Search

Introduction: This study aimed to compare the long-term effects of neoadjuvant therapy and upfront surgery on overall survival (OS) and progression-free survival (PFS) in patients with resectable pancreatic ductal adenocarcinoma (PDAC)., Methods: We retrospectively analyzed 202 patients, including 167 who had upfront surgery and 35 who received neoadjuvant therapy followed by surgery. Surgical outcomes and survival rates were compared using propensity score matching to minimize selection bias., Results: Neoadjuvant therapy showed significantly longer 75% OS (72.7 months vs. 28.3 months, p = 0.032) and PFS (29.6 months vs. 13.2 months, p < 0.001) compared to upfront surgery. Additionally, neoadjuvant therapy demonstrated significant improvements in surgical outcomes, including higher R0 resection rates (74.3% vs. 49.5%, p = 0.034), reduced tumor size (22.0 mm vs. 28.0 mm, p = 0.001), and decreased lymphovascular invasion (20.0% vs. 52.4%, p = 0.001)., Conclusion: Our study demonstrates the potential benefits of neoadjuvant therapy for resectable PDAC. The improved survival rates, delayed disease progression, and enhanced surgical outcomes underscore the potential of neoadjuvant therapy in addressing this aggressive disease. Despite limitations such as the retrospective design and small sample size, these findings support the effectiveness of neoadjuvant therapy in improving treatment outcomes for PDAC patients in real-world settings. Further prospective studies are required to validate these results., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

To identify risk factors and biomarker for early recurrence in patients diagnosed with pancreatic cancer who undergo curative resection. Early recurrence after curative resection of pancreatic cancer is an obstacle to long-term survival. We retrospectively reviewed 162 patients diagnosed with pancreatic cancer who underwent curative resection. Early recurrence was defined as recurrence within 12 months of surgery. We selected S100A2 as a biomarker and investigated its expression using immunohistochemistry. Of the total, 79.6% (n = 129) of patients received adjuvant chemotherapy after surgery and 117 (72.2%) experienced recurrence, of which 73 (45.1%) experience early recurrence. In multivariate analysis, age < 60 years, presence of lymph node metastasis, and no adjuvant chemotherapy were significantly associated with early recurrence (all P < 0.05). The proportion of patients with high S100A2 expression (H-score > 5) was significantly lower in the early recurrence group (41.5% vs. 63.3%, P = 0.020). The cumulative incidence rate of early recurrence was higher in patients with an S100A2 H-score < 5 (41.5% vs. 63.3%, P = 0.012). The median overall survival of patients with higher S100A2 expression was longer than those with lower S100A2 expression (median 30.1 months vs. 24.2 months, P = 0.003). High-risk factors for early recurrence after surgery for pancreatic cancer include young age, lymph node metastasis, and no adjuvant therapy. Neoadjuvant treatment or intensive adjuvant therapy after surgery may improve the prognosis of patients with high-risk signatures. In patients who receive adjuvant therapy, high S100A2 expression is a good predictor., (© 2024. The Author(s).)

Biochar derived from lignocellulosic biomass has been used as a low-cost adsorbent in wastewater treatment applications. Due to its rich porous structure and good electrical conductivity, biochar can be used as a cost-effective electrode material for capacitive deionization of water. In this work, willow biochar was prepared through carbonization of shrub willow chips, activated with potassium hydroxide, and loaded with manganese dioxide (WBC-K-MnO 2 nanocomposite). The prepared materials were used to electrochemically adsorb Pb 2+ from aqueous solutions. Under the applied potential of 1.0 V, the WBC-K-MnO 2 electrode exhibited a high Pb 2+ specific electrosorption capacity (23.3 mg/g) as compared to raw willow biochar (4.0 mg/g) and activated willow biochar (9.2 mg/g). KOH activation followed by MnO 2 loading on the surface of raw biochar enhanced its BET surface area (178.7 m 2 /g) and mesoporous volume ratio (42.1%). Moreover, the WBC-K-MnO 2 nanocomposite exhibited the highest specific capacitance value of 234.3 F/g at a scan rate of 5 mV/s. The electrosorption isotherms and kinetic data were well explained by the Freundlich and pseudo-second order models, respectively. The WBC-K-MnO 2 electrode demonstrated excellent reusability with a Pb 2+ electrosorption efficiency of 76.3% after 15 cycles. Thus, the WBC-K-MnO 2 nanocomposite can serve as a promising candidate for capacitive deionization of heavy metal contaminated water.

Background: Recent studies using single-cell transcriptomic analysis have reported several distinct clusters of neoplastic epithelial cells and cancer-associated fibroblasts in the pancreatic cancer tumor microenvironment. However, their molecular characteristics and biological significance have not been clearly elucidated due to intra- and inter-tumoral heterogeneity., Methods: We performed single-cell RNA sequencing using enriched non-immune cell populations from 17 pancreatic tumor tissues (16 pancreatic cancer and one high-grade dysplasia) and generated paired spatial transcriptomic data from seven patient samples., Results: We identified five distinct functional subclusters of pancreatic cancer cells and six distinct cancer-associated fibroblast subclusters. We deeply profiled their characteristics, and we found that these subclusters successfully deconvoluted most of the features suggested in bulk transcriptome analysis of pancreatic cancer. Among those subclusters, we identified a novel cancer cell subcluster, Ep&#95;VGLL1, showing intermediate characteristics between the extremities of basal-like and classical dichotomy, despite its prognostic value. Molecular features of Ep&#95;VGLL1 suggest its transitional properties between basal-like and classical subtypes, which is supported by spatial transcriptomic data., Conclusions: This integrative analysis not only provides a comprehensive landscape of pancreatic cancer and fibroblast population, but also suggests a novel insight to the dynamic states of pancreatic cancer cells and unveils potential therapeutic targets., (© 2024. The Author(s).)

