Feasibility of a fast-track randomized controlled trial of cell-free and concentrated ascites reinfusion therapy for patients with refractory malignant ascites.

BACKGROUND: Malignant ascites often causes discomfort in advanced cancer patients. Paracentesis is the most common treatment modality, but it requires frequently repeated treatment. Cell-free and concentrated ascites reinfusion therapy (CART) may prolong the paracentesis interval, but controlled trials are lacking. We assessed the feasibility of a randomized controlled trial of CART vs. paracentesis alone for patients with refractory malignant ascites. METHODS: This study was an open-label, fast-track, randomized controlled, feasibility trial. Patients admitted to four designated cancer hospitals who received no further anticancer treatments were eligible. Patients were randomly assigned 1:1 to a CART arm or control (simple paracentesis) arm. The feasibility endpoint was the percentage of patients who completed the study intervention. Secondary endpoints included paracentesis-free survival, patient's request on the questionnaire for paracentesis (PRO-paracentesis)-free survival (the period until the patients first reported that they would want paracentesis if indicated), and adverse events. RESULTS: We screened 953 patients for eligibility. Of 61 patients with refractory malignant ascites, 21 patients were determined as eligible. Finally, 20 patients consented and were allocated; 18 patients (90%, 95% CI: 68.3-98.8) completed the study intervention. All patients had an ECOG performance status of 3 or 4. The median drained ascites volume was 3,200 mL in the CART arm and 2,500 mL in the control arm. In the CART arm, the median reinfused albumin volume was 12.6 g. Median paracentesis-free survivals were 5 days (95% CI: 2-6) in the CART arm, and 6 days (3-9) in the control arm. Median PRO-paracentesis-free survivals were 4 days (2-5) and 5 days (1-9), respectively. A total of 73% of patients received paracentesis within 2 days from their first request for the next paracentesis. One patient in the CART arm developed Grade 1 fever. CONCLUSIONS: A fast-track randomized controlled trial of CART for patients with malignant ascites is feasible. The efficacy and safety of CART should be assessed in future trials. PRO-paracentesis-free survival may be a complementary outcome measure with paracentesis-free survival in future trials. TRIAL REGISTRATION: Registered at University Hospital Medical Information Network Clinical Trial Registry as UMIN000031029 . Registered on 28/01/2018.

Preventing Premature Convergence in Evolutionary Structure Determination of Complex Molecular Systems: Demonstration in Few-Nanometer-Sized TiCl4-Capped MgCl2 Nanoplates.

The combination of genetic algorithm-based global search and local geometry optimization enables nonempirical structure determination for complex materials such as practical solid catalysts. However, premature convergence in the genetic algorithm hinders the determination of the global minimum for complicated molecular systems. Here, we implemented a distributed genetic algorithm based on the migration from a structure database for avoiding the premature convergence, and thus we realized the structure determination for TiCl4-capped MgCl2 nanoplates with experimentally consistent sizes. The obtained molecular models are featured with a realistic size and nonideal surfaces, representing actual primary particles of catalysts.

Preclinical antitumor activity of S-222611, an oral reversible tyrosine kinase inhibitor of epidermal growth factor receptor and human epidermal growth factor receptor 2.

Epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2) are validated molecular targets in cancer therapy. Dual blockade has been explored and one such agent, lapatinib, is in clinical practice but with modest activity. Through chemical screening, we discovered a novel EGFR and HER2 inhibitor, S-222611, that selectively inhibited both kinases with IC50 s below 10 nmol/L. S-222611 also inhibited intracellular kinase activity and the growth of EGFR-expressing and HER2-expressing cancer cells. In addition, S-222611 showed potent antitumor activity over lapatinib in a variety of xenograft models. In evaluations with two patient-oriented models, the intrafemoral implantation model and the intracranial implantation model, S-222611 exhibited excellent activity and could be effective against bone and brain metastasis. Compared to neratinib and afatinib, irreversible EGFR/HER2 inhibitors, S-222611 showed equivalent or slightly weaker antitumor activity but a safer profile. These results indicated that S-222611 is a potent EGFR and HER2 inhibitor with substantially better antitumor activity than lapatinib at clinically relevant doses. Considering the safer profile than for irreversible inhibitors, S-222611 could be an important option in future cancer therapy.

