New targeted treatments for advanced sarcomas.

PURPOSE OF REVIEW: The purpose of this review is to provide the rationale and results behind recent clinical trials regarding molecular-targeted agents for advanced sarcomas. RECENT FINDINGS: Tazemetostat, a first-in-class EZH2 inhibitor, was approved to treat advanced epithelioid sarcoma. In synovial sarcoma, the interaction between pathognomonic SS18-SSX fusion protein and the BAF complex has brought insight in using BRD9 inhibitors as a treatment based on synthetic lethality. MDM2 overexpression is an important mechanism to suppress p53 function, and MDM2 gene amplification is pathognomonic in well differentiated and dedifferentiated liposarcoma. Two MDM2 inhibitors, milademetan and BI907828, have both reached the optimal dosing and have shown promising efficacy in MDM2-amplified liposarcoma. Late-stage pivotal studies are ongoing for both of these MDM2 inhibitors. The co-amplification of CDK4 and MDM2 in liposarcoma also provided a rationale for CDK4/6 inhibitors as a potential therapy. Selinexor, an exportin-1 inhibitor, has shown single-agent activity in dedifferentiated liposarcoma and action in gastrointestinal stromal tumour in combination with imatinib. Lastly, a new formulation of mTOR inhibitor, nab-sirolimus, was recently approved for perivascular epithelioid cell tumour (PEComa). SUMMARY: Molecular-guided precision medicine holds a bright future in bringing more active treatments for advanced sarcoma patients.

A radiomics approach for lung nodule detection in thoracic CT images based on the dynamic patterns of morphological variation.

OBJECTIVES: To propose and evaluate a set of radiomic features, called morphological dynamics features, for pulmonary nodule detection, which were rooted in the dynamic patterns of morphological variation and needless precise lesion segmentation. MATERIALS AND METHODS: Two datasets were involved, namely, university hospital (UH) and LIDC datasets, comprising 72 CT scans (360 nodules) and 888 CT scans (2230 nodules), respectively. Each nodule was annotated by multiple radiologists. Denoted the category of nodules identified by at least k radiologists as ALk. A nodule detection algorithm, called CAD-MD algorithm, was proposed based on the morphological dynamics radiomic features, characterizing a lesion by ten sets of the same features with different values extracted from ten different thresholding results. Each nodule candidate was classified by a two-level classifier, including ten decision trees and a random forest, respectively. The CAD-MD algorithm was compared with a deep learning approach, the N-Net, using the UH dataset. RESULTS: On the AL1 and AL2 of the UH dataset, the AUC of the AFROC curves were 0.777 and 0.851 for the CAD-MD algorithm and 0.478 and 0.472 for the N-Net, respectively. The CAD-MD algorithm achieved the sensitivities of 84.4% and 91.4% with 2.98 and 3.69 FPs/scan and the N-Net 74.4% and 80.7% with 3.90 and 4.49 FPs/scan, respectively. On the LIDC dataset, the CAD-MD algorithm attained the sensitivities of 87.6%, 89.2%, 92.2%, and 95.0% with 4 FPs/scan for AL1-AL4, respectively. CONCLUSION: The morphological dynamics radiomic features might serve as an effective set of radiomic features for lung nodule detection. KEY POINTS: • Texture features varied with such CT system settings as reconstruction kernels of CT images, CT scanner models, and parameter settings, and so on. • Shape and first-order statistics were shown to be the most robust features against variation in CT imaging parameters. • The morphological dynamics radiomic features, which mainly characterized the dynamic patterns of morphological variation, were shown to be effective for lung nodule detection.

Adjuvant versus Neoadjuvant Immunotherapy for Hepatocellular Carcinoma: Clinical and Immunologic Perspectives.

Advancement in systemic therapy, particularly immune checkpoint inhibitor (ICI)-based combination regimens, has transformed the treatment landscape for patients with advanced hepatocellular carcinoma (HCC). The advancement in systemic therapy also provides new opportunities of reducing recurrence after curative therapy through adjuvant therapy or improving resectability through neoadjuvant therapy. Improved recurrence-free survival by adjuvant or neoadjuvant ICI-based therapy has been reported in other cancer types. In this article, developments of systemic therapy in adjuvant and neoadjuvant settings for HCC were reviewed. The design of adjuvant and neoadjuvant therapy using ICI-based regimens and potential challenges of trial conduct and result analysis was discussed. Results from these trials may extend the therapeutic benefit of ICI-based systemic therapy beyond the advanced-stage disease and lead to a new era of multidisciplinary management for HCC.

