Search

BRCA1 interacting helicase 1 (BRIP1) alteration was crucial in tumors and it was a potential therapeutic target in ovarian serous cystadenocarcinoma (OV). Although a small number of studies had focused on BRIP1, an extensive study of BRIP1 genetic mutation and its clinical application in different cancer types had not been analyzed. In the current study, we analyzed BRIP1 abnormal expression, methylation, mutation, and their clinical application via several extensive datasets, which covered over 10,000 tumor samples across more than 30 cancer types. The total mutation rate of BRIP1 was rare in pan cancer. Its alteration frequency, oncogenic effects, mutation, and therapeutic implications were different in each cancer. 242 BRIP1 mutations were found across 32 cancer types. UCEC had the highest alteration (mutation and CNV) frequency. In addition, BRIP1 was a crucial oncogenic factor in OV and BRCA. BRIP1 mutation in PRAD was targetable, and FDA had approved a new drug. Moreover, Kaplan–Meier curve analysis showed that BRIP1 expression and genetic aberrations were closely related to patient survival in several cancers, indicating their potential for application as new tumor markers and therapeutic targets. The current study profiled the total BRIP1 mutation spectrum and offered an extensive molecular outlook of BRIP1 in a pan cancer analysis. And it suggested a brand-new perspective for clinical cancer therapy. [ABSTRACT FROM AUTHOR]

As an energy storage technology, supercapacitors (SCs) have become an important part of many electronic systems because of their high-power density, long cycle life, and maintenance-free characteristics. However, the widespread development and use of electronics, including SCs, have led to the generation of a large amount of e-waste. In addition, achieving compatibility between stability and biodegradability has been a prominent challenge for implantable electronics. Therefore, environmentally friendly SCs based on polypyrrole (PPy)-stabilized polypeptide (FF) are demonstrated in this study. The fully degradable SC has a layer-by-layer structure, including polylactic acid/chitosan (PLA–C) support layers, current collectors (Mg), FF/PPy composite layers, and a polyvinyl alcohol/phosphate buffer solution (PVA/PBS) hydrogel. It has the advantages of being light, thin, flexible, and biocompatible. After 5000 cycles in air, the capacitance retention remains at up to 94.7%. The device could stably operate for 7 days in a liquid environment and completely degrade in vitro within 90 days without any adverse effect on the environment. This work has important implications for eco-friendly electronics and will have a significant impact on the implantable biomedical electronics. [ABSTRACT FROM AUTHOR]

Background: Ovarian cancer (OC) seriously threatens women's life. Ferroptosis plays an essential role in the initiation and development of OC. However, more molecular targets and mechanisms for ferroptosis in OC remain to be further elucidated.Methods: Several OC datasets were integrated in this study and three candidate genes including PRNP were further screened out as the ferroptosis-related gene which was differentially expressed in OC. Then, comprehensive evaluations concerning gene expression, clinical implication, in vitro validation of expression and functional experiments, prediction of downstream molecules and related signal pathways, and immune-modulating function were performed.Results: PRNP was the only downregulated ferroptosis-related gene with prognostic value for OC patients. The decreased mRNA and protein expression was verified in OC tissues and cell lines. PRNP was significantly correlated with cancer stages, primary therapy outcomes, and age in OC patients. Moreover, we found that overexpression of PRNP inhibited the proliferation, migration, and invasion ability of OC cells through in vitro experiments. PRNP was enriched to the Ras signaling pathway. PRNP expression was positively correlated with the infiltration of immune cells, such as mast cells, T effector memory cells, plasmacytoid DC cells, NK cells, and eosinophils. In addition, the association of PRNP with other immune signatures was also found.Conclusion: This study demonstrated for the first time showed that ferroptosis-related gene PRNP exerted a tumor suppressive role in OC and the aberrant expression and function of PRNP making it a potential novel biomarker for OC diagnosis, prognosis, and response to immunotherapies. [ABSTRACT FROM AUTHOR]

Ultrasonic welding (USW) of Titanium (Ti) sheets presents several challenges, notably crack formation due to sliding friction. To overcome this problem, the present study applied USW to pure α -Ti sheets both with and without different interlayer metals (Al, Ni, and Fe). Al interlayer improved the strength at room temperature significantly to cause base metal fracture (1700 N) by inducing concentrated plastic deformation, facilitating bonding with Ti while minimizing damage. However, its strength decreased significantly at 150–300 °C, suggesting the limitation of using Al interlayer at elevated temperatures. Conversely, the Ni and Fe interlayers led to a two-phase strength development. This enhancement was due to β-phase transformation, which reduces the interfacial defects and generates a more pronounced β-stabilization effect. The Ni interlayer, which has a higher β-transus point (765 °C) and lower molybdenum equivalency, required a higher welding energy (1800 J) and longer diffusion time into Ti, resulting in a gradual increase in strength due to a slower β-Ti transformation. On the other hand, the Fe interlayer with a lower β-transus point relative to Ti (595 °C) achieved peak strength at a lower welding energy of 1200 J. Both Fe and Ni interlayers displayed only a slight decrease in strength (1500–1600 N) at 300 °C with base metal fracture, revealing better joint performance at higher temperatures. These insights suggest a strategical interlayer selection based on the operation temperature, where Al interlayers were advantageous for low-energy welding at room temperature application, Fe and Ni interlayers offer sufficient strength at elevated temperatures by facilitating the β-Ti formation. [ABSTRACT FROM AUTHOR]

The invasion capability of HCC cells was critically disrupted after the co-knockdown of BTBD7 and HIF-1 , and was moderately decreased when si-BTBD7 or si-HIF-1 was transfected separately (Figure S4). Luciferase assay proved that the transcriptional activity of BTBD7 was abolished under hypoxia by HRE2-mut (PGL3-BTBD7-581M) instead of HRE1-mut (PGL3-BTBD7-1000M) and HRE3-mut (PGL3-BTBD7-40M) (Figure 2C). Dear Editor, This study is the first to demonstrate that HIF-1 could activate BTBD7 under hypoxia, thus promoting HCC metastasis through tumor cell adhesion and EMT. Besides, the overexpression of BTBD7 or HIF-1 enhanced the invasion activity of HepG2 cells and exhibited a combined effect when BTBD7 and HIF-1 were co-overexpressed (Figure 2E). [Extracted from the article]

