Ultra-early rt-PA administration should improve patient outcome on mechanical thrombectomy: Post hoc analysis of SKIP.

Background: To investigate whether ultra-early recombinant tissue-plasminogen activator (rt-PA) administration can improve patient outcomes on mechanical thrombectomy (MT) in patients with large vessel occlusion (LVO).

Methods: Participants comprised rt-PA-eligible 204 patients with internal carotid artery or middle cerebral artery occlusion in the SKIP trial, who were randomly assigned to receive mechanical thrombectomy alone or combined intravenous thrombolysis (rt-PA: alteplase at 0.6 mg/kg) plus mechanical thrombectomy.

Stabilization of CDK6 by ribosomal protein uS7, a target protein of the natural product fucoxanthinol.

Cyclins and cyclin-dependent kinases (CDKs) regulate the cell cycle, which is important for cell proliferation and development. Cyclins bind to and activate CDKs, which then drive the cell cycle. The expression of cyclins periodically changes throughout the cell cycle, while that of CDKs remains constant.

The Effects of Side-Chain Configurations of a Retro-Inverso-Type Inhibitor on the Human T-Cell Leukemia Virus (HTLV)-1 Protease.

In this study, the effects of side-chain configurations of D-Ile residues of a retro-inverso (RI)-type inhibitor on the human T-cell leukemia virus type 1 (HTLV-1) protease containing a hydroxyethylamine dipeptide isostere were clarified. Prior to evaluation using the RI-type inhibitor, the effects of side-chain configurations of Ile residues of the substrate peptide on the HTLV-1 protease were examined to estimate the influence of side-chain configurations on enzyme activity. Based on the estimation of the influence of side-chain configurations on protease affinity, the RI-type inhibitors containing a D-allo-Ile residue in the corresponding substrate sequence, instead of a D-Ile residue, were synthesized via 9-fluorenylmethoxycarbonyl-based solid-phase peptide synthesis.

Macrocyclic BACE1 inhibitors with hydrophobic cross-linked structures: Optimization of ring size and ring structure.

Based on the X-ray crystallography of recombinant BACE1 and a hydroxyethylamine-type peptidic inhibitor, we introduced a cross-linked structure between the P1 and P3 side chains of the inhibitor to enhance its inhibitory activity. The P1 and P3 fragments bearing terminal alkenes were synthesized, and a ring-closing metathesis of these alkenes was used to construct the cross-linked structure. Evaluation of ring size using P1 and P3 fragments with various side chain lengths revealed that 13-membered rings were optimal, although their activity was reduced compared to that of the parent compound.

Structure-activity relationship study of hydroxyethylamine isostere and P1' site structure of peptide mimetic BACE1 inhibitors.

An aromatic substituent has been introduced into a known hydroxyethylamine (HEA)-type BACE1 inhibitor containing the superior substrate sequence to enhance inhibitory activity. The HEA-type isosteres bearing different hydroxyl group and methyl group configurations were prepared through a branched synthesis approach using intra- and inter-molecular epoxide opening reactions. The effect of their configuration was evaluated, showing that an R-configuration improved the inhibitory activity, while introduction of a methyl group on the isostere decreased the activity.

Intravenous Alteplase is Associated with First Pass Effect in Stent-retriever but not ADAPT Thrombectomy : Post Hoc Analysis of the SKIP Study.

Purpose: To investigate the effect of alteplase, either combined with stent-retriever thrombectomy or a direct aspiration first pass technique (ADAPT), in patients with large-vessel occlusion stroke.

Methods: This was a retrospective post hoc analysis of data from The Direct Mechanical Thrombectomy in Acute LVO Stroke (SKIP) study. Patients were divided into two groups according to the first-line thrombectomy technique: stent-retriever and ADAPT.

[Studies on Functional Molecules Based on Peptide Chemistry].

Studies on functional molecules starting from syntheses of cysteine-containing peptides and protein are described. Starting from evaluation of a cysteine specific side-reaction, a specific reaction for disulfide-bond formation was developed. The reaction made it possible to independently construct a disulfide bridge without effecting the existing disulfide bonds, which resulted in a unique approach for the synthesis of human insulin by site-specific disulfide bond formation.

Effect of Mechanical Thrombectomy Without vs With Intravenous Thrombolysis on Functional Outcome Among Patients With Acute Ischemic Stroke: The SKIP Randomized Clinical Trial.

Importance: Whether intravenous thrombolysis is needed in combination with mechanical thrombectomy in patients with acute large vessel occlusion stroke is unclear.

Objective: To examine whether mechanical thrombectomy alone is noninferior to combined intravenous thrombolysis plus mechanical thrombectomy for favorable poststroke outcome.

Design, Setting, And Participants: Investigator-initiated, multicenter, randomized, open-label, noninferiority clinical trial in 204 patients with acute ischemic stroke due to large vessel occlusion enrolled at 23 hospital networks in Japan from January 1, 2017, to July 31, 2019, with final follow-up on October 31, 2019.