Introduction: The incidence of postendoscopic retrograde cholangiopancreatography (ERCP) infections is reported to be up to 18% in patients with biliary obstruction. Antibiotic prophylaxis may reduce the risk of infectious complications after ERCP; however, the clinical value of prophylactic antibiotics in ERCP remains controversial., Methods: We conducted a double-blind, placebo-controlled, randomized trial to investigate whether the use of prophylactic antibiotics would reduce infectious complications after ERCP in patients with biliary obstruction. We randomly assigned patients in a 1:1 ratio to receive either a single dose of 1 g intravenous cefoxitin or normal saline as a placebo 30 minutes before undergoing ERCP. The primary outcome was the incidence of infectious complications after ERCP., Results: We enrolled 378 patients, and 189 patients were assigned to each group. The risk of infectious complications after ERCP was 2.8% (5 of 176 patients) in the antibiotic prophylaxis group and 9.8% (17 of 173 patients) in the placebo group (risk ratio, 0.29; 95% confidence interval [CI], 0.11-0.74, P = 0.0073). The incidence rates of bacteremia were 2.3% (4 of 176 patients) and 6.4% (11 of 173 patients), respectively (risk ratio, 0.36; 95% CI, 0.12-1.04; P = 0.0599). The incidence rate of cholangitis was 1.7% (3 of 176 patients) in the antibiotic prophylaxis group and 6.4% (11 of 173 patients) in the placebo group (risk ratio, 0.27; 95% CI, 0.08-0.87; P = 0.0267)., Discussion: Antibiotic prophylaxis before ERCP in patients with biliary obstruction resulted in a significantly lower risk of infectious complications, especially cholangitis, than placebo ( ClinicalTrials.gov trial number NCT02958059)., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of The American College of Gastroenterology.)

Objective: Early chemoresistance and tumor mass progression are associated with poor prognosis in pancreatic ductal adenocarcinoma (PDAC). Circulating tumor cells (CTCs) have been studied as potential predictors of treatment response and prognosis in PDAC; however, this approach has yet to be applied in clinical practice. The aim of our study was to investigate the phenotypic characteristics of CTCs and determine their predictive value for PDAC progression., Methods: We prospectively enrolled 40 patients who were pathologically diagnosed with PDAC and collected blood samples at diagnosis, 2 months after diagnosis, and during disease progression or recurrence. We used a microfabricated filter-based enrichment system to retrieve and analyze CTCs, which were classified using immunofluorescence staining (CD45, EpCAM, and vimentin)., Results: Our study included 20 women and 20 men (median age, 66 years). Overall, 45% of the patients (18/40) had disseminated disease, and 77.5% (31/40) received chemotherapy. Multivariate analysis revealed that the total CTC count and carbohydrate antigen 19-9 level at 2 months after diagnosis were associated with disease progression ( P <0.05). Linear mixed model analysis revealed that the total CTC count and vimentin-positive CTCs were significantly correlated with treatment response during chemotherapy ( P =0.024 and 0.017, respectively). Kaplan-Meier analysis showed that total CTC positivity at 2 months was significantly associated with poor progression-free survival ( P =0.038)., Conclusion: Our study's findings suggest that CTCs can serve as predictive biomarkers of clinical outcomes in patients with PDAC receiving palliative chemotherapy. In particular, the total CTC count and vimentin-positive CTCs showed changes associated with the chemotherapy response., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Lee, Jung, Shin, Park, Park, Jung, Leem, Kim, Jo, Chung, Park, Bang, Park and Song.)

As genomic analysis technology has advanced, it has become possible to sub-classify intrahepatic cholangiocarcinoma (ICC) at the histological or molecular level. Here, we verify the recently suggested two subgroups of ICC in the organoids model, compare the characteristics between types. ICC patients are subclassified into small-duct (SD) and large-duct (LD) subtype according to histological characteristics. ICC organoids are established, and unsupervised principal component analysis clustering separates each type of ICC. Differential gene expression reveals enrichment on KRAS, TGFβ and ERBB2 signaling pathways in LD-type compared with SD-type (P < 0.05). Gene set enrichment analysis demonstrates that the cholangiocarcinoma class 2 signature, defined by Andersen et al., is enriched in the LD-type (enrichment Score = 2.19, P < 0.001). A protein-protein interaction network analysis identifies ZNF217 as a significant hub protein (odds ratio = 4.96, P = 0.0105). We perform prospective modeling of histological subtype using patient-derived organoids. Moreover, gene expression profiling of ICC organoids enables identification of type-specific targetable pathways., (© 2023. The Author(s).)

The selective cleavage of C-C/C-O linkages represents a key step toward achieving the chemical conversion of biomass to targeted value-added chemical products under ambient conditions. Using photoelectrosynthetic solar cells is a promising method to address the energy intensive depolymerization of lignin for the production of biofuels and valuable chemicals. This feature article gives an in-depth overview of recent progress using dye-sensitized photoelectrosynthetic solar cells (DSPECs) to initiate the cleavage of C-C/C-O bonds in lignin and related model compounds. This approach takes advantage of N -oxyl mediated catalysis in organic electrolytes and presents a promising direction for the sustainable production of chemicals currently derived from fossil fuels.