Background. All YTH domain family members are m6A reader proteins accounting for the methylation modulation involved in the process of tumorgenesis and tumor progression. However, the expression profiles and roles of the YTH domain family in lung adenocarcinoma (LUAD) remain to be further illustrated. Methods. GEPIA2 and TNMplot databases were used to generate the expression profiles of the YTH family. Kaplan-Meier plotter database was employed to analysis the prognostic value of the YTH family. Coexpression profiles and genetic alterations analysis of the YTH family were undertaken using the cBioPortal database. YTH family protein-associated protein-protein interaction (PPI) network was identified by using STRING. Functional enrichment analysis was performed with the help of the WebGestalt database. The correlation analysis between the YTH family and immune cell infiltration in LUAD was administrated by using the TIMER2.0 database. Results. mRNA expression of YTHDC1 and YTHDC2 was significantly lower in LUAD, whereas YTHDF1, YTHDF2, and YTHDF3 with apparently higher expression. YTHDF2 expression was observed to be the highest in the nonsmoker subgroup, and its expression gradually decreased with the increased severity of smoking habit. LUAD patients with low expression of YTHDC2, YTHDF1, and YTHDF2 were correlated with a better overall survival (OS) time. The YTHDF1 genetic alteration rate was 26%, which was the highest in the YTH family. The major cancer-associated functions of YTH family pointed in the direction of immunomodulation, especially antigen processing and presentation. Most of the YTH family members were significantly correlated with the infiltration of CD4+ T cells, CD8+ T cells, macrophages, and neutrophils, indicating the deep involvement of the YTH domain family in the immune cell infiltration in LUAD. Conclusion. The molecular and expression profiles of the YTH family were dysregulated in LUAD. YTH family members (especially YTHDC2) were promising biomarkers and potential therapeutic targets that may bring benefit for the patients with LUAD. [ABSTRACT FROM AUTHOR]

Background: In clinical practice, the vast array of potential drug combinations necessitates swift and accurate assessments of pharmacokinetic drug–drug interactions (DDIs), along with recommendations for adjustments. Current methodologies for clinical DDI evaluations primarily rely on basic extrapolations from clinical trial data. However, these methods are limited in accuracy owing to their lack of a comprehensive consideration of various critical factors, including the inhibitory potency, dosage, and type of the inhibitor, as well as the metabolic fraction and intestinal availability of the substrate. Objective: This study aims to propose an efficient and accurate clinical pharmacokinetic-mediated DDI assessment tool, which comprehensively considers the effects of inhibitory potency and dosage of inhibitors, intestinal availability and fraction metabolized of substrates on DDI outcomes. Methods: This study focuses on DDIs caused by cytochrome P450 3A4 enzyme inhibition, utilizing extensive clinical trial data to establish a methodology to calculate the metabolic fraction and intestinal availability for substrates, as well as the concentration and inhibitory potency for inhibitors ( K i or k inact / K I ). These parameters were then used to predict the outcomes of DDIs involving 33 substrates and 20 inhibitors. We also defined the risk index for substrates and the potency index for inhibitors to establish a clinical DDI risk scale. The training set for parameter calculation consisted of 73 clinical trials. The validation set comprised 89 clinical DDI trials involving 53 drugs. which was used to evaluate the reliability of in vivo values of K i and k inact / K I , the accuracy of DDI predictions, and the false-negative rate of risk scale. Results: First, the reliability of the in vivo K i and k inact / K I values calculated in this study was assessed using a basic static model. Compared with values obtained from other methods, this study values showed a lower geometric mean fold error and root mean square error. Additionally, incorporating these values into the physiologically based pharmacokinetic-DDI model facilitated a good fitting of the C–t curves when the substrate's metabolic enzymes are inhibited. Second, area under the curve ratio predictions of studied drugs were within a 1.5 × margin of error in 81% of cases compared with clinical observations in the validation set. Last, the clinical DDI risk scale developed in this study predicted the actual risks in the validation set with only a 5.6% incidence of serious false negatives. Conclusions: This study offers a rapid and accurate approach for assessing the risk of pharmacokinetic-mediated DDIs in clinical practice, providing a foundation for rational combination drug use and dosage adjustments. [ABSTRACT FROM AUTHOR]

• Ultrasonic welding (USW) is applied in joining of less ductile hexagonal close-packed metals. • The intrinsic brittleness of α-Ti inhibited the increase in joint strength in USW. • A deposition of a thin Fe interlayer purposefully introduced an α-to-β transformation. • A β-Ti layer formed by Fe diffusion without obvious Fe–Ti intermetallics after USW. • A strong Ti/Ti bond was obtained with a continuous α/β/α interfacial microstructure. We investigated ultrasonic welding (USW) of pure α -Ti sheets, which exhibited an insufficient weldability due to the extensive formation of cracks caused by sliding friction during the USW. To overcome this issue, an α /β/ α heterogeneous interfacial microstructure was designed by introducing a thin Fe interlayer, a beta stabilizer, between α -Ti sheets. The diffusion of Fe interlayers triggered the formation of a continuous β-Ti thin layer (⁓1–2 μm) without Fe–Ti intermetallics near the bonding interface after USW. The continuous thin β-Ti layer exhibited a significant improvement in the joining of the brittle α -Ti, where the bonding strength was increased from 350 to 1700 N. This study provides a potential approach to design an interfacial microstructure that promotes the formation of a deformable phase, overcoming the inherent brittleness of hexagonal close-packed metals and enabling production of strong joints. [Display omitted] [ABSTRACT FROM AUTHOR]

The de novo design of stapled peptide-based self-assemblies attracts vast interest, yet still remains challenging. The development of an oxidation trigger for peptide stapling and subsequent self-assembly is described here. A self-assembling sequence, Fmoc-R(RCEX)2-NH2, transformed from a random coil to an α-helical structure upon disulphide bonding of the flanking cysteine residues positioning at the i/i + 4 locations. The stapling form of this peptide enforces a conformational restraint that affords the driving force for self-assembly into nanorod/nanovesicle structures. Moreover, these assembled materials can transport siRNA into cancer cells and immediately release the cargo in a reductive environment. [ABSTRACT FROM AUTHOR]

CCN gene family members have recently been identified as multifunctional regulators involved in diverse biological functions, especially in vascular and skeletal development. In the present study, a comparative genomic and phylogenetic analysis was performed to show the similarities and differences in structure and function of CCNs from different organisms and to reveal their potential evolutionary relationship. First, CCN homologs of metazoans from different species were identified. Then we made multiple sequence alignments, MEME analysis, and functional sites prediction, which show the highly conserved structural features among CCN metazoans. The phylogenetic tree was further established, and thus CCNs were found undergoing extensive lineage-specific duplication events and lineage-specific expansion during the evolutionary process. Besides, comparative analysis about the genomic organization and chromosomal CCN gene surrounding indicated a clear orthologous relationship among these species counterparts. At last, based on these research results above, a potential evolutionary scenario was generated to overview the origin and evolution of the CCN gene family. [ABSTRACT FROM AUTHOR]