Design, synthesis, biological evaluation and in silico studies of certain aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles as potent metallo-β-lactamase inhibitors.

Based on a structure-guided approach, aryl sulfonyl hydrazones conjugated with 1,3-diaryl pyrazoles were designed to target metallo-β-lactamases (MBLs), using Klebsiella pneumoniaeNDM-1 as a model. The in vitro MBLs inhibition showed remarkable inhibition constant for most of the designed compounds at a low micromolar range (1.5-16.

Design and Evaluation of Anti-SARS-Coronavirus Agents Based on Molecular Interactions with the Viral Protease.

Three types of new coronaviruses (CoVs) have been identified recently as the causative viruses for the severe pneumonia-like respiratory illnesses, severe acute respiratory syndrome (SARS), Middle East respiratory syndrome (MERS), and corona-virus disease 2019 (COVID-19). Neither therapeutic agents nor vaccines have been developed to date, which is a major drawback in controlling the present global pandemic of COVID-19 caused by SARS coronavirus 2 (SARS-CoV-2) and has resulted in more than 20,439,814 cases and 744,385 deaths. Each of the 3C-like (3CL) proteases of the three CoVs is essential for the proliferation of the CoVs, and an inhibitor of the 3CL protease (3CL) is thought to be an ideal therapeutic agent against SARS, MERS, or COVID-19.

Enhancement of direct membrane penetration of arginine-rich peptides by polyproline II helix structure.

The left-handed, extended polyproline II (PPII) helix is a unique secondary structure which potently modulates peptide/protein functions through its constraint conformation. To investigate the effect of PPII helix on the direct cell membrane penetration of arginine-rich peptides, we designed a polyproline-containing arginine-rich peptide P9R7W (PPPPPPPPPRRRRRRRW) by introducing nine proline residues into a linear R7W (RRRRRRRW) peptide. Circular dichroism spectroscopy showed that P9R7W has the PPII helix structure in solution whereas R7W is predominantly in random coil structure.

Evaluation of an octahydroisochromene scaffold used as a novel SARS 3CL protease inhibitor.

An octahydroisochromene scaffold has been introduced into a known SARS 3CL protease inhibitor as a novel hydrophobic core to interact with the S2 pocket of the protease. An alkyl or aryl substituent was also introduced at the 1-position of the octahydroisochromene scaffold and expected to introduce additional interactions with the protease. Sharpless-Katsuki asymmetric epoxidation and Sharpless asymmetric dihydroxylation were employed to construct the octahydroisochromene scaffold.

Stent Migration during Coil Embolization with an Open Cell Stent: A Report of Three Cases.

Objective: Among 36 cerebral aneurysm cases of stent-assisted coil embolization with the Neuroform Atlas since April 2017, there were three cases of stent migration during the operation. The status of stent deployment, cause of trouble, results of coil embolization, and complications were assessed.

Case Presentations: There were two cases with trouble during stent deployment, a case of internal carotid artery aneurysm, and a case of middle cerebral artery (MCA) aneurysm.

Optimal Heating Temperature and Time for Echelon 10 and Excelsior SL-10 Shaping Using a Heat Gun.

Objective: The optimal heating temperature and time for the Echelon10 and Excelsior SL-10 microcatheters using a heat gun was investigated. The durability of the microcatheters after heat gun shaping for the second and third times was also examined.

Methods: HAKKO FV-310 was used as the heat gun in this study.

Cerebral Microbleeds Detected Using 3.0T Magnetic Resonance Imaging in 2,003 Patients with Ischemic or Hemorrhagic Stroke.

Introduction: Compared with 1.5T magnetic resonance imaging (MRI), using 3.0T MRI makes it easier to detect cerebral microbleeds (CMBs).

The randomized study of endovascular therapy with versus without intravenous tissue plasminogen activator in acute stroke with ICA and M1 occlusion (SKIP study).

Rationale: Bridging therapy with endovascular therapy (EVT) and intravenous thrombolysis (IVT) has been reported to improve outcomes for acute stroke patients with large-vessel occlusion in the anterior circulation. While the IVT may increase the reperfusion rate, the risk of hemorrhagic complications increases. Whether EVT without IVT (direct EVT) is equally effective as bridging therapy in acute stroke remains unclear.

Convergent Synthesis of trans-2,6-Disubstituted Piperidine Alkaloid, (-)-iso-6-Spectaline by Palladium-Catalyzed Cyclization.

The plant alkaloids, iso-6-spectaline and spectaline, isolated from the Cassia or Senna genera contain a characteristic 2,6-disubstituted piperidin-3-ol scaffold. Although both natural products are reported to exhibit a variety of interesting biological activities, few stereo-selective schemes for the construction of the 2,6-disubstituted scaffold have been reported. Following our previous studies regarding the synthesis of (+)-spectaline, herein we report the first convergent synthesis of (-)-iso-6-spectaline using a cross-metathesis under thermal conditions where the cis-2,6-disubstituted piperidin-3-ol scaffold is condensed with a long alkyl chain containing a terminal olefin.