate brain penetration. Here, we perform preclinical characterization of vepafestinib (TAS0953/HM06), a next-generation RET inhibitor with a unique binding mode. We demonstrate that vepafestinib has best-in-class selectivity against RET, while exerting activity against commonly reported on-target resistance mutations (variants in RETL730, RETV804 and RETG810), and shows superior pharmacokinetic properties in the brain when compared to currently approved RET drugs. We further show that these properties translate into improved tumor control in an intracranial model of RET-driven cancer. Our results underscore the clinical potential of vepafestinib in treating RET-driven cancers.

Lemon Myrtle (Backhousia citriodora) Extract and Its Active Compound, Casuarinin, Activate Skeletal Muscle Satellite Cells In Vitro and In Vivo.

Sarcopenia is an age-related skeletal muscle atrophy. Exercise is effective in improving sarcopenia via two mechanisms: activation of skeletal muscle satellite cells (SCs) and stimulation of muscle protein synthesis. In contrast, most nutritional approaches for improving sarcopenia focus mainly on muscle protein synthesis, and little is known about SC activation. Here, we investigated the effect of lemon myrtle extract (LM) on SC activation both in vitro and in vivo. Primary SCs or myoblast cell lines were treated with LM or its derived compounds, and incorporation of 5-bromo-2'-deoxyuridine, an indicator of cell cycle progression, was detected by immunocytochemistry. We found that LM significantly activated SCs (p < 0.05), but not myoblasts. We also identified casuarinin, an ellagitannin, as the active compound in LM involved in SC activation. The structure−activity relationship analysis showed that rather than the structure of each functional group of casuarinin, its overall structure is crucial for SC activation. Furthermore, SC activation by LM and casuarinin was associated with upregulation of interleukin-6 mRNA expression, which is essential for SC activation and proliferation. Finally, oral administration of LM or casuarinin to rats showed significant activation of SCs in skeletal muscle (p < 0.05), suggesting that LM and casuarinin may serve as novel nutritional interventions for improving sarcopenia through activating SCs.

Aqueous Synthesis of Manganese Phosphate Hydrate Crystals for Creating Inorganic Pigment Materials.

Manganese phosphate hydrate crystals were prepared from aqueous solutions containing MnCl2, (NH4)2HPO4, and citric acid. Switzerite [Mn3(PO4)2·7H2O] and niahite (NH4MnPO4·H2O) phases were produced at room temperature, and then, hureaulite [Mn5(PO3OH)2(PO4)2·4H2O] particles were obtained by aging at 80 °C or by hydrothermal treatment at 100-180 °C. The lower aging temperature (80 °C) and the chelation of Mn2+ ions by citric acid provided a slower crystal growth, resulting in large hexagonal prism blocks of ca. 500 µm in size. These were found to be single crystals of hureaulite by powder and single-crystal X-ray diffraction analysis. Diffuse reflectance spectroscopy and evaluation using L*a*b* color parameters indicated that the large single crystals present a vivid pink color and high transparency.

[Euglycemic Diabetic Ketoacidosis Caused by a Sodium-glucose Co-transporter (SGLT) 2 Inhibitor after Coronary Artery Bypass Grafting].

A 65-year-old woman with type Ⅱ diabetes and unstable angina presented with chest pain due to in-stent restenosis. Her regular medication comprised an sodium-glucose co-transporter( SGLT) 2 inhibitor. Because of unstable hemodynamic status, semi-emergency coronary artery bypass grafting (CABG) was performed. Postoperatively, the cardiac and hemodynamic status stabilized, but there was progression of metabolic acidosis. Based on the presence of massive urinary ketone bodies without hyper glycosuria, the patient was diagnosed with euglycemic diabetic ketoacidosis( DKA) caused by an SGLT2 inhibitor. Ketoacidosis without elevated blood glucose( i.e., euglycemic DKA) has been reported to be associated with intake of an SGLT2 inhibitor, which promoted glucose excretion in the urine. Our patient developed euglycemic DKA due to the progression of myocardial ischemia and surgical stress. Guidelines in other countries have stipulated that SGLT2 inhibitor should be stopped 24 hours preoperatively. In our case, euglycemic DKA occurred even when the SGLT2 inhibitor was stopped for more than 24 hours preoperatively. Further studies on the withdrawal of an SGLT2 inhibitor in the appropriate perioperative period are required.