Graphical abstract Highlights • A one pot protocol for the synthesis of quaternary α-aminosuccinimides. • Ferric Nitrate promote imidazo[1,2-a]pyridine structural metamorphosis. • A potential way to synthesize α-aromatic ring substituted quaternary amino acids. Abstract An efficient protocol has been accomplished for the synthesis of quaternary α-aminosuccinimides in toluene medium involving 2-phenylimidazo[1, 2-a]pyridine in a one-pot reaction promoted by Ferric Nitrate at 120 °C. The protocol presented herein, is for the first time, via a novel transformation where Ferric Nitrate promotes imidazo[1,2-a]pyridine structural metamorphosis to the title compound quaternary succinimides. High compatibility, easy work-up, and excellent yields are the advantages of this protocol. The quaternary α-aminosuccinimides are expected to have great potential in synthesizing quaternary α-amino acids and applications in medicinal chemistry. [ABSTRACT FROM AUTHOR]

Imidazolium-based elastomeric ionomers (i-BIIR) were facilely synthesized by ionically modified brominated poly(isobutylene-co-isoprene) (BIIR) with different alkyl chain imidazole and thoroughly explored as novel toughening agents for poly(lactic acid) (PLA). The miscibility, thermal behavior, phase morphology and mechanical property of ionomers and blends were investigated through dynamic mechanical analyses (DMA), differential scanning calorimetry (DSC), scanning electron microscopy (SEM), tensile and impact testing. DMA and SEM results showed that better compatibility between the PLA and i-BIIR was achieved compared to the PLA/unmodified BIIR elastomer. A remarkable improvement in ductility with an optimum elongation at break up to 235% was achieved for the PLA/i-BIIR blends with 1-dodecylimidazole alkyl chain (i-BIIR-12), more than 10 times higher than that of pure PLA. The impact strengths of PLA were enhanced from 1.9 kJ/m2 to 4.1 kJ/m2 for the PLA/10 wt% i-BIIR-12 blend. Toughening mechanism had been established by systematical analysis of the compatibility, intermolecular interaction and phase structures of the blends. Interfacial cavitations initiated massive shear yielding of the PLA matrix owing to a suitable interfacial adhesion which played a key role in the enormous toughening effect in these blends. We believed that introducing imidazolium group into the BIIR elastomer was vital for the formation of a suitable interfacial adhesion. [ABSTRACT FROM AUTHOR]

Warfarin exerts its anticoagulation activity by blocking the vitamin K-epoxide cycle. A quantitative understanding of how warfarin and related genes interact with the vitamin K-epoxide cycle and the associated change of coagulation activity in the human body may help study the pharmacodynamics of warfarin. The plasma concentration of vitamin K 1 (VK 1 ) and vitamin K 1 2,3-epoxide (VK 1 O) could reflect the status of vitamin K-epoxide cycle. However, their determination is a challenging task due to their extremely low concentrations in human plasma and the severe interferences caused by co-extracted lipids. In this study, we developed an LC-APCI-MS/MS method for the simultaneous determination of VK 1 and VK 1 O in human plasma using stable deuterium-labeled vitamin K 1 (vitamin K 1 -d7) as the internal standard (IS). Plasma samples were prepared through protein denaturation followed by one-step liquid extraction with cyclohexane. Chromatographic separation of analytes from isobaric interferences and endogenous ion suppressor was performed on a Synergi Hydro-RP column (150 mm × 4.6 mm, 4 μm) under the reversed-phase condition with isocratic elution. The selective reaction monitoring (SRM) transitions were chosen as m/z  = 451.5→187.3 for VK 1 , m/z  = 467.5→161.2 for VK 1 O, and m/z  = 458.6→194.3 for IS in APCI positive mode. The assay was linear in the range of 100–10,000 pg/mL for the two analytes and achieved considerable extraction recoveries (87.8–93.3%, 91.0–96.9%, and 92.0% for VK 1 , VK 1 O, and IS, respectively), negligible matrix effects (93.6–96.0%, 96.3–100.1%, and 95.5%), and high selectivity with a small sample volume requirement (0.2 mL) and short run time (15 min). The validated method was successfully applied in a clinical pharmacodynamic study of warfarin, and the clotting activity was found to be negatively correlated with the plasma concentration ratio of VK 1 O to VK 1 . [ABSTRACT FROM AUTHOR]

The evolution of the facet-facet groove at grain boundaries in multi-crystalline Si during solidification was investigated by in situ observation of the melt/crystal interface. The grain boundaries changed their propagation direction without any new grain formation or grain boundaries interaction during crystal growth. We monitored the melt/crystal interface over time and carefully estimated the growth velocities on two facets. We found that the facet velocities are different in some of our experimental observations and the development of random grain boundary is strongly dependent on the facet velocities. On the basis of our experimental observations, we discussed the direction of random grain boundary during solidification by considering the growth velocities on two facets. [ABSTRACT FROM AUTHOR]

The effects of N-methylation on CIH peptides’ biophysical properties were systematically studied. N-Methylation at the N terminal NH could help improve the peptides’ cellular uptake with a retained helical conformation. This N-methylation strategy could also be applied to longer peptides to improve their stability and cellular uptake. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is a lethal and aggressive human malignancy. The present study examins the anti‐tumor effects of deubiquitylating enzymes (DUB) inhibitors in HCC. It is found that the inhibitor of ubiquitin specific peptidase 8 (USP8) and DUB‐IN‐3 shows the most effective anti‐cancer responses. Targeting USP8 inhibits the proliferation of HCC and induces cell ferroptosis. In vivo xenograft and metastasis experiments indicate that inhibition of USP8 suppresses tumor growth and lung metastasis. DUB‐IN‐3 treatment or USP8 depletion decrease intracellular cystine levels and glutathione biosynthesis while increasing the accumulation of reactive oxygen species (ROS). Mechanistical studies reveal that USP8 stabilizes O‐GlcNAc transferase (OGT) via inhibiting K48‐specific poly‐ubiquitination process on OGT protein at K117 site, and STE20‐like kinase (SLK)‐mediated S716 phosphorylation of USP8 is required for the interaction with OGT. Most importantly, OGT O‐GlcNAcylates solute carrier family 7, member 11 (SLC7A11) at Ser26 in HCC cells, which is essential for SLC7A11 to import the cystine from the extracellular environment. Collectively, this study demonstrates that pharmacological inhibition or knockout of USP8 can inhibit the progression of HCC and induce ferroptosis via decreasing the stability of OGT, which imposes a great challenge that targeting of USP8 is a potential approach for HCC treatment. [ABSTRACT FROM AUTHOR]