The photoelectrochemical production of fuels, exemplified by light-driven water splitting to hydrogen and oxygen, offers a sustainable option to offset dependence on fossil fuels. A low-cost, efficient, and stable photoelectrochemical approach to solar fuels remains elusive but using similar materials and photoelectrodes for chemical production or biomass conversion offers an appealing alternative. This work reports a facile method for fabricating pristine (undoped) BiVO 4 photoanodes to carry out TEMPO-mediated benzyl alcohol oxidation to benzaldehyde in organic media (TEMPO=2,2,6,6-tetramethylpiperidinyl-N-oxyl). The best performing BiVO 4 photoanode studied here gave a faradaic efficiency (FE) of 85±5% for benzaldehyde formation in the presence of TEMPO and pyridine during a 2.5-hour reaction. Compared with direct electrocatalytic conversion under the same conditions, light capture and conversion by the BiVO 4 surface decreased the required applied bias by 46 %. To our knowledge, this is the first report of visible light assisted, TEMPO-mediated benzyl alcohol oxidation using pristine BiVO 4 photoanodes in organic media., (© 2022 Wiley-VCH GmbH.)

Background and Aim: This study investigated the administration of combination therapy, allogeneic natural killer (NK) cells and pembrolizumab in the treatment of advanced biliary tract cancer to determine the safety and tolerability (phase 1) and the efficacy and safety (phase 2a)., Methods: Forty patients (phase 1, n = 6; phase 2a, n = 34) were enrolled between December 2019 and June 2021. The patients received highly activated allogeneic NK cells ("SMT-NK") on weeks 1 and 2 and pembrolizumab on week 1. This 3-week schedule (one cycle) was repeated until confirmed disease progression, intolerable adverse events (AEs), patient withdrawal, or finishing the maximum treatment schedule. The tumor response was evaluated after every three cycles., Results: In phase 1, four patients (66.7%) experienced seven AEs, but no severe AE was observed. In phase 2a, 126 AEs occurred in 29 patients (85.3%). Severe AEs (≥grade 3) were reported in 16 patients (47.1%). The overall response rate (ORR) was 17.4% in the full analysis set and 50.0% in the per-protocol set., Conclusions: SMT-NKs plus pembrolizumab resulted in no severe AEs directly related to the drug combination. The combination therapy also exerted antitumor activity with improved efficacy compared to the recent monotherapy with pembrolizumab in patients with advanced biliary tract cancer.

Background: Tumour-unrelated, virus-specific bystander CD8 + T cells were recently shown to be abundant among tumour-infiltrating lymphocytes (TILs). However, their roles in tumour immunity have not been elucidated yet., Methods: We studied the characteristics of bystander CD8 + TILs from non-small cell lung cancer (NSCLC) tissues (N=66) and their activation by interleukin (IL)-15 to repurpose them for tumour immunotherapy., Results: We show that bystander CD8 + TILs specific to various viruses are present in human NSCLC tissues. We stimulated CD8 + TILs ex vivo using IL-15 without cognate antigens and found that IL-15 treatment upregulated NKG2D expression on CD8 + TILs, resulting in NKG2D-dependent production of interferon (IFN)-γ (p=0.0006). Finally, we tested whether IL-15 treatment can control tumour growth in a murine NSCLC model with or without a history of murine cytomegalovirus (MCMV) infection. IL-15 treatment reduced the number of tumour nodules in the lung only in mice with MCMV infection (p=0.0037). We confirmed that MCMV-specific bystander CD8 + TILs produced interferon (IFN)-γ after IL-15 treatment, and that IL-15 treatment in MCMV-infected mice upregulated tumour necrosis factor-α and IFN-γ responsive genes in tumour microenvironment., Conclusion: Thus, the study demonstrates that bystander CD8 + TILs can be repurposed by IL-15 for tumour immunotherapy., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

This study aims to increase the specific surface area of multi-walled carbon nanotubes (MWCNTs) by forming and subsequently removing various metal oxide nanoparticles on them. We used facile methods, such as forming the particles without using a vacuum or gas and removing these particles through simple acid treatment. The shapes of the composite structures on which the metal oxide particles were formed and the formation of multi-vacancy-defect MWCNTs were confirmed via transmission electron microscopy and scanning electron microscopy. The crystallinity of the formed metal oxide particles was confirmed using X-ray diffraction analysis. Through specific surface area analysis and Raman spectroscopy, the number of defects formed and the degree and tendency of defect-formation in each metal were determined. In all the cases where the metal oxide particles were removed, the specific surface area increased, and the metal inducing the highest specific surface area was determined.

