Tuning Surface Plasmon Resonance Responses through Size and Crosslinking Control of Multivalent Protein Binding-Capable Nanoscale Hydrogels.

Surface plasmon resonance (SPR) phenomena have been widely studied to detect biomolecules because of their high sensitivity and ability to determine biomolecular interactions with kinetic information. However, highly selective detection in specific concentration ranges relevant to target biomolecules is still a challenging task. Recently, we developed bioresponsive nanoscale hydrogels to selectively intensify SPR signals through multivalent protein binding (MPB) events with target biomolecules, including IL-2, where we were able to demonstrate exceptional selectivity for target biomolecules with minimal responses to nonspecific and monovalent binding events. In this work, we systematically explored the relationship between the physical properties of MPB-capable nanoscale hydrogels and their SPR response induced in the presence of the programmed cell death protein 1 antibody (PD-1Ab) as a model target biomolecule. First, we developed a synthetic protocol by controlling various reaction parameters to construct a library of nanoscale poly(N-isopropylacrylamide-co-acrylic acid) hydrogels (NHs) with different sizes (from 400 nm to 1 µm) and degrees of crosslinking (from 2 to 8%). Then, by incorporating MPB-capable PD-1 receptors onto the surface of NHs to form PD-1-responsive nanoscale hydrogels (PNHs), the hydrogel size and crosslinking dependency of their SPR responses were investigated. Our results reveal the appropriate hydrogel size regime and degree of crosslinking for effective PD-1Ab detection at specific concentrations range between a few nM and 1 µM. Overall, our study demonstrates that by tuning the physical properties of the nanoscale hydrogel matrix, the sensitivity and detection range of MPB-based SPR sensors can be modulated to potentially benefit clinical applications such as monitoring diverse therapeutic biomolecules.

New Tool for Rapid and Accurate Detection of Interleukin-2 and Soluble Interleukin-2 Receptor α in Cancer Diagnosis Using a Bioresponsive Microgel and Multivalent Protein Binding.

Interleukin-2 (IL-2) and its α receptor in soluble form (sIL-2Rα) are considered biomarkers for cancers and immune-related diseases. Enzyme-linked immunosorbent assay is the most common method used to evaluate biomarkers in clinical practice; it is precise but time-consuming and involves complicated procedures. Here, we have developed a rapid yet accurate modality for cancer diagnosis that enables on-site evaluation of cancer markers, that is, IL-2 and sIL-2Rα, without complicated pretreatment of cancer patient-derived blood samples. Surface plasmon resonance and bioresponsive microgels conjugated with IL-2 receptors, that is, IL-2Rß and IL-2Rγ, were utilized to measure IL-2 and sIL-2Rα levels via multivalent protein binding (MPB) between the ligands and their receptors. Our results showed that this novel method enables us to perform cancer diagnosis with a 1000-fold dilution of serum in 10 min. The advantage of MPB-based cancer diagnosis originates from its great selectivity for a target molecule and tolerance to a myriad of nonspecific substances in serum, which allows on-site clinical evaluation. Importantly, our finding implies that MPB-based cancer diagnosis provides a new paradigm not only for improving cancer treatment but also for evaluating a target molecule in unpurified and complex solutions such as blood.

Label-Free Analysis of Multivalent Protein Binding Using Bioresponsive Nanogels and Surface Plasmon Resonance (SPR).