The helical peptide KLA (KLAKLAKKLAKLAK) is a well-known inducer of cellular apoptosis, acting to disrupt the mitochondrial membrane. However, its weak cellular uptake impedes development of any further applications. Here, we have utilized a novel in-tether chiral center induced helicity strategy (CIH) to develop a potent apoptosis inducer based on this KLA sequence. Notably, for the two resulting epimers of the CIH-KLA peptide, the CIH-KLA-(R) epimer exhibited superior cellular uptakes and special mitochondrial targeting when compared with its S counterpart. This work provides a promising and versatile method to modify the KLA peptide and a proof-of-concept application for the CIH strategy in modifying bioactive peptides. [ABSTRACT FROM AUTHOR]

Mycobacterium tuberculosis ( Mtb) has a proteasome system that is essential for its ability to cause lethal infections in mice. A key component of the system is the proteasomal adenosine triphosphatase (ATPase) Mpa, which captures, unfolds, and translocates protein substrates into the Mtb proteasome core particle for degradation. Here, we report the crystal structures of near full-length hexameric Mtb Mpa in apo and ADP-bound forms. Surprisingly, the structures revealed a ubiquitin-like β-grasp domain that precedes the proteasome-activating carboxyl terminus. This domain, which was only found in bacterial proteasomal ATPases, buries the carboxyl terminus of each protomer in the central channel of the hexamer and hinders the interaction of Mpa with the proteasome core protease. Thus, our work reveals the structure of a bacterial proteasomal ATPase in the hexameric form, and the structure finally explains why Mpa is unable to stimulate robust protein degradation in vitro in the absence of other, yet-to-be-identified co-factors. [ABSTRACT FROM AUTHOR]

In some cases, helical peptides stabilized by an i, i + 7 tether exhibit better target binding and cellular functions compared to their i, i + 4 analogues. Herein, we carried out a systematic study of the effects of an in-tether chiral center on the i, i + 7 system. We screened the optimal cross linking mode, tether length, in-tether chiral center positions, and absolute configurations. From these studies, we determined that a chiral center of R absolute configuration at the γ-position to the C-terminal of a 10-membered tether could function to efficiently induce helicity of the backbone peptides. This is an important addition to the current i, i + 4 in-tether chiral center induced helicity strategy (CIH strategy), and could have broad biological applications. [ABSTRACT FROM AUTHOR]

The addition of a precisely positioned chiral center in the tether of a constrained peptide is reported, yielding two separable peptide diastereomers with significantly different helicity, as supported by circular dichroism (CD) and NMR spectroscopy. Single crystal X-ray diffraction analysis suggests that the absolute configuration of the in-tether chiral center in helical form is R, which is in agreement with theoretical simulations. The relationship between the secondary structure of the short peptides and their biochemical/biophysical properties remains elusive, largely because of the lack of proper controls. The present strategy provides the only method for investigating the influence of solely conformational differences upon the biochemical/biophysical properties of peptides. The significant differences in permeability and target binding affinity between the peptide diastereomers demonstrate the importance of helical conformation. [ABSTRACT FROM AUTHOR]

The immunosuppressive microenvironment of malignant tumors severely hampers the effectiveness of anti-tumor therapy. Moreover, abnormal tumor vasculature interacts with immune cells, forming a vicious cycle that further interferes with anti-tumor immunity and promotes tumor progression. Our pre-basic found excellent anti-tumor effects of c -di-AMP and RRx-001, respectively, and we further explored whether they could be combined synergistically for anti-tumor immunotherapy. We chose to load these two drugs on PVA-TSPBA hydrogel scaffolds that expressly release drugs within the tumor microenvironment by in situ injection. Studies have shown that c -di-AMP activates the STING pathway, enhances immune cell infiltration, and reverses tumor immunosuppression. Meanwhile, RRx-001 releases nitric oxide, which increases oxidative stress injury in tumor cells and promotes apoptosis. Moreover, the combination of the two presented more powerful pro-vascular normalization and reversed tumor immunosuppression than the drug alone. This study demonstrates a new design option for anti-tumor combination therapy and the potential of tumor environmentally responsive hydrogel scaffolds in combination with anti-tumor immunotherapy. [Display omitted] [ABSTRACT FROM AUTHOR]

All-solid-state supercapacitors have gained increasing attention as wearable energy storage devices, partially due to their flexible, safe, and lightweight natures. However, their electrochemical performances are largely hampered by the low flexibility and durability of current polyvinyl alcohol (PVA) based electrolytes. Herein, a novel polyvinyl alcohol-polyethyleneimine (PVA-PEI) based, conductive and elastic hydrogel was devised as an all-in-one electrolyte platform for wearable supercapacitor (WSC). For proof-of-concept, we assembled all-solid-state supercapacitors based on boron nitride nanosheets (BNNS) intercalated graphene electrodes and PVA-PEI based gel electrolyte. Furthermore, by varying the electrolyte ions, we observed synergistic effects between the hydrogel and the electrode materials when KOH was used as electrolyte ions, as the Graphene/BNNS@PVA-PEI-KOH WSCs exhibited a significantly improved areal capacitance of 0.35 F/cm2 and a smaller ESR of 6.02 ohm/cm2. Moreover, due to the high flexibility and durability of the PVA-PEI hydrogel electrolyte, the developed WSCs behave excellent flexibility and cycling stability under different bending states and after 5000 cycles. Therefore, the conductive, yet elastic, PVA-PEI hydrogel represents an attractive electrolyte platform for WSC, and the Graphene/BNNS@PVA-PEI-KOH WSCs shows broad potentials in powering wearable electronic devices. [ABSTRACT FROM AUTHOR]