Visible-light-driven organic oxidations carried out under mild conditions offer a sustainable approach to performing chemical transformations important to the chemical industry. This work reports an efficient photocatalytic benzyl alcohol oxidation process using one-dimensional (1D) TiO 2 nanorod (NR)-based photoanodes with surface-adsorbed ruthenium polypyridyl photocatalysts at room temperature. The photocatalyst bis(2,2'-bipyridine)(4,4'-dicarboxy-2,2'-bipyridine)Ru(II) (RuC) was covalently anchored onto TiO 2 nanorod arrays grown on fluorine-doped tin oxide (FTO) electrode surfaces (FTO|t-TiO 2 |RuC, t = the thickness of TiO 2 NR). Under aerobic conditions, the photophysical and photocatalytic properties of FTO|t-TiO 2 |RuC ( t = 1, 2, or 3.5 μm) photoanodes were investigated in a solution containing a hydrogen atom transfer mediator (4-acetamido-2,2,6,6-tetramethylpiperidine-N-oxyl, ACT) as cocatalyst. Dye-sensitized photoelectrochemical cells (DSPECs) using the FTO|t-TiO 2 |RuC ( t = 1, 2, or 3.5 μm) photoanodes and ACT-containing electrolyte were investigated for carrying out photocatalytic oxidation of a lignin model compound containing a benzylic alcohol functional group. The best-performing anode surface, FTO|1-TiO 2 |RuC (shortest NR length), oxidized the 2° alcohol of the lignin model compound to the C α -ketone form with a > 99% yield over a 4 h photocatalytic experiment with a Faradaic efficiency of 88%. The length of TiO 2 NR arrays (TiO 2 NRAs) on the FTO substrate influenced the photocatalytic performance with longer NRAs underperforming compared to the shorter arrays. The influence of the NR length is hypothesized to affect the homogeneity of the RuC coating and accessibility of the ACT mediator to the RuC-coated TiO 2 surface. The efficient photocatalytic alcohol oxidation with visible light at room temperature as demonstrated in this study is important to the development of sustainable approaches for lignin depolymerization and biomass conversion.

The seed-mediated method is a general procedure for the synthesis of gold nanorods (Au NRs), and reducing agents such as ascorbic acid (AA) and hydroquinone (HQ) are widely used for the growth process. Further, they are mild reducing agents; however, when AA is used, controlling the size of Au NRs with a higher aspect ratio (localized surface plasmon resonance (LSPR) peak, λ Lmax  > 900 nm) is challenging because it results in a faster growth rate of Au NRs. In contrast, when HQ is used, Au NRs with a higher aspect ratio can be synthesized as it slows down the growth rate of the Au NRs and greatly enhanced the λ Lmax . However, the increase in λ Lmax is still needs not satisfactory due to the limited enhancement in the aspect ratio of Au NRs due to utilization of single reducing agent. The growth kinetics of the Au NRs can be modulated by controlling the reducing power of the reducing agents. In such scenario, judicious use of two reducing agents such as AA and HQ simultaneously can help us to design Au NRs of higher aspect ratio in a controlled manner due to the optimum growth rate resulting from the combined effect of both the reducing agents. In this study, we investigated the effect of the two reducing agents by controlling the volume ratios. When the growth solution contains both the reducing agents, the growth of Au NRs is first initiated by the fast reduction of Au 3+ to Au + due to stronger reducing power of the AA and when the AA in the growth solution is completely utilized, further growth of the Au NRs continues as a result of the HQ thereby resulting to high aspect ratio Au NRs. Consequently, the LSPR peak (λ Lmax  > 1275 nm) can be tuned by controlling the volume ratios of the reducing agents., (© 2022. The Author(s).)

Integrating multidisciplinary research in plant genetic engineering and renewable deep eutectic solvents (DESs) can facilitate a sustainable and economic biorefinery. Herein, we leveraged a plant genetic engineering approach to specifically incorporate C 6 C 1 monomers into the lignin structure. By expressing the bacterial ubiC gene in sorghum, p-hydroxybenzoic acid (PB)-rich lignin was incorporated into the plant cell wall while this monomer was completely absent in the lignin of the wild-type (WT) biomass. A DES was synthesized with choline chloride (ChCl) and PB and applied to the pretreatment of the PB-rich mutant biomass for a sustainable biorefinery. The release of fermentable sugars was significantly enhanced (∼190 % increase) compared to untreated biomass by the DES pretreatment. In particular, the glucose released from the pretreated mutant biomass was up to 12 % higher than that from the pretreated WT biomass. Lignin was effectively removed from the biomass with the preservation of more than half of the β-Ο-4 linkages without condensed aromatic structures. Hydrogenolysis of the fractionated lignin was conducted to demonstrate the potential of phenolic compound production. In addition, a simple hydrothermal treatment could selectively extract PB from the same engineered lignin, showing a possible circular biorefinery. These results suggest that the combination of PB-based DES and engineered PB-rich biomass is a promising strategy to achieve a sustainable closed-loop biorefinery., (© 2021 Wiley-VCH GmbH.)

Background: Our understanding of adaptive immune responses in patients with coronavirus disease 2019 (COVID-19) is rapidly evolving, but information on the innate immune responses by natural killer (NK) cells is still insufficient., Objective: We aimed to examine the phenotypic and functional status of NK cells and their changes during the course of mild and severe COVID-19., Methods: We performed RNA sequencing and flow cytometric analysis of NK cells from patients with mild and severe COVID-19 at multiple time points in the course of the disease using cryopreserved PBMCs., Results: In RNA-sequencing analysis, the NK cells exhibited distinctive features compared with healthy donors, with significant enrichment of proinflammatory cytokine-mediated signaling pathways. Intriguingly, we found that the unconventional CD56 dim CD16 neg NK-cell population expanded in cryopreserved PBMCs from patients with COVID-19 regardless of disease severity, accompanied by decreased NK-cell cytotoxicity. The NK-cell population was rapidly normalized alongside the disappearance of unconventional CD56 dim CD16 neg NK cells and the recovery of NK-cell cytotoxicity in patients with mild COVID-19, but this occurred slowly in patients with severe COVID-19., Conclusions: The current longitudinal study provides a deep understanding of the NK-cell biology in COVID-19., (Copyright © 2021 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

If generated from water using renewable energy, hydrogen could serve as a carbon-zero, environmentally benign fuel to meet the needs of modern society. Photoelectrochemical cells integrate the absorption and conversion of solar energy and chemical catalysis for the generation of high value products. Tandem photoelectrochemical devices have demonstrated impressive solar-to-hydrogen conversion efficiencies but have not become economically relevant due to high production cost. Dye-sensitized solar cells, those based on a monolayer of molecular dye adsorbed to a high surface area, optically transparent semiconductor electrode, offer a possible route to realizing tandem photochemical systems for H 2 production by water photolysis with lower overall material and processing costs. This review addresses the design and materials important to the development of tandem dye-sensitized photoelectrochemical cells for solar H 2 production and highlights current published reports detailing systems capable of spontaneous H 2 formation from water using only dye-sensitized interfaces for light capture.