Spinal fractures in diffuse idiopathic skeletal hyperostosis: Advantages of percutaneous pedicle screw fixation.

PURPOSE: To validate the effectiveness of percutaneous pedicle screw (PPS) fixation for spinal fractures associated with diffuse idiopathic skeletal hyperostosis (DISH) by comparing surgical outcomes for PPS fixation and conventional open posterior fixation. Patients with DISH are vulnerable to unstable spinal fractures caused by trivial trauma, and these fractures have high rates of delayed paralysis, postoperative complications, and mortality. METHODS: This retrospective study assessed surgical outcomes for 16 patients with DISH (12 men; mean age 76.1 ± 9.4 years) who underwent PPS fixation for spinal fractures (pedicle screw (PS) group), and for a control group of 25 patients with DISH (18 men; mean age 77.9 ± 9.9 years) who underwent conventional open fixation (O group) at our affiliated hospitals from 2007 to 2017. We evaluated the preoperative physical condition (American Society of Anesthesiologists (ASA) classification), neurological status (Frankel grade), and improvement after surgery, fusion length, operating time, estimated blood loss, and perioperative complications. RESULTS: Preoperatively, the PS group consisted of one ASA-1 patient, eight ASA-2 patients, six ASA-3 patients, and one ASA-4 patient; by Frankel grade, there were 2 grade B patients, 13 grade C, 4 grade D, and 6 grade E patients. The O group had 2 ASA-1 patients, 13 ASA-2, 9 ASA-3, and 1 ASA-4 patients. Frankel grades in the O group reflected severe neurological deficits, with 3 grade C patients, 2 grade D, and 11 grade E ( p = 0.032) patients. The two groups had similar rates of neurological improvement (33.3% of PS and 40.0% of O patients; p = 0.410) and mean fusion length (PS 5.1 ± 0.8 segments; O 4.9 ± 1.2). The mean operating time and estimated blood loss were 168.1 ± 46.7 min and 133.9 ± 116.5 g, respectively, in the PS group, and 224.6 ± 49.8 min and 499.9 ± 368.5 g in the O group. Three O-group patients died of hypovolemic shock, respiratory failure, and pneumonia, respectively, within a year of surgery. CONCLUSION: Conventional open posterior fixation and PPS fixation for DISH-related spinal fractures were similar in fusion length and neurological improvement. However, PPS fixation was less invasive and had lower complication rates.

TAS-121, A Selective Mutant EGFR Inhibitor, Shows Activity Against Tumors Expressing Various EGFR Mutations Including T790M and Uncommon Mutations G719X.

TAS-121 is a novel orally active selective covalent inhibitor of the mutant EGFR. We performed preclinical characterization of TAS-121 and compared its efficacy and selectivity for common EGFR mutations (Ex19del and L858R), first- and second- generation EGFR-tyrosine kinase inhibitor (EGFR-TKI) resistance mutation (T790M), and uncommon mutations (G719X and L861Q) with those of other EGFR-TKIs. We also commenced investigation of the clinical benefits of TAS-121. The IC50 for intracellular EGFR phosphorylation was determined by using Jump-In GripTite HEK293 cells transiently transfected with EGFR expression vectors. Mouse xenograft models were used to evaluate the antitumor activity of TAS-121. TAS-121 potently inhibited common activating and resistance EGFR mutations to the same extent as another third-generation EGFR-TKI (osimertinib). In addition, TAS-121 showed equivalent inhibitory activity against some uncommon mutations such as G719X and L861Q. Furthermore, TAS-121 demonstrated greater selectivity for mutant EGFRs versus the wild-type EGFR compared with other EGFR-TKIs. Moreover, TAS-121 displayed antitumor activity in SW48 (EGFR G719S) and NCI-H1975 (EGFR L858R/T790M) xenograft models, and achieved an objective response in patients with NSCLC with EGFR mutations including G719A mutation. In conclusion, TAS-121 is a novel third-generation EGFR-TKI and demonstrates antitumor activities in patients with NSCLC expressing either common or uncommon EGFR mutations.