New Brush Copolymers as an Effective Dispersant for Stabilizing Concentrated Suspensions of Silver Nanoparticles.

Silver nanopowders (nano-Ag) have extremely high surface energy and are generally difficult to have an effective dispersant for their dispersion stabilization. This study proposes two brush copolymers that show a strong preference for adsorption on the nano-Ag surface via their backbone, while their side chains extend into the dispersion solvent for particle stabilization. After adding only 5 wt % (based on the mass of nano-Ag) of the proposed dispersants, the nano-Ag particles can be stably suspended without settling for at least 2 months. Besides, 5 wt % of these dispersants can well stabilize at least 40 wt % nano-Ag dispersed in di(ethylene glycol) ethyl ether, which is a common solvent for conductive inks and pastes. For applications, a thin film cast using the dispersed nano-Ag shows greatly improved surface flatness as compared to that made without the dispersant, and a low electrical resistivity of 2 × 10-5 Ω cm is obtained after the film is annealed at 170 °C for 20 min.

Dispersion of Poly(urea-formaldehyde)-Based Microcapsules for Self-Healing and Anticorrosion Applications.

An effective dispersant, oleyl phosphate (OP), for the dispersion of poly(urea-formaldehyde)-based microcapsules in a typical epoxy coating material is proposed. Based on electron microscopy observations and rheological and mechanical characterizations, it is observed that the addition of merely 0.5 wt % of OP is sufficient to obtain good dispersion of the microcapsules in the epoxy. In the self-healing and anticorrosion experiments, a microcapsule content of at least 15 wt % is required to efficiently restore the epoxy matrix and provide corrosion protection to underlying low-carbon steel when the particles are not dispersed; however, the amount of microcapsules required to obtain good self-healing and anticorrosion efficiencies can be greatly reduced to only 5 wt % when the microcapsules are dispersed by OP.

New Approach for the Synthesis of Nanozirconia Fortified Microcapsules.

Robust poly(urea-formaldehyde) (PUF) microcapsules with composite shells comprising zirconia (ZrO2) nanopowder incorporated in PUF were fabricated via a novel and facile one-pot synthesis. ZrO2 nanopowder was chosen because it owns one of the highest mechanical strengths among ceramics. The nanopowder was predispersed in the core material to combine encapsulation and fortification into a single process. In the core, the well-dispersed nanopowder migrated to the interface, where PUF polymerization took place. The mechanical strength of the microcapsule with nano-ZrO2 incorporated in the shell (42% by weight) is three times greater than that of the microcapsule without ZrO2. In a preliminary application wherein the microcapsules were embedded in a model of poly(vinyl alcohol) (PVA) membrane, the PVA specimen exhibited a higher ultimate tensile strength when fortified microcapsules were embedded than when unfortified microcapsules were used.

Baseline Circulating miR-125b Levels Predict a High FIB-4 Index Score in Chronic Hepatitis B Patients after Nucleos(t)ide Analog Treatment.

The regulatory role of microRNAs (miRNAs) in HBV-associated HCC pathogenesis has been reported previously. This study aimed to investigate the association between serum miR-125b and liver fibrosis progression in chronic hepatitis B (CHB) patients after nucleos(t)ide analog (NA) treatment. Baseline serum miR-125b levels and other relevant laboratory data were measured for 124 patients who underwent 12-month NA therapy. Post-12-month NA therapy, serum miR-125, platelet, AST, and ALT levels were measured again for post-treatment FIB-4 index calculation. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for a higher post-treatment FIB-4 index. Results showed that baseline miR-125b levels were inversely correlated with the post-treatment FIB-4 index (ρ = −0.2130, p = 0.0082). In logistic regression analyses, age (OR = 1.17, p < 0.0001), baseline platelet level (OR = 0.98, p = 0.0032), and ALT level (OR = 1.00, p = 0.0241) were independent predictors of FIB-index > 2.9 post-12-month treatment. The baseline miR-125b level was not significantly associated with a higher post-treatment FIB-4 index (p = 0.8992). In 59 patients receiving entecavir (ETV) monotherapy, the alternation of serum miR-125b in 12 months and age were substantially associated with a higher post-treatment FIB-4 index (>2.9), suggesting that miR-125b is a reliable biomarker for detecting early liver fibrosis under specific anti-HBV NA treatments (e.g., ETV).