Precise identification of protein-protein interactions is required to improve our understanding of biochemical pathways for biology and medicine. In physiology, how proteins interact with other proteins or small molecules is crucial for maintaining biological functions. For instance, multivalent protein binding (MPB), in which a ligand concurrently interacts with two or more receptors, plays a key role in regulating complex but accurate biological functions, and its interference is related to many diseases. Therefore, determining MPB and its kinetics has long been sought, which currently requires complicated procedures and instruments to distinguish multivalent binding from monovalent binding. Here, we show a method for quickly evaluating the MPB over monovalent binding and its kinetic parameters in a label-free manner. Engaging pNIPAm-co-AAc nanogels with MPB-capable moieties (e.g., PD-1 antigen and biocytin) permits a surface plasmon resonance (SPR) instrument to evaluate the MPB events by amplifying signals from the specific target molecules. Using our MPB-based method, PD-1 antibody that forms a type of MPB by complexing with two PD-1 proteins, which are currently used for cancer immunotherapy, is detectable down to a level of 10 nM. In addition, small multivalent cations (e.g., Ca2+, Fe2+, and Fe3+) are distinguishably measurable over monovalent cations (e.g., Na+ and K+) with the pNIPAm-co-AAc nanogels.

Sub-2 V, Transfer-Stamped Organic/Inorganic Complementary Inverters Based on Electrolyte-Gated Transistors.

Organic/inorganic hybrid complementary inverters operating at low voltages (1 V or less) were fabricated by transfer-stamping organic p-type poly(3-hexylthiophene) (P3HT) and inorganic n-type zinc oxide (ZnO) electrolyte-gated transistors (EGTs). A semicrystalline homopolymer-based gel electrolyte, or an ionogel, was also transfer-stamped on the semiconductors for use as a high-capacitance gate insulator. For the ionogel stamping, the thermoreversible crystallization of phase-separated homopolymer crystals, which act as network cross-links, was employed to improve the contact between the gel and the semiconductor channel. The homopolymer ionogel-gated P3HT transistor exhibited a high hole mobility of 2.81 cm2/(V s), and the ionogel-gated n-type ZnO transistors also showed a high electron mobility of 2.06 cm2/(V s). The transfer-stamped hybrid complementary inverter based on the P3HT and ZnO EGTs showed a low-voltage operation with appropriate inversion characteristics including a high voltage gain of ∼18. These results demonstrate that the transfer-stamping strategy provides a facile and reliable processing route for fabricating electrolyte-gated transistors and logic circuits.

Screening Biomarker as an Alternative to Endoscopy for the Detection of Early Gastric Cancer: The Combination of Serum Trefoil Factor Family 3 and Pepsinogen.

OBJECTIVE: The serum pepsinogen test has limitation in its predictive power as a noninvasive biomarker for gastric cancer screening. We aimed to investigate whether the combination of TFF3 and pepsinogen could be an effective biomarker for the detection of gastric cancer even in the early stages. METHODS: In total, 281 patients with early gastric cancer (EGC), who underwent endoscopic submucosal dissection in Korea, and 708 healthy individuals from Japan were enrolled in the derivation cohort. The validation cohort included 30 Korean patients with EGC and 30 Korean healthy control blood donors. Serum TFF3 levels were examined using enzyme-linked immunosorbent assay. RESULTS: Using a cutoff of 6.73 ng/mL in the derivation cohort, the sensitivity of the combination of tests for EGC detection was superior (87.5%) to that of TFF3 (80.4%) or pepsinogen test alone (39.5%). Similarly, in the validation cohort, the sensitivity of TFF3 plus pepsinogen was higher (90.4%) than that of TFF3 (80.0%) or pepsinogen test alone (33.3%). CONCLUSION: The combination of serum TFF3 and pepsinogen is a more effective noninvasive biomarker for gastric cancer detection compared with pepsinogen or TFF3 alone, even in EGC. This trial is registered with NCT03046745.

Area-Controllable Stamping of Semicrystalline Copolymer Ionogels for Solid-State Electrolyte-Gated Transistors and Light-Emitting Devices.