Spinal fractures in patients with diffuse idiopathic skeletal hyperostosis: Clinical characteristics by fracture level.

BACKGROUND: Diffuse idiopathic skeletal hyperostosis (DISH) makes the spine prone to unstable fractures with neurological deterioration. This study was conducted to assess clinical and radiographic features of spinal fractures in DISH by the level of spinal injury, and to evaluate the optimal treatment for each level. METHODS: A multicenter retrospective study over a 5-year period, including 46 patients (35 males; 11 females) with a mean age of 77.2 ± 9.7 years at the time of injury. By fracture level, there were 7 cervical (15.2%), 25 thoracic (54.3%), and 14 lumbar (30.4%) fractures. We recorded the cause of injury, whether diagnosis was delayed, and neurological status by Frankel grade. Ossification and fracture patterns were assessed by CT-multi-planar reconstruction (MPR). RESULTS: Neurological status immediately after the cervical-spine injury was C (28.6%) or E (71.4%); after thoracic injury, C (12.0%) or E (88.0%); and after lumbar injury, D (21.4%) or E (78.6%). Inability to walk at admission was more frequent in patients with a spinal-cord injury above the lumbar level (P = .033). Vertebral-body fractures were observed in 14.3% of the cervical injuries, 80.0% of the thoracic injuries, and 50.0% of the lumbar injuries (P = .004). Most patients with a cervical fracture had a disc-level fracture (85.7%). Posterior-column ankylosis was observed in 14.3% of the cervical-fracture group, 72.0% of the thoracic-fracture group, and 78.6% of the lumbar-fracture group (P = .008). CONCLUSION: Ossification and fracture patterns in patients with DISH varied distinctly by the level of spinal injury. Intervertebral-disc fractures were frequently observed in the cervical spine. Delayed diagnosis, vertebral-body fracture, and posterior-column ankylosis were observed in the thoracolumbar spine. This study recommends 3 above and 3 below fusion, to avoid instrumentation failure in the fixation of spinal fracture in patients with DISH.

CT-based morphological analysis of spinal fractures in patients with diffuse idiopathic skeletal hyperostosis.

PURPOSE: To clarify correlations between spinal fracture and delayed paralysis in patients with diffuse idiopathic skeletal hyperostosis (DISH) using computed tomography (CT) with multiplanar reformatting (CT-MPR). DISH increases susceptibility to unstable spinal fractures, leading to neurological deterioration. The pathomechanism of the neurological injury is unclear. METHODS: This multicenter retrospective study included 42 DISH patients (32 male; 10 female) treated for 45 spinal fractures during a 5-year period. The mean age at the time of injury was 77.1 ± 10.1 years. The cause of injury, delay in diagnosis, fracture location, and neurological status were recorded, and anterior- and posterior-column fractures, a fracture displacement over 3 mm, and posterior-column ankylosis were assessed using CT-MPR. RESULTS: Most fractures (73.8%) resulted from trivial trauma, such as falling from a standing or sitting position. Diagnosis was delayed in 47.6% of the patients, primarily due to delays in seeking medical attention (65.0%). Although 78.6% of the patients were neurologically intact at the time of injury, 54.8% developed paralysis, defined by a change in one or more Frankel-score levels during short-term follow-up. Of the fractures, 39.1% were in the vertebral body, and 60.9% were at the disc level. Fractures with posterior-column ankylosis were significantly associated with delayed paralysis. CONCLUSIONS: CT-MPR was useful for evaluating spinal fractures and determining treatment in patients with DISH. Fractures associated with posterior-column ankylosis resulted in unstable three-column injuries that led to delayed neurological deterioration. Early surgical stabilization of such fractures is recommended to avoid delayed paralysis.