Biomass has incredible potential as an alternative to fossil fuels for energy production that is sustainable for the future of humanity. Hydrogen evolution from photocatalytic biomass conversion not only produces valuable carbon-free energy in the form of molecular hydrogen but also provides an avenue of production for industrially relevant biomass products. This photocatalytic conversion can be realized with efficient, sustainable reaction materials (biomass) and inexhaustible sunlight as the only energy inputs. Reported herein is a general strategy and mechanism for photocatalytic hydrogen evolution from biomass and biomass-derived substrates (including ethanol, glycerol, formic acid, glucose, and polysaccharides). Recent advancements in the synthesis and fundamental physical/mechanistic studies of novel photocatalysts for hydrogen evolution from biomass conversion are summarized. Also summarized are recent advancements in hydrogen evolution efficiency regarding biomass and biomass-derived substrates. Special emphasis is given to methods that utilize unprocessed biomass as a substrate or synthetic photocatalyst material, as the development of such will incur greater benefits towards a sustainable route for the evolution of hydrogen and production of chemical feedstocks.

Background and Aim: We aimed to measure the natural killer (NK) cell activity and pro-inflammatory cytokine levels in the peripheral blood of pancreatic cancer patients and investigate the correlation of NK cell activity and cytokines with cancer status and clinical outcomes., Methods: We prospectively enrolled patients who were pathologically diagnosed with pancreatic ductal adenocarcinoma (PDAC) between 2016 and 2017 at a tertiary hospital in Seoul, South Korea. As a control group, healthy participants were enrolled by mobile application recruitment., Results: A total of 203 patients were enrolled for this study (PDAC, n = 102; healthy participants, n = 101). The peripheral blood NK cell activity of PDAC patients was significantly lower than that of healthy participants (median level, 95 pg/mL vs 2000 pg/mL, P < 0.001), and decreased NK cell activity was correlated to poor clinical outcome in terms of response to chemotherapy, tumor progression, and survival. The pro-inflammatory cytokine interleukin-6 had a strong negative correlation with NK cell activity., Conclusions: In pancreatic cancer patients, NK cell activity decreased as cancer progressed, and decreased NK cell activity was associated with poor clinical outcomes., (© 2020 Journal of Gastroenterology and Hepatology Foundation and John Wiley & Sons Australia, Ltd.)

Background: Responses to immunotherapy vary between different cancer types and sites. Here, we aimed to investigate features of exhaustion and activation in tumor-infiltrating CD8 T cells at both the primary and metastatic sites in epithelial ovarian cancer., Methods: Tumor tissues and peripheral blood were obtained from 65 patients with ovarian cancer. From these samples, we isolated tumor-infiltrating lymphocytes (TILs) and peripheral blood mononuclear cells. These cells were used for immunophenotype using multicolor flow cytometry, gene expression profile using RNA sequencing and ex vivo functional restoration assays., Results: We found that CD39 + CD8 TILs were enriched with tumor-specific CD8 TILs, and that the activation status of these cells was determined by the differential programmed cell death protein 1 (PD-1) expression level. CD39 + CD8 TILs with high PD-1 expression (PD-1 high ) exhibited features of highly tumor-reactive and terminally exhausted phenotypes. Notably, PD-1 high CD39 + CD8 TILs showed similar characteristics in terms of T-cell exhaustion and activation between the primary and metastatic sites. Among co-stimulatory receptors, 4-1BB was exclusively overexpressed in CD39 + CD8 TILs, especially on PD-1 high cells, and 4-1BB-expressing cells displayed immunophenotypes indicating higher degrees of T-cell activation and proliferation, and less exhaustion, compared with cells not expressing 4-1BB. Importantly, 4-1BB agonistic antibodies further enhanced the anti-PD-1-mediated reinvigoration of exhausted CD8 TILs from both primary and metastatic sites., Conclusion: Severely exhausted PD-1 high CD39 + CD8 TILs displayed a distinctly heterogeneous exhaustion and activation status determined by differential 4-1BB expression levels, providing rationale and evidence for immunotherapies targeting co-stimulatory receptor 4-1BB in ovarian cancers., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

To evaluate the pathophysiology of autoimmune hepatitis (AIH) following acute hepatitis A (AHA) in immunologic aspects, we performed multi-color flow cytometry with peripheral blood mononuclear cells of a patient who underwent liver transplantation due to AIH-induced liver failure. Unlike general AHA patients, the proportion of tumor necrosis factor-α-producing Treg cells remained high for 6 months after diagnosis of AHA until she underwent a liver transplantation. The conversion of Treg cells into mediators of inflammation may have played a role in the autoimmune pathogenesis following AHA., Competing Interests: The authors have no potential conflicts of interest to disclose., (© Copyright: Yonsei University College of Medicine 2020.)