• BNCT has more potential to effectively target multicentric deposits of tumors. • This review focuses on tumor-targeting boron delivery agents developed recently. • This review provides a summary and critical perspective of boron delivery agents. Boron neutron capture therapy (BNCT) is a potential cancer radiotherapeutic modality, which takes advantage of the neutron capture response that occurs when boron (10B) is struck by low-energy thermal neutrons, triggering a nuclear fission reaction that ultimately causes cell death. Because the fatal radiation is restricted to approximately a single cell diameter, only cells with significant boron accumulation that are in the neutron field will be destroyed. Tumor-targeted 10B delivery agents are an essential component of BNCT. Currently, two low molecular weight boron-containing compounds, sodium mercaptoundecahydro-closo-dodecaborate (BSH) and borylphenylalanine (BPA), are mainly used in BNCT. Although both have suboptimal tumor selectivity, they have shown some therapeutic effect in patients with high-grade gliomas and several other kinds of tumors. In order to improve the efficacy of BNCT, significant effort has been devoted to developing new boron delivery agents that possess better uptake and favorable pharmacokinetic characteristics for clinical use. This review focuses on various boron delivery agents that have been developed over the past 40 years, including boron-containing amino acids, boron-containing compound conjugated-nucleosides, porphyrin derivatives, peptides, monoclonal antibodies, and different types of nanomaterials for 10B delivery. The principles underlying BNCT and the clinical trials with BNCT are briefly introduced in the first part of this review. In the second part, we provide a detailed overview of various boron delivery agents and discuss their merits and limitations. Additionally, the preclinical outcomes of these agents are included in this review and the most promising delivery agents are highlighted and compared. In summary, this article provides an overview of boron delivery agents, and critically analyzes their clinical prospects, from the view of medicinal chemists and nuclear medicine physicians. [ABSTRACT FROM AUTHOR]

Ubiquitination was considered to be a crucial factor in intrahepatic cholangiocarcinoma (iCCA) development. Herein, we identified Ubiquitin-specific peptidase 8 (USP8) as a key regulator for promoting the tumorigenesis of iCCA cell via stabilizing OGT. USP8 was overexpressed in human tumor tissues and correlated with worse survival. Moreover, the mass spectrometry and co-immunoprecipitation analysis indicated that USP8 interacted with OGT. USP8 worked as a bona fide deubiquitylase of OGT. It stabilized OGT in a deubiquitylation activity-dependent manner. Meanwhile, DUB-IN3, the USP8 inhibitor, could also restrain the malignancy of intrahepatic cholangiocarcinoma. In addition, USP8 depletion promoted the response of iCCA to pemigatinib. In conclusion, our findings pointed to a previously undocumented catalytic role for USP8 as a deubiquitinating enzyme of OGT. The USP8-OGT axis could be a potential target for iCCA therapy. [ABSTRACT FROM AUTHOR]

Correction for ‘Developing native peptide-based radiotracers for PD-L1 PET imaging and improving imaging contrast by pegylation’ by Kuan Hu et al., Chem. Commun., 2019, DOI: URL10.1039/c9cc00445a/URL. [ABSTRACT FROM AUTHOR]

Recently, our group reported that a precisely positioned chiral center on a thioether tether could dominate the backbone peptides' secondary structures and modulate the peptides' biophysical properties. Helical peptides constructed with this chirality induced helicity (CIH) method were named as CIH peptide. In this work, we examined the effects of substituting the thioether tether with an all hydrocarbon tether for the biophysical property differences. Two peptide epimers were prepared and showed distinct secondary structures and the R epimer is helical. Comparing with its thioether counterpart, the all‐hydrocarbon R epimer showed slightly higher helical content, modest improved binding affinity with mammal double minute 2 (MDM2), while similar cell permeability and slightly higher membrane toxicity. [ABSTRACT FROM AUTHOR]

Fibroblast activation protein (FAP) is a serine protease characterized by its high expression in cancer-associated fibroblasts (CAFs) and near absence in adult normal tissues and benign lesions. This unique expression pattern positions FAP as a prospective biomarker for targeted tumor radiodiagnosis and therapy. The advent of FAP-based radiotheranostics is anticipated to revolutionize cancer management. Among various types of FAP ligands, peptides and antibodies have shown advantages over small molecules, exemplifying prolonged tumor retention in human volunteers. Within its scope, this review summarizes the recent research progress of the FAP radiopharmaceuticals based on antibodies and peptides in tumor imaging and therapy. Additionally, it incorporates insights from recent studies, providing valuable perspectives on the clinical utility of FAP-targeted radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the most common type of primary hepatic liver cancer. Dysregulated Wnt/β-catenin activation is closely related to the progression of cancer. Nevertheless, the mechanism that sustains the abnormal expression of β-catenin in HCC has yet to be identified. In this study, we find that UCHL3 is overexpressed in HCC tissues and correlated with β-catenin protein level. High expression of UCHL3 is associated with poor prognosis. UCHL3 knockdown markedly reduces the protein level of β-catenin in HCC cells. TOP-luciferase activity and β-catenin target genes expression are also decreased upon UCHL3 depletion. We find that the ARM domain of β-catenin is required for the interaction with UCHL3. UCHL3 increases β-catenin protein stability via removing K48-specific poly-ubiquitin chains from β-catenin protein. Furthermore, the depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. These impacts could be restored by the overexpression of β-catenin. In addition, the UCHL3 inhibitor TCID inhibits the aggressive phenotype of HCC through the degradation of β-catenin. In general, our results indicates that UCHL3 increases the stability of β-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC. [Display omitted] • UCHL3 was overexpressed in HCC tissues and correlated with β-catenin protein level and poor prognosis. • The depletion of UCHL3 induces ferroptosis and hinders the growth, invasion, and stem cell properties of HCC cells. • UCHL3 increases the stability of β-catenin, which in turn facilitates tumorigenesis of HCC, suggesting that targeting UCHL3 may be a promising approach for the treatment of HCC. [ABSTRACT FROM AUTHOR]

Background: In the past four decades, the incidence of cholangiocarcinoma, especially intrahepatic cholangiocarcinoma (ICC), has raised rapidly worldwide. Completeness of resection, max size of tumor and etc. are widely recognized as prognostic factors. However, the prognosis significance of perineural invasion (PNI) on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is controversial.Methods: ICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Patients were grouped by existence of PNI and outcomes were compared between groups. The potential relationship between PNI and postoperative chemotherapy was also investigated.Results: There was no significant difference in demographic, clinical staging or tumor index between two groups, except positive hepatitis B surface antigen and CA19-9. PNI negative group showed a better prognosis in RFS (P < 0.0001) and OS (P < 0.0001). COX regression analyses showed PNI as an independent risk factor in RFS and OS. ICC with postoperative chemotherapy showed better effects in the whole cohort on both RFS (P = 0.0023) and OS (P = 0.0011). In PNI negative group, postoperative chemotherapy also showed significant benefits on RFS and OS, however not in PNI positive group (P = 0.4920 in RFS and P = 0.8004 in OS).Conclusion: PNI was an independent risk factor in R0-resected ICC, presenting worse recurrence and survival outcomes. Meanwhile, negative PNI may act as an indication of postoperative chemotherapy. [ABSTRACT FROM AUTHOR]