Histone H2A T120 Phosphorylation Promotes Oncogenic Transformation via Upregulation of Cyclin D1.

How deregulation of chromatin modifiers causes malignancies is of general interest. Here, we show that histone H2A T120 is phosphorylated in human cancer cell lines and demonstrate that this phosphorylation is catalyzed by hVRK1. Cyclin D1 was one of ten genes downregulated upon VRK1 knockdown in two different cell lines and showed loss of H2A T120 phosphorylation and increased H2A K119 ubiquitylation of its promoter region, resulting in impaired cell growth. In vitro, H2A T120 phosphorylation and H2A K119 ubiquitylation are mutually inhibitory, suggesting that histone phosphorylation indirectly activates chromatin. Furthermore, expression of a phosphomimetic H2A T120D increased H3 K4 methylation. Finally, both VRK1 and the H2A T120D mutant histone transformed NIH/3T3 cells. These results suggest that histone H2A T120 phosphorylation by hVRK1 causes inappropriate gene expression, including upregulated cyclin D1, which promotes oncogenic transformation.

Enantio- and diastereoselective asymmetric allylic alkylation catalyzed by a planar-chiral cyclopentadienyl ruthenium complex.

We report asymmetric allylic alkylation of allylic chloride with ß-diketones as the prochiral carbon nucleophiles using a planar-chiral Cp'Ru catalyst. The reaction proceeds under mild conditions; the resulting chiral products containing vicinal tertiary stereocenters are obtained with high regio-, diastereo-, and enantioselectivities. These chiral products can then be transformed into a chiral diol by controlling the four stereocentres.

[Traumatic injury of the proximal aortic arch after blunt chest trauma;report of a case].

We report a rare case of an proximal aortic arch injury caused by blunt chest trauma. A 48-year-old woman was transferred to our hospital because of traffic accident. Computed tomography (CT) showed a small ulcer-like projection (ULP) at the proximal part of the aortic arch. An elective surgery for aortic repair was performed because of significant enlargement of the ULP in the aortic arch revealed by follow-up CT. The patient's postoperative course was uneventful, and she was discharged on the 14th postoperative day.

Genotoxicity and subacute toxicity studies of a new astaxanthin-containing Phaffia rhodozyma extract.

Experimental and clinical studies demonstrate that astaxanthin (AXN), a xanthophyll carotenoid, has protective effects against oxidative damage. Because most of these studies assessed AXN derived from Haematococcus pluvialis that were cultivated at industrial scales, few studies have examined the toxicity of AXN derived from Phaffia rhodozyma. To evaluate the safety of astaxanthin-containing P. rhodozymaextract (AXN-PRE), genotoxicity was assessed in bacterial reverse mutation test and mouse bone marrow micronucleus test, and general toxicity was assessed in 4-week repeated oral toxicity study in rats. AXN-PRE did not induce reverse mutations in the Salmonella typhimurium strains TA98 or TA100 at concentrations of 5,000 µg/plate with or without S9 mix, and no chromosome damage was observed at a dose of 2,000 mg/kg in mouse micronucleus test. In the subacute toxicity study, male and female Sprague-Dawley rats were given AXN-PRE at doses of 0, 500, and 1,000 mg/kg by gavage for 4 weeks. Body weights, urinalysis, hematology, serum biochemistry, organ weights, or histopathological lesions indicated no distinct toxicity. In conclusion, AXN-PRE had no effect in bacterial reverse mutation test and mouse bone marrow micronucleus test. The no-observed-adverse-effect level for AXN-PRE in 4-week repeated oral toxicity study in rats was determined to be greater than 1,000 mg/kg (corresponding to dose of 50 mg/kg AXN) regardless of gender.