Two types of thin-film electrochemical devices (electrolyte-gated transistors and electrochemical light-emitting cells) are demonstrated using area-controllable ionogel patches generated by transfer-stamping. For the successful transfer of ionogel patches on various target substrates, thermoreversible gelation by phase-separated polymer crystals within the ionogel is essential because it allows the gel to form a conformal contact with the acceptor substrate, thereby lowering the overall Gibbs energy of the system upon transfer of the ionogel. This crystallization-mediated stamping provides a much more efficient deposition route for producing thin films of ionically conductive high-capacitance solid ionogel electrolytes. The lateral dimensions of the transferred ionogels range from 1 mm × 1 mm to 40 mm × 40 mm. These ionogel patches are incorporated in organic p-type and inorganic n-type thin-film transistors and electrochemical light-emitting devices. The resulting transistors show sub-1 V device operation with high transconductance currents, and the optoelectronic devices emit orange light through a series of electrochemical redox reactions. These results demonstrate a simple yet versatile route to employ physical ionogels for various solid-state electrochemical device applications.

Physically Cross-Linked Homopolymer Ion Gels for High Performance Electrolyte-Gated Transistors.

A new type of physically cross-linked solid polymer electrolyte was demonstrated by using a poly(vinylidene fluoride) (PVDF) homopolymer in a room-temperature ionic liquid. The physical origins of gelation, specific capacitance, ionic conductivity, mechanical property, and capacitive charge modulation in organic thin-film electrochemical transistors were investigated systematically. Gelation occurs through bridging phase-separated homopolymer crystals by polymer chains in the composite electrolyte, thereby forming a rubbery network. The resulting homopolymer ion gels are able to accommodate both outstanding electrical (ionically conductive and capacitive) and mechanical (flexible and free-standing) characteristics of the component ionic liquid and the structuring polymer, respectively. These ion gels were successfully applied to organic thin-film transistors as high-capacitance gate dielectrics. Therefore, these results provide an effective route to generate a highly conductive rubbery polymer electrolyte that can be used in widespread electronic and electrochemical devices.

Comparison of scoring systems for nonvariceal upper gastrointestinal bleeding: a multicenter prospective cohort study.

BACKGROUND AND AIM: The Glasgow-Blatchford score (GBS) and Rockall score (RS) are widely used to assess risk in patients with upper gastrointestinal bleeding (UGIB). We compared both scoring systems and evaluated their clinical usefulness. METHODS: Between February 2011 and December 2013, 1584 patients with nonvariceal UGIB were included in the study. A prospective study was conducted to compare the performance of the GBS, pre-RS, and full RS. We compared the performance of these scores using receiver operating characteristic curves. RESULTS: For prediction of the need for hospital-based intervention, the GBS was similar to the full RS (area under the receiver operating characteristic curves [AUROC] 0.705 vs 0.727; P = 0.282) and superior to the pre-RS (AUROC 0.705 vs 0.601; P < 0.0001). In predicting death, the full RS was superior to the GBS (AUROC 0.758 vs 0.644; P = 0.0006) and similar to the pre-RS (AUROC 0.758 vs 0.754; P = 0.869). In predicting rebleeding, the full RS was superior to both GBS (AUROC 0.642 vs 0.585; P = 0.031) and pre-RS (AUROC 0.642 vs 0.593; P = 0.0003). Of 1584 patients, 13 (0.8%) scored 0 on the GBS. Therapeutic intervention was not performed in any of these patients. CONCLUSIONS: The GBS is more useful than the pre-RS for predicting the need for hospital-based intervention. A cutoff value of 0 for low-risk patients who might be suitable for outpatient management is useful. The full RS is helpful in predicting death. None of the systems accurately predict rebleeding with a low AUROC. ( CLINICAL TRIAL: cris.nih.go.kr/KCT0000514).

Advanced fibrosis is not a negative pretreatment predictive factor for genotype 2 or 3 chronic hepatitis C patients.