1. 2-[1-Hexyloxyethyl]-2-devinyl pyropheophorbide-a (HPPH), a second-generation photosensitizer, has been widely employed in photodynamic therapy (PDT) for the treatment of malignant lesions. The objective of this study was to characterize the pharmacokinetics of HPPH in Chinese patients using a population pharmacokinetic (PopPK) approach. 2. For the first time, a PopPK model of HPPH for Chinese (n = 20) was developed (registration number: CTR20160425). The pharmacokinetics of HPPH was described by a three-compartment model with linear elimination. Through the stepwise addition (p < 0.05) and backward elimination (p < 0.001) approach, fat-free mass (FFM) was identified to be the most significant covariate and V1 increased with FFM. Visual predictive check (VPC) was employed for the evaluation of the final model. Subsequent full covariate analysis indicated that FFM has considerable impact (∼30%) on HPPH exposure and fat mass also has a modest (∼25%) impact. 3. The simulations suggested that a dose adjustment of HPPH may be necessary for Chinese and the dose of 3 mg/m2 should be appropriate. HPPH exposure increases with fat mass while being inversely related to FFM. HPPH-PDT for overweight patients should be monitored with more caution and PDT conditions should be optimized if necessary. [ABSTRACT FROM AUTHOR]

MicroRNAs (miRNAs) function as critical regulators of gene expression and their deregulation is associated with the development and progression of various cancers. This study aimed to investigate the biological role and mechanism of miR-205 in ovarian cancer (OC). MiR-205 was upregulated in OC tissues and cells in comparison to the controls. Meanwhile, overexpression of miR-205 was significantly associated with poor overall survival of OC patients. Functional study indicated that ectopic expression of miR-205 significantly promoted cell proliferation, migration, invasion and chemoresistance of OC cells. SMAD4 and PTEN were identified as direct targets of miR-205 using luciferase reporter assays, real-time PCR (qRT-PCR), and western blot. Most interestingly, in vivo studies indicated that miR-205 markedly promoted the growth and metastasis of tumors and the expression of miR-205 was also found to be inversely correlated with that of SMAD4 and PTEN in nude mice. Overall, we suggest that miR-205 functions as an oncogenic miRNA by directly binding to SMAD4 and PTEN, providing a novel target for the molecular treatment of ovarian cancer. [ABSTRACT FROM AUTHOR]

In recent years, bird droppings flashover faults frequently occur on transmission lines. Based on the existing conditions of the laboratory, this paper explores the flashover mechanism of 110 kV bird droppings. A new type of bird droppings propulsion device was designed and developed, and the process of bird droppings falling in the natural state was simulated without voltage. According to several typical forms of bird droppings, the main findings are ① the bird droppings connected to the two poles are the most serious short circuit situation; ② the bird droppings flashover fault of the 110 kV line is actually a single-phase grounding fault of the line through a resistance, and the grounding resistance is between 20 and 300 kΩ; and ③ the conductivity is the most sensitive factor affecting bird droppings flashover. [ABSTRACT FROM AUTHOR]

During the opening and closing process of the contact, it will undergo repeated arc ablation and wear. After each ablation and wear, the composition, performance, and shape of the contact surface constantly change, leading to cracks, slag drop, melting, evaporation, and other phenomena on the contact surface, ultimately causing the contact to fail, resulting in the switch not being able to open and close normally. In order to study the failure mechanism of arc contacts caused by arc erosion after breaking short-circuit current, a pair of arc contacts for the cumulative breaking short circuit current test was selected as the research object. The metallographic, microscopic morphology, and energy spectrum analysis of the arc contacts were conducted, and the analysis results were compared with the new arc contacts to reveal the evolution and development process of arc contacts from cumulative arc erosion to failure during breaking. [ABSTRACT FROM AUTHOR]

CCN1, also named Cyr61 (cysteine-rich protein 61), is the first identified member of the CCN family that is composed of 6 secreted extracellular matrix-associated glycoproteins. CCN1 has been demonstrated to participate in pathogenesis of rheumatoid arthritis through various pathways. A monoclonal antibody, namely, 093G9, is effective to antagonize the effects of CCN1 and hence has potential therapeutic benefits against rheumatoid arthritis. Here, we show that the epitope recognized by 093G9 is mapped to residues 77 to 80 of CCN1, and a cyclic peptide encompassing residues 75 to 81 of CCN1 displays high binding affinity for 093G9. The crystal structure of the 093G9 Fab in complex with the cyclic peptide was determined at 2.7 Å resolution, which reveals the intensive interactions between CCN1 and 093G9. Particularly, residues Asn79 and Phe80 of CCN1 are inserted into cavities mainly formed by residues of complementarity-determining region loop L3 and framework region L2 and by residues of complementarity-determining region loops H2 and H3, respectively, which contribute most of the interactions and therefore are critical for the recognition by 093G9. Together, these findings not only identify the epitope of CCN1 for 093G9 but also reveal the molecular mechanism of recognition and binding of CCN1 by 093G9. [ABSTRACT FROM AUTHOR]

Chemoresistance in patients with glioblastoma multiforme (GBM) is a common reason hindering the success of treatment. Recently, ferroptosis has been reported to be associated with chemoresistance in different types of cancer, while the role of ferroptosis‐related genes in GBM have not been fully elucidated. This study aimed to demonstrate the roles and mechanism of ferroptosis‐related genes in chemoresistance and metastasis of GBM. First, two candidate genes, squalene epoxidase (SQLE) and FANCD2, were identified to be associated with ferroptosis‐related chemoresistance in GBM from three temozolomide (TMZ) therapeutic datasets and one ferroptosis‐related gene dataset. Then, comprehensive bio‐informatics data from different databases testified that SQLE was significantly downregulated both in GBM tissue and cells and displayed a better prognosis in GBM. Clinical data identified lower expression of SQLE was significantly associated with WHO grade and 1p/19q codeletion. Moreover, through in vitro experiments, SQLE was confirmed to suppress ERK‐mediated TMZ chemoresistance and metastasis of GBM cells. The KEGG analysis of SQLE‐associated co‐expressed genes indicated SQLE was potentially involved in the cell cycle. Furthermore, SQLE was found to have the most significant correlations with tumor‐infiltrating lymphocytes and immunomodulators. These findings highlighted that SQLE could be a potential target and a biomarker for therapy and prognosis of patients with GBM. [ABSTRACT FROM AUTHOR]