Well-Dispersed Garnet Crystallites for Applications in Solid-State Li-S Batteries.

A uniform ceramic tape of well-dispersed garnet-type Li6.4La3Zr1.4Ta0.6O12 particles (LLZTO) with a high solid content of 70 wt % is prepared as an electrolyte in solid-state Li-S batteries. The use of appropriate dispersants is crucial for achieving fine dispersion and uniform distribution of LLZTO particles in the ceramic tape. This leads to improved surface flatness and mechanical strength of the ceramic tape. Moreover, the ionic conductivity increases remarkably at the same time from 10-5 to 10-4 to 10-4 to 10-3 S cm-1, and the Li+ transport number doubles from 0.35 to 0.70. The Li-S battery constructed with the dispersed LLZTO electrolyte shows an adequate capacity of above 600 mA h g-1 after 100 cycles at a discharge current of 84 mA g-1, and it is capable of charging/discharging at a high current of 1672 mA g-1. In comparison, the battery with a nondispersed LLZTO electrolyte functions only at the lower current of 84 mA g-1 and fails to work after 25 cycles.

Impact of diabetes mellitus on the prognosis of patients with oral squamous cell carcinoma: a retrospective cohort study.

BACKGROUND: Diabetes mellitus (DM) is a prevalent chronic metabolic disease reported to affect the treatment outcomes of malignancies. This study explores the impact of diabetes on the prognosis of oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: Clinicopathological characteristics and survival in terms of overall survival (OS), recurrence-free survival (RFS), and cancer-specific survival (CSS) of patients with OSCC who underwent surgical intervention at the Taipei Veterans General Hospital between 2002 and 2005 were stratified by diabetic status and compared. RESULTS: Patients with DM tend to have a lower OS, RFS, and CSS compared with nondiabetics (adjusted hazard ratio [HR] = 2.22, 2.42, and 2.16, respectively) even in less aggressive tumor stages (stage I and II). In advanced tumors, diabetic patients who were not prescribed adjuvant therapy had a significantly higher recurrence rate than nondiabetic patients (HR = 2.66). However, there was no significant difference in treatment outcome in patients with locally advanced tumors amenable to receive adjuvant therapy, even with the delayed initiation of adjuvant therapy in the DM group (49.1 +/- 22.3 days vs. 40.0 +/- 16.6 days, P = .04). DM was also associated with a higher frequency of perineural invasion (adjusted odds ratio [OR] = 2.53). CONCLUSION: DM status could be a prognostic factor for OSCC, particularly for its effect in the survival and perineural invasion. Although diabetes-associated comorbidities may impair decision making toward less aggressive therapeutic modality, adjuvant treatment may be essential for DM patients to improve their survival.

Encapsulating Well-Dispersed Carbon Nanoparticles for Applications in the Autonomous Restoration of Electronic Circuits.

Two types of conductive microcapsules with a median size of less than 5 µm are proposed, and their high potential as a key functional material for self-restorable conductive pastes for applications in printed electronic circuits is verified. A well-dispersed suspension of carbon nanoparticles in toluene is prepared as the core material of the microcapsules. The restoration capabilities of the microcapsules for the physical structure and electrical conductivity of silver-based electronic circuit lines are compared. In the assessment of the microcapsule restoration efficiency, the two conductive microcapsules exhibit distinct capabilities for the restoration of damages caused by different mechanical fracturing. That is, the smaller microcapsule is more effective than the larger one to restore circuit lines from a tensile test, whereas the opposite result is obtained from a scratching test, demonstrating the significance of microcapsule size for the restoration of dissimilar fractures that may occur in various applications.

Dispersion of microcapsules for the improved thermochromic performance of smart coatings.