Enhancing Mechanical Properties of Graft-Type Nanocomposites Using Organically Modified SiO2 and Polypropylene Containing Reactive Methoxy Groups.

In situ grafting of a reactive matrix and nanofillers is a promising strategy to fabricate graft-type polypropylene (PP)-based nanocomposites, where the grafting efficiency is affected by the initial dispersion of nanofillers in the matrix. In this work, influences of surface organic modification of nanofillers were investigated on properties of PP/SiO2 nanocomposites using poly(propylene-co-octenyltrimethoxysilane) as a reactive matrix. The surface modification of SiO2, especially with longer alkyl chains, led to improved dispersion of nanoparticles, thus promoting the grafting reaction and mechanical properties. The combination of in situ grafting and surface modification of nanofillers provided several benefits, most notably in balancing the strength and the toughness, which could not be achieved by the grafting alone.

Machine-Learning Approaches for Predicting the Need of Oxygen Therapy in Early-Stage COVID-19 in Japan: Multicenter Retrospective Observational Study.

Background: Early prediction of oxygen therapy in patients with coronavirus disease 2019 (COVID-19) is vital for triage. Several machine-learning prognostic models for COVID-19 are currently available. However, external validation of these models has rarely been performed. Therefore, most reported predictive performance is optimistic and has a high risk of bias. This study aimed to develop and validate a model that predicts oxygen therapy needs in the early stages of COVID-19 using a sizable multicenter dataset. Methods: This multicenter retrospective study included consecutive COVID-19 hospitalized patients confirmed by a reverse transcription chain reaction in 11 medical institutions in Fukui, Japan. We developed and validated seven machine-learning models (e.g., penalized logistic regression model) using routinely collected data (e.g., demographics, simple blood test). The primary outcome was the need for oxygen therapy (≥1 L/min or SpO2 ≤ 94%) during hospitalization. C-statistics, calibration slope, and association measures (e.g., sensitivity) evaluated the performance of the model using the test set (randomly selected 20% of data for internal validation). Among these seven models, the machine-learning model that showed the best performance was re-evaluated using an external dataset. We compared the model performances using the A-DROP criteria (modified version of CURB-65) as a conventional method. Results: Of the 396 patients with COVID-19 for the model development, 102 patients (26%) required oxygen therapy during hospitalization. For internal validation, machine-learning models, except for the k-point nearest neighbor, had a higher discrimination ability than the A-DORP criteria (P < 0.01). The XGboost had the highest c-statistic in the internal validation (0.92 vs. 0.69 in A-DROP criteria; P < 0.001). For the external validation with 728 temporal independent datasets (106 patients [15%] required oxygen therapy), the XG boost model had a higher c-statistic (0.88 vs. 0.69 in A-DROP criteria; P < 0.001). Conclusions: Machine-learning models demonstrated a more significant performance in predicting the need for oxygen therapy in the early stages of COVID-19.

Dataset of energetically accessible structures of MgCl2/TiCl4 clusters for Ziegler-Natta catalysts.

This data article provides a dataset of the energetically accessible structures including the most stable structures of xMgCl2/yTiCl4 nanoplates (x = 6-19, y = 0-4). TiCl4-capped MgCl2 nanoplates are regarded as the building block of the Ziegler-Natta catalyst. The most stable structures were determined for MgCl2/TiCl4 nanoplates of different sizes and chemical compositions using a combination of the genetic algorithm and the DFT geometry optimization. The evolution in the genetic algorithm produced a number of meta-stable structures. A set of isomeric structures having similar energy to the most stable structure (termed energetically accessible structures) are provided as realistic models of MgCl2/TiCl4 nanoplates. These structures are useful for further investigation on the structural distribution of Ti species on MgCl2 regarding the Ziegler-Natta catalyst.

Modulator-free approach towards missing-cluster defect formation in Zr-based UiO-66.

By rigorous control of water, missing-cluster defects in Zr-based UiO-66 were generated to a remarkable extent without the need of acidic modulators. The presence of missing-cluster defects created hierarchical pore structures, which had a profound effect on the catalytic performance.

Antitumor efficacy of recombinant human interleukin-2 combined with sorafenib against mouse renal cell carcinoma.