The hierarchical porous carbon aerogel (CA) with vanadium nitride (VN) was effectively prepared via a facile in-situ method with organic acid catalyzing and non-supercritical drying. The surface morphology and structure of the VN/CA (VCA) composites, and the electrochemical performance of these composites based sulfur cathodes were investigated systematically. This mono-dispersed microsphere composite presents hierarchical pore and uniform dispersion of vanadium nitride, and effectively immobilizes the polysulfides due to the synergistic effects between the VN and CA matrix. Moreover, the VN on the CA has catalytic effect on the electrode reaction, displaying high discharge voltages. In particular, a higher initial discharge capacity of 1279 mAh g −1 can be obtained at 0.2 C, and it retains 1001 mAh g −1 after 100 cycles. Even at a higher rate of 1 C, the capacity still delivers 802 mAh g −1 after 100 cycles. [ABSTRACT FROM AUTHOR]

Purpose: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Experimental design: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Results: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy.Conclusions: Multiple myeloma (MM) is characterized by the uncontrolled proliferation of monoclonal plasma cells (PC) in the bone marrow (BM). B-cell maturation antigen (BCMA) is predominantly expressed in malignant plasma cells, and associated with the proliferation, survival, and progression of various myeloma cells. Given these important roles, BCMA emerges as an ideal target antigen for MM therapy. However, effective stratification of patients who may benefit from targeted BCMA therapy and real-time monitoring the therapeutic efficacy poses significant clinical challenge. This study aims to develop a BCMA targeted diagnostic modality, and preliminarily explore its potential value in the radio-immunotherapy of MM.Using zirconium-89 (89Zr, t1/2 = 78.4 h) for labeling the BCMA-specific antibody, the BCMA-targeting PET tracer [89Zr]Zr-DFO-BCMAh230430 was prepared. The EC50 values of BCMAh230430 and DFO-BCMAh230430 were determined by ELISA assay. BCMA expression was assessed in four different tumor cell lines (MM.1S, RPMI 8226, BxPC-3, and KYSE520) through Western blot and flow cytometry. In vitro binding affinity was determined by cell uptake studies of [89Zr]Zr-DFO-BCMAh230430 in these tumor cell lines. For in vivo evaluation, PET imaging and ex vivo biodistribution studies were conducted in tumor-bearing mice to evaluate imaging performance and systemic distribution of [89Zr]Zr-DFO-BCMAh230430. Immunochemistry analysis was performed to detect BCMA expression in tumor tissues, confirming the specificity of our probe. Furthermore, we explored the anti-tumor efficacy of Lutetium-177 labeled BCMA antibody, [177Lu]Lu-DTPA-BCMAh230430, in tumor bearing-mice to validate its radioimmunotherapy potential.The radiolabeling of [89Zr]Zr-DFO-BCMAh230430 and [177Lu]Lu-DTPA-BCMAh230430 showed satisfactory radiocharacteristics, with a radiochemical purity exceeding 99%. ELISA assay results revealed closely aligned EC50 values for BCMAh230430 and DFO-BCMAh230430, which are 57 pM and 67 pM, respectively. Western blot and flow cytometry analyses confirmed the highest BCMA expression level. Cell uptake data indicated that MM.1S cells had a total cellular uptake (the sum of internalization and surface binding) of 38.3% ± 1.53% for [89Zr]Zr-DFO-BCMAh230430 at 12 h. PET imaging of [89Zr]Zr-DFO-BCMAh230430 displayed radioactive uptake of 7.71 ± 0.67%ID/g in MM.1S tumors and 4.13 ± 1.21%ID/g in KYSE520 tumors at 168 h post-injection (n = 4) (P < 0.05), consistent with ex vivo biodistribution studies. Immunohistochemical analysis of tumor tissues confirmed higher BCMA expression in MM.1S tumors xenograft compared to KYSE520 tumors. Notably, [177Lu]Lu-DTPA-BCMAh230430 showed some anti-tumor efficacy, evidenced by slowed tumor growth. Furthermore, no significant difference in body weight was observed in MM.1S tumor-bearing mice over 14 days of administration with or without [177Lu]Lu-DTPA-BCMAh230430.Our study has successfully validated the essential role of [89Zr]Zr-DFO-BCMAh230430 in non-invasively monitoring BCMA status in MM tumors, showing favorable tumor uptake and specific binding affinity to MM tumors. Furthermore, our research revealed, as a proof-of-concept, the effectiveness of [177Lu]Lu-DTPA-BCMAh230430 in radioimmunotherapy for MM tumors. In conclusion, we present a novel BCMA antibody-based radiotheranostic modality that holds promise for achieving efficient and precise MM diagnostic and therapy. [ABSTRACT FROM AUTHOR]

RET (rearranged during transfection), encoding a tyrosine kinase receptor, is a novel therapeutic target for cancers. The aberrations of RET are commonly found in cancers. Here, we profiled a comprehensive genomic landscape of RET mutations, copy number variants (CNVs), co-occurrence of RET and its mRNA expression and methylation levels in pan cancer, paving the way to the development of new RET-targeted therapies in clinic. Analysis of RET somatic mutations, CNVs, co-occurrence, mRNA expression and methylation were performed among 32 cancer types from The Cancer Genome Atlas (TCGA) dataset covering a total of 10,953 patients with 10,967 samples. RET aberrations were found in 3.0% of diverse cancers. The top two RET-altered tumors were skin cutaneous melanoma (SKCM) and uterine corpus endometrial carcinoma (UCEC) with dominant mutations in the other and PKinase_Tyr domains. RET-G823E and RET-S891L were most commonly found in SKCM and UCEC. Thyroid carcinoma (THCA) demonstrated the highest rate of coiled-coil domain containing 6 (CCDC6)-RET fusions, which constitutively activate RET kinase. Two FDA-approved RET inhibitors—pralsetinib and selpercatinib have been implied for the treatment of patients with RET S891L mutant UCEC and the treatment of patients with metastatic RET-fusion positive THCA and non-small cell lung cancer (NSCLC) at therapeutic level 1. We also identified four RET M918T-altered cases in patients with pheochromocytoma and paraganglioma (PCPG), which may induce drug resistance against multikinase inhibitors. Next, 273 co-occurring aberrations, most frequently in Notch signaling, TGF-β pathway, cell cycle, and Ras-Raf-MEK-Erk/JNK signaling, were uncovered among 311 RET altered cases. TP53 mutations (162 patients) leads to the most significant co-occurrence associated with RET aberrations. Furthermore, the RET expression was found most significantly increased in breast invasive carcinoma (BRCA) and neck squamous cell carcinoma (HNSC), as compared to their corresponding normal tissues. At last, patients with higher expression and sequence variant frequency have a worse prognosis, such as sarcoma patients. This work provided a profound and comprehensive analysis of RET and co-occurred alterations, RET mRNA expression and the clinical significance in pan cancer, offering new insights into targeted therapy for patients with RET anomalies. [ABSTRACT FROM AUTHOR]