Although immune checkpoint blockade therapies have demonstrated clinical efficacy in cancer treatment, harnessing this strategy is largely encumbered by resistance in multiple cancer settings. Here, we show that tumor-infiltrating T cells are severely exhausted in the microsatellite stable (MSS) colorectal cancer (CRC), a representative example of PD-1 blockade-resistant tumors. In MSS CRC, we found wound healing signature to be up-regulated and that T cell exhaustion is driven by vascular endothelial growth factor-A (VEGF-A). We report that VEGF-A induces the expression of transcription factor TOX in T cells to drive exhaustion-specific transcription program in T cells. Using a combination of in vitro, ex vivo, and in vivo mouse studies, we demonstrate that combined blockade of PD-1 and VEGF-A restores the antitumor functions of T cells, resulting in better control of MSS CRC tumors., (Copyright © 2019 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Background & Aims: There is no proven treatment for ursodeoxycholic acid (UDCA)-refractory primary biliary cholangitis (PBC) other than obeticholic acid. Although fibrates have been reported to improve biochemical parameters, the long-term effects remain unclear. This study evaluated the effect of fibrate on clinical outcomes of UDCA-refractory PBC., Methods: Patients whose alkaline phosphatase (ALP) was not normalized with at least 13 mg/kg of UDCA treatment for >1 year were included from two tertiary referral centres. The primary outcome was ALP normalization. Secondary outcomes included the development of cirrhosis and hepatic deterioration. Immortal time bias was adjusted using the Mantel-Byar method., Results: A total of 100 UDCA-refractory PBC patients were included: 71 patients received UDCA alone (the UDCA group) and 29 patients received UDCA plus additional fibrate treatment of 160 mg/d fenofibrate or 400 mg/d bezafibrate (the fibrate/UDCA group). During the follow-up period, the probability of ALP normalization was significantly higher in the fibrate/UDCA group (hazard ratio [HR] = 5.00, 95% confidence interval = 2.87-8.27, P < 0.001). Among 58 non-cirrhotic patients (43 in the UDCA group and 15 in the fibrate/UDCA group), 19 patients (44.1%) in the UDCA group and none in the fibrate/UDCA group developed cirrhosis (HR = 0.12, P = 0.04). Hepatic deterioration (Child-Pugh score increase or signs of decompensated cirrhosis) occurred in 17 patients (23.9%) of the UDCA group and none in the fibrate/UDCA group in which the difference was significant (HR = 0.12, P = 0.04)., Conclusions: In patients with UDCA-refractory PBC, additional fibrate treatment is associated with a higher probability of ALP normalization and a lower risk of cirrhosis development and hepatic deterioration., (© 2019 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)

Because of the importance of hydrogen atom transfer (HAT) in biology and chemistry, there is increased interest in new strategies to perform HAT in a sustainable manner. Here, we describe a sustainable, net redox-neutral HAT process involving hydrosilanes and alkali metal Lewis base catalysts - eliminating the use of transition metal catalysts - and report an associated mechanism concerning Lewis base-catalysed, complexation-induced HAT (LBCI-HAT). The catalytic LBCI-HAT is capable of accessing both branch-specific hydrosilylation and polymerization of vinylarenes in a highly selective fashion, depending on the Lewis base catalyst used. In this process, earth abundant, alkali metal Lewis base catalyst plays a dual role. It first serves as a HAT initiator and subsequently functions as a silyl radical stabilizing group, which is critical to highly selective cross-radical coupling. EPR study identified a potassiated paramagnetic species and multistate density function theory revealed a high HAT character, yet multiconfigurational nature in the transition state of the reaction.

Background/aims: Recent studies have revealed that contrast-enhanced harmonic endoscopic ultrasonography (CEH-EUS) is beneficial in the differential diagnosis of malignant neoplasms of the pancreas and gallbladder from benign masses, in terms of the evaluation of microvasculature and real-time perfusion. In this study, we aimed to prove the clinical value of CEH-EUS in the differential diagnosis of pancreatic and gallbladder masses by direct comparison with that of conventional EUS., Methods: We reviewed the sonographic images and medical information of 471 patients who underwent conventional EUS and CEH-EUS for the diagnosis of pancreatic and gallbladder masses at a single medical center (Severance Hospital, Seoul, Korea) between March 2010 and March 2016., Results: The enhancement pattern of CEH-EUS of the pancreatic solid masses showed higher sensitivity and specificity in differentiating pancreatic adenocarcinoma and neuroendocrine tumors (82.0% and 87.9% for pancreatic adenocarcinoma and 81.1% and 90.9% for neuroendocrine tumors, respectively), and the area under the receiver operating characteristic curves was higher than that of conventional EUS. The enhancement texture of CEH-EUS of the gallbladder masses showed a higher sensitivity in differentiating malignant masses than that of conventional EUS; however, the difference between the areas under the receiver operating characteristic curves was not statistically significant., Conclusions: CEH-EUS can complement conventional EUS in the diagnosis of pancreatic and gallbladder masses, in terms of the limitations of the latter.