BACKGROUND/AIMS: Chronic hepatitis C patients with advanced fibrosis have unsatisfactory sustained virological response (SVR) rates. Few data demonstrating the efficacy of combination therapy in chronic hepatitis C patients with advanced fibrosis in South Korea are available. The purpose of this study was to assess whether the stage of fibrosis impacts the efficacy of combination therapy for chronic hepatitis C. METHODS: We retrospectively reviewed data for a total of 109 patients with chronic hepatitis C, treated with peginterferon alfa and ribavirin. SVR according to the stage of liver fibrosis assessed by pretreatment liver biopsy and genotype results were analyzed. RESULTS: Data from 66 genotype 1 patients (60.6%) and 43 genotype 2 or 3 patients (39.4%) among the 109 patients were analyzed. SVR rates for the genotype 1 patients were significantly lower for the stage 3-4 group (32.1%) than the stage 0-2 group (78.9%; P<0.001). SVR rates (92.0% for stage 0-2, 77.8% for stage 3-4, P=0.184) of genotype 2 or 3 patients were not significantly different according to fibrosis stage. Likewise, the frequency of adverse events was not significantly different according to fibrosis stage. CONCLUSIONS: Compared to patients without advanced fibrosis, we can anticipate good SVR rates for genotype 2 or 3 patients with advanced fibrosis and they did not show an inferior tolerability for peginterferon and ribavirin combination therpy. Our results suggest that active treatment is needed for genotype 2 or 3 patients with advanced fibrosis.

[Could nafamostat or gabexate prevent the post endoscopic retrograde cholangiopancreatography pancreatitis?].

BACKGROUND/AIMS: ERCP is the most common procedure for the diagnosis and treatment of bile duct and pancreatic disease, but Post-ERCP pancreatitis makes poor outcome in some cases. The protease inhibitors, nafamostat and gabexate, have been used to prevent pancreatitis related to ERCP, but there is some debate. We tried to evaluate the efficacy of gabexate and nafamostat for the prevention of post-ERCP pancreatitis. METHODS: Two hundred forty two patients (73 patients in the gabexate group, 88 patients in the nafamostat group and 81 patients in the placebo group) were included in the study after selective exclusion. The incidence of pancreatitis after ERCP was compared among groups. RESULTS: The incidence of pancreatitis were 6.8% in the gabexate group, 5.7% in the nafamostat group and 6.2% in the placebo group (p=0.954). CONCLUSIONS: There was no meaningful difference among the gabexate, nafamostat and placebo group.

[A case of primary colon amyloidosis presenting as hematochezia].

Amyloidosis is characterized by a deposition of insoluble fibrils in various organs and tissues. Amyloid deposition, in the gastrointestinal track, provokes a dysfunction of the organ, due to an accumulation of fibrils, and causes a variety of clinical symptoms and endoscopic findings. Primary amyloidosis in the gastrointestinal tract is rarely reported in Korea. We experienced a case of recurrent intestinal bleeding, in a 59-year-old female patient with primary amyloidosis. A colonoscopy revealed the presence of multiple large circular ulcers. In the entire colon, diffuse nodular lesions with edema and bleeding were found. A colonoscopic biopsy established the diagnosis of amyloidosis, to the exclusion of other disease components. We concluded that the patient had localized amyloidosis. Though a definitive therapeutic strategy has not been established for localized gastrointestinal amyloidosis, the patient has been successfully treated with a high-dose of steroids and azathioprine.

[Abscesso-colonic fistula following radiofrequency ablation therapy for hepatocellular carcinoma; a case successfully treated with histoacryl embolization].

Hepatocellular carcinoma (HCC) is one of the most common malignant neoplasms occuring worldwide. Although surgical resection still remains the treatment of choice for HCC, radiofrequency ablation (RFA) has emerged as reliable alternatives to resection. It is less invasive and can be repeated after short intervals for sequential ablation in case of multiple lesions. The most common complication of RFA is liver abscess, and bile duct injury such as bile duct stricture has been reported. This is a case report of a rare complication of abscesso-colonic fistula after RFA for HCC. The case was treated by percutaneous abscess drainage and antibiotics and occlusion of abscesso-colonic fistula with n-butyl-2-cyanoacrylate embolization.