OBJECTIVE: Recombinant human interleukin-2 (rhIL-2) has been clinically used in the treatment of renal cell carcinoma (RCC). Sorafenib, a multi-targeted kinase inhibitor, has been approved for RCC as well as IL-2. The purpose of this study was to evaluate the antitumor efficacy of IL-2 combined with sorafenib in three different murine renal cancer models using Renca cells. METHODS: We established the subcutaneous tumor model by inoculating wild-type Renca cells into the backs of BALB/c mice, the pulmonary metastatic tumor model by an intravenous injection of luciferase-expressing Renca cells into the tail vain and the orthotopic tumor model by injecting luciferase-expressing Renca cells into the renal subcapsule. These tumor-bearing mice were treated intra-peritoneally with rhIL-2 and/or per os with sorafenib. The antitumor efficacy was evaluated by measuring the tumor size of the subcutaneous tumor or photon intensity of the pulmonary metastatic tumor and the orthotopic tumor. RESULTS: When rhIL-2 was combined with sorafenib, the antitumor efficacy was significantly augmented in comparison with either rhIL-2 or sorafenib alone in all the models. Sorafenib did not inhibit rhIL-2-induced natural killer cell expansion and rhIL-2 had no effect on the anti-angiogenic activity of sorafenib. CONCLUSIONS: The results suggest that the combination of rhIL-2 and sorafenib may offer significant potential as a novel therapeutic approach for patients with RCC.

Development of Large-Scale Stopped-Flow Technique and its Application in Elucidation of Initial Ziegler-Natta Olefin Polymerization Kinetics.

The stopped-flow (SF) technique has been extensively applied to study Ziegler-Natta (ZN) olefin polymerization kinetics within an extremely short period (typically <0.2 s) for understanding the nature of the active sites as well as the polymerization mechanisms through microstructure analyses of obtained polymers. In spite of its great applicability, a small amount of polymer that is yielded in a short-time polymerization has been a major bottleneck for polymer characterizations. In order to overcome this limitation, a large-scale SF (LSF) system has been developed, which offers stable and scalable polymerization over an expanded time range from a few tens milliseconds to several seconds. The scalability of the LSF technique has been further improved by introducing a new quenching protocol. With these advantages, the LSF technique has been effectively applied to address several unknown issues in ZN catalysis, such as the role of physical and chemical transformations of a catalyst on the initial polymerization kinetics, and regiochemistry of ZN propylene polymerization. Here, we review the development of the LSF technique and recent efforts for understanding heterogeneous ZN olefin polymerization catalysis with this new system.

Three-dimensional volume rendering of fetal MR images for the diagnosis of congenital cystic adenomatoid malformation.

RATIONALE AND OBJECTIVES: Great expertise is necessary to mentally compile a series of individual two-dimensional image sections into a three-dimensional (3D) composite view that can aid in differential diagnosis. The purpose of this study was to test 3D volume-rendering techniques for differentiating congenital cystic adenomatoid malformation from congenital diaphragmatic hernia. MATERIALS AND METHODS: The authors acquired T2-weighted magnetic resonance (MR) images of a 27-week fetus in the sagittal plane and then applied the 3D volume-rendering method to the MR image data sets to obtain a composite 3D image. RESULTS: It was unclear on the MR images whether the intestines were situated above or below the diaphragm. The composite image showed that the intestines were not herniated into the chest, and this facilitated a diagnosis of congenital cystic adenomatoid malformation rather than congenital diaphragmatic hernia. CONCLUSION: The 3D volume-rendering techniques aided in the assessment of fetal organ structure and could be applied also to preoperative simulation and planning of fetal surgery.

Enzymatic synthesis of novel oligosaccharides from N-acetylsucrosamine using ß-fructofuranosidase from Aspergillus oryzae.