A polystyrene-based chromophore-catalyst assembly (poly-2) has been synthesized and assembled at a mesoporous metal oxide photoanode. The assembly contains water oxidation catalyst centers based on [Ru(trpy) (phenq)] 2+ (Ru-Cat) and [Ru(bpy) 3 ] 2+ derivatives (Ru-C) as chromophores (trpy= 2,2';6,2″- terpyridine, phenq = 2-(quinol-8'-yl)-1,10-phenanthroline and bpy = 2,2'-bipyridine). The photophysical and electrochemical properties of the polychromophore-oxidation catalyst assembly were investigated in solution and at the surface of mesoporous metal oxide films. The layer-by-layer (LbL) method was utilized to construct multilayer films with cationic poly-2 and anionic poly(acrylic acid) (PAA) for light-driven photochemical oxidations. Photocurrent measurements of (PAA/poly-2) 10 LbL films on mesoporous TiO 2 demonstrate light-driven oxidation of phenol and benzyl alcohol in aqueous solution. Interestingly, illumination of (PAA/poly-2) 5 LbL films on a fluorine doped SnO 2 /TiO 2 core/shell photoanode in aqueous solution gives rise to an initial photocurrent (∼18.5 μA·cm -2 ) that is in part ascribed to light driven water oxidation.

The synthesis of polymer-based assemblies for light harvesting has been motivated by the multi-chromophore antennas that play a role in natural photosynthesis for the potential use in solar conversion technologies. This review describes a general strategy for using polymer-based chromophore-catalyst assemblies for solar-driven water oxidation at a photoanode in a dye-sensitized photoelectrochemical cell (DSPEC). This report begins with a summary of the synthetic methods and fundamental photophysical studies of light harvesting polychormophores in solution which show these materials can transport excited state energy to an acceptor where charge-separation can occur. In addition, studies describing light harvesting polychromophores containing an anchoring moiety (ionic carboxylate) for covalent bounding to wide band gap mesoporous semiconductor surfaces are summarized to understand the photophysical mechanisms of directional energy flow at the interface. Finally, the performance of polychromophore/catalyst assembly-based photoanodes capable of light-driven water splitting to oxygen and hydrogen in a DSPEC are summarized.

A polychromophoric light-harvesting assembly featuring a polystyrene (PS) backbone with ionic carboxylate-functionalized Ru(II) polypyridyl complexes as pendant groups (PS-Ru-A) was synthesized and successfully anchored onto mesoporous structured TiO2 films (TiO2 //PS-Ru-A). Studies of the resulting TiO2 //PS-Ru-A films carried out by transmission electron microscopy (TEM), scanning electron microscopy (SEM), and atomic force microscopy (AFM) confirmed that the ionic carboxylated Ru(II) complexes from PS-Ru-A led to the surface immobilization on the TiO2 film. Monochromatic light photocurrent spectroscopy (IPCE) and white light (AM1.5G) current-voltage studies of dye-sensitized solar cells using the TiO2 //PS-Ru-A photoanode give rise to modest photocurrent and white light efficiency (24 % peak IPCE and 0.33 % PCE, respectively). The photostability of surface-bound TiO2 //PS-Ru-A films was tested and compared to a monomeric Ru(II) complex (TiO2 //Ru-A), showing an enhancement of ∼14 % in the photostability of PS-Ru-A. Transient absorption measurements reveal that electron injection from surface-bound pendants occurs on the picosecond time scale, similar to TiO2 //Ru-A, while time-resolved emission measurements reveal delayed electron injection occurring in TiO2 //PS-Ru-A on the nanosecond time scale, underscoring energy transport from unbound to surface-bound complexes. Additionally, charge recombination is delayed in PS-Ru-A, pointing towards intra-assembly hole transport to complexes away from the surface. Molecular dynamics simulations of PS-Ru-A in fluid solution indicate that a majority of the pendant Ru(II) complexes lie within 10-20 Å of each other, facilitating efficient energy- and charge transport among the pendant complexes., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Two sets of conjugated polyelectrolytes with different molecular weights (Mn) in each set were synthesized. All polymers feature the same conjugated backbone with alternating (1,4-phenylene) and (2,5-thienylene ethynylene) repeating units, but different linkages between the backbone and side chains, namely, oxy-methylene (-O-CH2-) (P1-O-n, where n = 7, 9, and 14) and methylene (-CH2-) (P2-C-n, n = 7, 12, and 18). They all bear carboxylic acid moieties as side chains, which bind strongly to titanium dioxide (TiO2) nanoparticles. The two sets of polymers were used as light-harvesting materials in dye-sensitized solar cells. Despite the difference in molecular weight, polymers within each set have very similar light absorption properties. Interestingly, under the same working conditions, the overall cell efficiency of the P1-O-n series increases with a decreasing molecular weight while the efficiency of the P2-C-n series remains constant regardless of the molecular weight. Steady state photophysical measurements and dynamic light scattering investigation prove that P1-O-n polymers aggregate in solution while P2-C-n series are in the monomeric state. In P1-O-n series, a higher-molecular weight polymer results in a larger aggregate, which reduces the amount of polymers that are adsorbed onto TiO2 films and overall cell efficiency.