Microcapsules are widely applied in coatings; however, there are very few reports on the dispersion of microcapsules in the coating material or the effects of dispersion on their performance. Herein, the efficiency of three types of dispersants bearing distinctive functional groups for the dispersion of concentrated thermochromic microcapsules in a solvent and coating resin is studied. The dispersion properties of 35 wt% thermochromic microcapsules in toluene and in coating resin are investigated by measuring their sedimentation and rheological behavior. Interactions between the dispersant and microcapsules are characterized by Fourier transform infrared spectroscopy in order to identify the dominant dispersion mechanism. The physical quality and thermochromic performance of the coating films are characterized by electron microscopy observations and temperature variation tests. The most effective dispersant for thermochromic microcapsules is determined. Compared to the coating film containing non-dispersed microcapsules, the film with well-dispersed microcapsules shows improved surface flatness, with few or no pores in the microstructure. In addition, the color of the film with well-dispersed thermochromic microcapsules shows faster response to temperature variation, resulting in complete and uniform color transformation.

Preparation of highly dispersed and concentrated aqueous suspensions of nanodiamonds using novel diblock dispersants.

HYPOTHESIS: Finding an efficient dispersant for obtaining a good dispersion of 5-nm detonation nanodiamond (DND) is always a challenge. Two newly designed diblock copolymers, both poly(ammonium methacrylate)-block-poly(2-phenoxyethyl acrylate) (PMA-b-PBEA) but with different molar ratios of PMA to PBEA, were proposed to be efficient dispersants in stabilizing the concentrated aqueous suspensions of DND. EXPERIMENTS: The dispersion efficiency of dispersants for DND in aqueous suspensions was studied by the measurements of particle size, sedimentation property, and rheological behavior. The interactions between the added dispersants and DND were identified by the zeta potential and adsorption analyses. Calculations based on Derjaguin-Landau-Verwey-Overbeek (DLVO) theory were conducted for clarifying the dominant parameters relating to the dispersion efficiency of dispersants. FINDINGS: Compared with the commercially popular dispersant ammonium polyacrylate, these two diblock dispersants exhibited superior efficiency in the stabilization of DND suspensions. Using the diblock copolymers as dispersants, good dispersion stability in a DND suspension with an extremely high solid content of 30 wt% was achieved. According to experimental analyses and based on DLVO calculations, a low number of accompanied counter-ions, high adsorption capability, and thick PMA-b-PBEA adsorption layer are the main reasons for the extremely high dispersion efficiency of the two new dispersants.

Newly designed diblock dispersant for powder stabilization in water-based suspensions.

A newly designed dispersant for water-based suspensions, ammonium poly(methacrylate)-block-poly(2-phenoxyethyl acrylate) (PMA-b-PBEA), is proposed in this study. According to the results of rheological analysis, the dispersion efficiency of this new dispersant is superior to that of the commercially available ammonium polyacrylate (PAA-NH4). The diblock structure of PMA-b-PBEA, which simultaneously contains a low-polar anchoring head group and a water-dissociable stabilizing moiety, is the main cause for its extremely high efficiency for powder dispersion. The unique structure not only results in effective adsorption approximately double that of PAA-NH4, but also produces a low number of counter-ions that compress the electrical double layer and ruin powder stabilization. Based on Derjaquin-Landau-Verwey-Overbeek calculations, the large adsorbance of PMA-b-PBEA gives the powder, titania (TiO2) in this study, a high steric stabilization energy. In addition, PMA-b-PBEA provides TiO2 with a remarkably high electrostatic energy because it generates fewer counter-ions. This energy provides excellent dispersity of powder in the suspensions with a high solid content of 60wt% without showing any rheological hysteresis.

Tomatidine inhibits invasion of human lung adenocarcinoma cell A549 by reducing matrix metalloproteinases expression.