Mycelia of Aspergillus oryzae NBRC100959 contain 2 types of ß-fructofuranosidases, transfructosylation-catalyzing enzyme (ßFFaseI), and hydrolysis-catalyzing enzyme (ßFFaseII). Using ßFFaseI extracted from the mycelia of strain NBRC100959, two novel oligosaccharides consisting of GlcNAc and fructose, ß-d-fructofuranosyl-(2→1)-ß-d-fructofuranosyl-(2↔1)-2-acetamido-2-deoxy-α-d-glucopyranoside (N-acetyl-1-kestosamine, 1-KesNAc) and ß-d-fructofuranosyl-(2→1)-ß-d-fructofuranosyl-(2→1)-ß-d-fructofuranosyl-(2↔1)-2-acetamido-2-deoxy-α-d-glucopyranoside (N-acetylnystosamine, NysNAc), were synthesized from ß-d-fructofuranosyl-(2↔1)-2-acetamido-2-deoxy-α-d-glucopyranoside (N-acetylsucrosamine, SucNAc). We next planned to synthesize 1-KesNAc and NysNAc using A. oryzae mycelia. However, it was thought that the presence of ßFFaseII is disadvantageous for the production of these oligosaccharides by ßFFaseI, because ßFFaseII hydrolyzed 1-KesNAc and NysNAc. We succeeded to produce A. oryzae mycelia containing ßFFaseI as the major ß-fructofuranosidase, by increasing sucrose concentration in the culture medium. Then, using a dried sample of these A. oryzae mycelia, reaction for the oligosaccharide production was performed. As the results, 190mg of 1-KesNAc and 60mg of NysNAc were obtained from 0.6g of SucNAc. This whole-cell catalysis method facilitates the synthesis of 1-KesNAc and NysNAc because extraction and purification of ßFFaseI from mycelia are unnecessary.

Synthesis of ß-D-fructofuranosyl-(2→1)-2-acetamido-2-deoxy-α-D-glucopyranoside (N-acetylsucrosamine) using ß-fructofuranosidase-containing Aspergillus oryzae mycelia as a whole-cell catalyst.

Using soft granules consisting of Celite 535 and dried Aspergillus oryzae NBRC100959 mycelia containing ß-fructofuranosidase as a whole-cell catalyst, N-acetylsucrosamine [ß-D-fructofuranosyl-(2→1)-2-acetamido-2-deoxy-α-D-glucopyranoside] was produced from sucrose and 2-acetamido-2-deoxy-D-glucose by enzymatic transfructosylation. The isolated yield of N-acetylsucrosamine from the reaction mixture was 22.1% (from sucrose). The result of N-terminal amino acid sequence analysis indicated that the enzyme involved in the synthesis of N-acetylsucrosamine is a product from gene (NCBI accession number; NW_001884675, locus tag; AOR_1_1114084) encoding putative ß-fructofuranosidase on chromosome 6 of strain NBRC100959. The N-acetylsucrosamine we produced is highly soluble in water and is more stable in acidic solution than sucrose. The disaccharide was also produced using dried mycelia prepared from another A. oryzae strains.

Propylene Polymerization Performance of Isolated and Aggregated Ti Species Studied Using a Well-Designed TiCl(3) /MgCl(2) Ziegler-Natta Model Catalyst.

In propylene polymerization with MgCl(2) -supported Ziegler-Natta catalysts, it is known that the reduction of TiCl(4) with alkylaluminum generates Ti(3+) active species, and at the same time, leads to the growth of TiCl(x) aggregates. In this study, the aggregation states of the Ti species were controlled by altering the Ti content in a TiCl(3) /MgCl(2) model catalyst prepared from a TiCl(3) · 3C(5) H(5) N complex. It is discovered that all the Ti species become isolated mononuclear with a highly aspecific feature below 0.1 wt.-% of the Ti content, and that the isolated aspecific Ti species are more efficiently converted into highly isospecific ones by the addition of donors than active sites in aggregated Ti species.

Non-gated fetal MRI of umbilical blood flow in an acardiac twin.

Currently, the standard method of diagnosis of twin reversed arterial perfusion (TRAP) sequence is ultrasound imaging. The use of MRI for flow visualization may be a useful adjunct to US imaging for assessing the presence of retrograde blood flow in the acardiac fetus and/or umbilical artery. The technical challenge in fetal MRI flow imaging, however, is that fetal electrocardiogram (ECG) monitoring required for flow imaging is currently unavailable in the MRI scanner. A non-gated MRI flow imaging technique that requires no ECG monitoring was developed using the t-test to detect blood flow in 20 slices of phase-contrast MRI images randomly scanned at the same location over multiple cardiac cycles. A feasibility study was performed in a 24-week acardiac twin that showed no umbilical flow sonographically. Non-gated MRI flow images clearly indicated the presence of blood flow in the umbilical artery to the acardiac twin; however, there was no blood flow beyond the abdomen. This study leads us to conjecture that non-gated MRI flow imaging is sensitive in detecting low-range blood flow velocity and can be an adjunct to Doppler US imaging.