The novel VEGF receptor/MET-targeted kinase inhibitor TAS-115 has marked in vivo antitumor properties and a favorable tolerability profile.

VEGF receptor (VEGFR) signaling plays a key role in tumor angiogenesis. Although some VEGFR signal-targeted drugs have been approved for clinical use, their utility is limited by associated toxicities or resistance to such therapy. To overcome these limitations, we developed TAS-115, a novel VEGFR and hepatocyte growth factor receptor (MET)-targeted kinase inhibitor with an improved safety profile. TAS-115 inhibited the kinase activity of both VEGFR2 and MET and their signal-dependent cell growth as strongly as other known VEGFR or MET inhibitors. On the other hand, kinase selectivity of TAS-115 was more specific than that of sunitinib and TAS-115 produced relatively weak inhibition of growth (GI50 > 10 µmol/L) in VEGFR signal- or MET signal-independent cells. Furthermore, TAS-115 induced less damage in various normal cells than did other VEGFR inhibitors. These data suggest that TAS-115 is extremely selective and specific, at least in vitro. In in vivo studies, TAS-115 completely suppressed the progression of MET-inactivated tumor by blocking angiogenesis without toxicity when given every day for 6 weeks, even at a serum-saturating dose of TAS-115. The marked selectivity of TAS-115 for kinases and targeted cells was associated with improved tolerability and contributed to the ability to sustain treatment without dose reduction or a washout period. Furthermore, TAS-115 induced marked tumor shrinkage and prolonged survival in MET-amplified human cancer-bearing mice. These data suggest that TAS-115 is a unique VEGFR/MET-targeted inhibitor with improved antitumor efficacy and decreased toxicity.

Chiral phosphoric acid catalyzed transfer hydrogenation: facile synthetic access to highly optically active trifluoromethylated amines.

Amines to an end: highly optically active α-CF(3)-functionalized amines can be obtained using metal-free reaction conditions. The method involves the transfer hydrogenation of CF(3)-substituted ketimines catalyzed by 1 and reductive amination of CF(3)-substituted ketones. The synthetic utility of this method was demonstrated by the synthesis of a CF(3) analogue of NPS R-568. PMP=para-methoxyphenyl.

Stent failure in the management of malignant extrinsic ureteral obstruction: risk factors.

There is still controversy surrounding the indications for performing either a retrograde ureteral stent or percutaneous nephrostomy to manage malignant extrinsic ureteral obstruction (MEUO). We retrospectively analyzed 53 patients who underwent a decompression of MEUO using retrograde ureteral stent. Ureteral stent failure occurred in 18 of 53 patients (34%). Multivariate analysis showed that gastrointestinal cancer as the primary disease, poor preoperative performance status and severe preoperative hydronephrosis were independent predictors of stent failure. Based on the present data, we propose an algorithm for the management of MEUO.

Strings of metal half-shells fabricated using colloidal particle monolayer as a template.

A two-dimensional (2-D) polystyrene (PS) particle monolayer is demonstrated as a template for the fabrication of one-dimensional (1-D) strings of metal shells. Metal is deposited by vacuum evaporation onto the PS particle monolayer, which is tilted at an angle (theta) between the normal of the monolayer plane and the direction of metal deposition. The effects of the metal deposition thickness, the tilt angle (theta) of the particle monolayer, and the type of metal on the formation of 1-D strings of metal shells are investigated. Strings of fan-shaped Au shells are obtained at a given tilt angle and deposition thickness. On the other hand, 1-D strings of Cr and Ag cannot be obtained, and they tend to form 2-D films and half-shell dots of the metal, respectively.