Tomatidine is an aglycone of glycoalkaloid tomatine in tomato. Tomatidine is found to possess anti-inflammatory properties and may serve as a chemosensitizer in multidrug-resistant tumor cells. However, the effect of tomatidine on cancer cell metastasis remains unclear. This study examines the effect of tomatidine on the migration and invasion of human lung adenocarcinoma A549 cell in vitro. The data demonstrates that tomatidine does not effectively inhibit the viability of A549 cells. When treated with non-toxic doses of tomatidine, cell invasion is markedly suppressed by Boyden chamber invasion assay, while cell migration is not affected. Tomatidine reduces the mRNA level of matrix metalloproteinase-2 (MMP-2), MMP-9 and increases the expression of reversion-inducing cysteine-rich protein with kazal motifs (RECK), as well as tissue inhibitor of metalloproteinase-1 (TIMP-1). The immunoblotting assays indicate that tomatidine is very effective in suppressing the phosphorylation of Akt and extracellular signal regulating kinase (ERK). In addition, tomatidine significantly decreases the nuclear level of nuclear factor kappa B (NF-κB), which suggests that tomatidine inhibits NF-κB activity. Furthermore, the treatment of inhibitors specific for PI3K/Akt (LY294002), ERK (U0126), or NF-κB (pyrrolidine dithiocarbamate) to A549 cells reduced cell invasion and MMP-2/9 expression. The results suggest that tomatidine inhibits the invasion of A549 cells by reducing the expression of MMPs. It also inhibits ERK and Akt signaling pathways and NF-κB activity. These findings demonstrate a new therapeutic potential for tomatidine in anti-metastatic therapy.

Duality of the carbohydrate-recognition system of Pseudomonas aeruginosa-II lectin (PA-IIL).

The study of Pseudomonas aeruginosa-II lectin (PA-IIL) complexes with Man derivatives as a recognition factor has been neglected since its monomer is a very weak ligand. Here, the roles of Man oligomers and complexes in PA-IIL carbohydrate-recognition were studied by both enzyme-linked lectinosorbent and inhibition assays. From the results obtained, it is proposed that high density weak -OH conformation as seen in yeast mannan is also an important PA-IIL recognition factor. This finding provides a peculiar concept of the duality of PA-IIL recognition system for LFucalpha1--> and related complexes and for high density Manalpha1--> complexes present in polymannosylated target macromolecules.

Multiple recognition systems adopting four different glycotopes at the same domain for the Agaricus bisporus agglutinin-glycan interactions.

For the GalNAcalpha1--> specific Agaricus bisporus agglutinin (ABA) from an edible mushroom, the mechanism of polyvalent Galbeta1-->3/4GlcNAcbeta1--> complex in ABA-carbohydrate recognition has not been well defined since Gal and GlcNAc are weak ligands. By enzyme-linked lectinosorbent and inhibition assays, we show that the polyvalent Galbeta1-->3/4GlcNAcbeta1--> in natural glycans also play vital roles in binding and we propose that four different intensities of glycotopes (Galbeta1-3GalNAcalpha1-, GalNAcalpha1-Ser/Thr and Galbeta1-3/4GlcNAcbeta1-) construct three recognition systems at the same domain. This peculiar concept provides the most comprehensive mechanism for the attachment of ABA to target glycans and malignant cells at the molecular level.

An efficient approach to derive hydroxyl groups on the surface of barium titanate nanoparticles to improve its chemical modification ability.

Highly hydroxylated barium titanate (BaTiO(3)) nanoparticles have been prepared via an easy and gentle approach which oxidizes BaTiO(3) nanoparticles using an aqueous solution of hydrogen peroxide (H(2)O(2)). The hydroxylated BaTiO(3) surface reacts with sodium oleate (SOA) to form oleophilic layers that greatly enhance the dispersion of BaTiO(3) nanoparticles in organic solvents such as tetrahydrofuran, toluene, and n-octane. The results of Fourier transform infrared spectroscopy confirmed that the major functional groups on the surface of H(2)O(2)-treated BaTiO(3) nanoparticles are hydroxyl groups which are chemically active, favoring chemical bonding with SOA. The results of transmission electron microscopy of SOA-modified BaTiO(3) nanoparticles suggested that the oleate molecules were bonded to the surfaces of nanoparticles and formed a homogeneous layer having a thickness of about 2 nm. Furthermore, the improved dispersion capability of the modified BaTiO(3) nanoparticles in organic solvents was verified through analytic results of its settling and rheological behaviors.