The use of sunlight to make chemical fuels (i.e., solar fuels) is an attractive approach in the quest to develop sustainable energy sources. Using nature as a guide, assemblies for artificial photosynthesis will need to perform multiple functions. They will need to be able to harvest light across a broad region of the solar spectrum, transport excited-state energy to charge-separation sites, and then transport and store redox equivalents for use in the catalytic reactions that produce chemical fuels. This multifunctional behavior will require the assimilation of multiple components into a single macromolecular system. A wide variety of different architectures including porphyrin arrays, peptides, dendrimers, and polymers have been explored, with each design posing unique challenges. Polymer assemblies are attractive due to their relative ease of production and facile synthetic modification. However, their disordered nature gives rise to stochastic dynamics not present in more ordered assemblies. The rational design of assemblies requires a detailed understanding of the energy and electron transfer events that follow light absorption, which can occur on time scales ranging from femtoseconds to hundreds of microseconds, necessitating the use of sophisticated techniques. We have used a combination of time-resolved absorption and emission spectroscopies with observation times that span 9 orders of magnitude to follow the excited-state evolution within polymer-based molecular assemblies. We complement experimental observations with molecular dynamics simulations to develop a microscopic view of these dynamics. This Account provides an overview of our work on polymers decorated with pendant Ru(II) chromophores, both in solution and on surfaces. We have examined site-to-site energy transport among the Ru(II) complexes, and in systems incorporating π-conjugated polymers, we have observed ultrafast formation of a long-lived charge-separated state. When attached to TiO2, these assemblies exhibit multifunctional behavior in which photon absorption is followed by energy transport to the surface and electron injection to produce an oxidized metal complex. The oxidizing equivalent is then transferred to the conjugated polymer, giving rise to a long-lived charge-separated state.

Specifically tailored ω-alkenyl-1-carboxylic acids were synthesized for use as surfactants in the single-step preparation of manganese ferrite (MnFe2O4) nanoparticles (NPs). Monodisperse manganese ferrite NPs terminated with ω-alkenyl moieties were prepared via a one-pot reaction at high temperature without the need of ligand exchange. Using this approach, simple adjustment of the rate of heating allowed precise tuning of the size of the nanoparticles, which were characterized in bulk form by transmission electron microscopy (TEM), Fourier-transform infrared (FT-IR) spectroscopy, and X-ray diffraction (XRD). These surfactant-coated magnetic nanoparticles were then deposited onto hydrogen-terminated silicon(111) wafers and covalently anchored to the surface by UV-initiated covalent bonding. Analysis by scanning electron microscopy (SEM) and X-ray photoelectron spectroscopy (XPS) confirmed that the UV treatment led to covalent immobilization of the NPs on the silicon surface with a consistent packing density across the surface. The magnetic properties of the stable, surface-bound nanoparticle arrays were characterized using a superconducting quantum interference device (SQUID) magnetometer. The materials and methods described here are being developed for use in bit-patterned ultrahigh density magnetic recording media and nanoscale biomagnetic sensing.

This letter describes the preparation of monolayer-protected nanoparticle clusters (MPCs) from the adsorption of n-tetradecanethioacetate onto colloidal gold nanoparticles using the Brust-Schiffrin two-phase synthesis method. The MPCs were characterized by transmission electron microscopy (TEM), ultraviolet-visible (UV-vis) spectroscopy, (1)H nuclear magnetic resonance (NMR) spectroscopy, X-ray photoelectron spectroscopy (XPS), and Fourier transform infrared (FTIR) spectroscopy. These studies found that the monolayer coatings on the gold nanoparticles were nearly indistinct with regard to chemical composition, monolayer structure, and Au-S ligation when compared to those prepared from the analogous adsorption of n-tetradecanethiol (i.e., the thioacetate headgroup adsorbs to gold as a thiolate, with concurrent loss of the acetyl group). Under equivalent conditions of formation, however, the size of the gold nanoparticles formed was larger when using the alkanethioacetate adsorbate (e.g., 4.9 +/- 1.2 nm) compared to the alkanethiol adsorbate (e.g., 1.6 +/- 0.3 nm). The observed difference in size is rationalized on the basis of the stronger ligating ability of the thiol compared to that of the thioacetate during gold nanoparticle nucleation and/or growth. The use of alkanethioacetates affords significant control of particle size and allows the formation of MPCs with thiol-sensitive omega-functional groups.

This paper outlines the preparation of monodisperse MnFe(2)O(4) nanoparticles modified with omega-alkenyl moieties in a one-pot reaction, requiring no ligand-exchange step, followed by deposition of the resulting surfactant-coated nanoparticles onto a hydrogen-terminated silicon (111) wafer and covalent anchoring to the surface via UV-initiated bonding, creating a stable two-dimensional array of monodisperse magnetic nanoparticles.

Hexadecanethiol (n-C16), 2,2-dimethylhexadecane-1-thiol (DMC16), and the multidentate thiol-based ligands 2-tetradecylpropane-1,3-dithiol (C16C2), 2-methyl-2-tetradecylpropane-1,3-dithiol (C16C3), and 1,1,1-tris(mercaptomethyl)pentadecane (t-C16) were evaluated for their ability to stabilize large gold nanoparticles (>15 nm) in organic solution. Citrate-stabilized gold nanoparticles (20-50 nm) treated with the ligands were extracted from aqueous solution and dispersed into toluene. The degree of aggregation of the gold nanoparticles was monitored visually and further confirmed by UV-vis spectroscopy and dynamic light scattering (DLS). The bidentate ligands (C16C2 and C16C3) and particularly the tridentate ligand (t-C16) showed enhanced abilities to inhibit the aggregation of large gold nanoparticles in organic solution. For gold nanoparticles modified with these multidentate ligands, bound thiolate (S2p3/2 binding energy of 162 eV) was the predominant sulfur species (>85%) as evaluated by X-ray photoelectron spectroscopy (XPS). Although an entropy-based resistance to ordering of the loosely packed surfactant layers was initially considered to be a plausible mechanism for the enhanced stabilization afforded by the multidentate ligands, when taken as a whole, the data presented here support a model in which the enhanced stabilization arises largely (if not solely) from the multidentate chelate effect.