In recent years, optoelectronics and related industries have developed rapidly. As typical optoelectronics devices, photodetectors (PDs) are widely applied in various fields. The functional materials in traditional PDs exhibit high hardness, and the performance of these rigid detectors is thus greatly reduced upon their stretching or bending. Therefore, the development of new flexible PDs with bendable and foldable functions is of great significance and has much interest in wearable, implantable optoelectronic devices. Graphene with excellent electrical and optical performance constructed on various flexible and rigid substrates has great potential in PDs. In this review, recent research progress on graphene-based flexible PDs is outlined. The research states of graphene conductive films are summarized, focusing on PDs based on single-component graphene and mixed-structure graphene, with a systematic analysis of their optical and mechanical performance, and the techniques for optimizing the PDs are also discussed. Finally, a summary of the current applications of graphene flexible PDs and perspectives is provided, and the remaining challenges are discussed. [ABSTRACT FROM AUTHOR]

Tuberculosis (TB) is an important public health problem. Studies indicated that TAP plays a key role in the presentation and transport of antigenic peptides during anti-M.tb infection. Given the important biological role of the TAP gene involved in anti-M.tb infection, a family-based case–control study including 133 tuberculosis patients, 107 healthy household contacts, and 173 healthy controls was conducted to assess the association between TAP gene polymorphisms and TB susceptibility. The basic information of subjects and their blood samples were collected. Four SNPs including rs1135216, rs1057141, rs241447, and rs3819721 were genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP). Our results suggested that BMI, residence, bedroom crowding, indoor humidity, fitness activities, history of smoking, and TB exposure history were associated with the occurrence of tuberculosis (P < 0.05). A significant association was observed between the TAP1 rs1135216 CT/CC genotype and increased TB risk, and the ORs were 2.56 (95% CI 1.31–4.99) and 6.73 (95% CI 1.33–34.02), respectively. TAP2 rs3819721 GG genotype carriers also showed an increased risk of TB when compared TB patients to healthy household contacts. Haplotype analysis revealed that the haplotype CT at rs1057141 and rs1135216 (OR = 11.34, 95% CI 1.49–86.56; OR = 7.45, 95% CI 1.43–38.76), as well as TA at rs241447 and rs3819721 (OR = 2.20, 95% CI 1.07–4.56) had a significantly increased risk of TB. The genetic risk scores (GRS) analysis of the four loci indicated that the risk of tuberculosis increased with increasing GRS scores in TB vs HHC (Ptrend = 0.010) and in TB vs HC (Ptrend = 0.001). In conclusion, our findings suggested that the SNPs of rs1135216 and rs3819721 were associated with TB susceptibility among the tuberculosis-prone families in the Chinese Han population and the risk of developing tuberculosis increases with the number of risk alleles, which could help identify high-risk groups in time and take scientific preventive measures. Further cohort studies with large samples are needed to validate the role of TAP gene variants on TB susceptibility. [ABSTRACT FROM AUTHOR]

Abstract: Since 2000, the Industrial Development Bureau (IDB) of the Government in Taiwan has been implementing a policy of Electronic Manufacturing Promotion (e-MP) to assist firms to implement Business to Business Information System (B2BIS). In general, the actual performance of e-MP policy has just been based on the data given in a final report produced by the funded firm. Consequently there is no clear evidence as to the efficacy of the e-MP policy. Therefore, this paper mainly covers two parts (i) A Fuzzy analytic hierarchical process (Fuzzy AHP) was utilized to explore the weights of each policy item according to project leaders’ response of 17 funded cases to see whether the current e-MP policy really benefits firms and (ii) financial data of 30 cases was collected from the stock exchange in Taiwan to understand the actual performance and Fuzzy AHP was utilized to find the funded cases’ initial expectation to see whether the adoption of B2BIS by those cases funded by the Government actually met initial expectation. The results of this study indicate that the e-MP policy need to be adjust and costs decreased and work efficiencies rose are most important benefit in most of the funded cases after introduction of B2BIS and this meet their initial expectation. Finally, implications and suggestions are given for the e-MP policy to facilitate adjustments by the IDB. [Copyright &y& Elsevier]

To analyze the serotype distribution and drug resistance of Streptococcus pneumoniae isolated from hospitalized patients of all ages in Zhongjiang county, Sichuan province, where the young children have just begun to vaccinate the PCV13 in private sector. Serotypes were determined for 387 isolates of S. pneumoniae by Quellung reaction. Antibiotic susceptibility was tested with the E-test or disc diffusion method. The most common serotypes were type 19F and confirmed for 88 isolates (22.7%), followed by 19A (15.0%), 6B (7.8%), 16F (7.8%), 23F (7.0%) and 15A (4.4%). The coverage rates of PCV13 and PPSV23 were 63.3% and 65.1%. With the increase of age, the proportion of PCV13 types decreased significantly, from 71.3% (<2 years old) to 41.9% (≥60 years old). The intermediate rate and resistance rate of the isolates to oral penicillin were 48.6% and 45.2%, respectively. The resistance rate of erythromycin was high (94.4%). The PCV13 isolates was more resistant to penicillin than the non-PCV13 ones. The PCV13 coverage rate in pediatric isolates was higher than those in adult isolates. The adults, especially the elderly, may be the reservoir of non-PCV13 types. It is necessary to investigate the serotype distribution of S. pneumoniae based on all age population to assess potential epidemics of non-vaccine serotype associated with PCVs administration. [ABSTRACT FROM AUTHOR]

Introduction: Intrahepatic cholangiocarcinoma (ICC) stands as the second most common malignant tumor in the liver with poor patient prognosis. Increasing evidences have shown that inflammation plays a significant role in tumor progression, angiogenesis, and metastasis. However, the prognosis significance of inflammatory biomarkers on recurrence-free survival (RFS) and overall survival (OS) in ICC patients is poorly recognized. Methods: ICC patients who underwent curative hepatectomy and diagnosed pathologically were retrospectively analyzed. Inflammatory biomarkers, including neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (LMR), and systemic immune-inflammation index (SII), were investigated. Results: Receiver operating characteristic (ROC) curves showed no significance in NLR, PLR, and LMR in RFS and OS, while significant results were shown on SII in both RFS (P = 0.035) and OS (P = 0.034) with areas under ROC curve as 0.63 (95%CI 0.52–0.74) and 0.62 (95%CI 0.51–0.72), respectively. Kaplan-Meier curves revealed a statistically significant better survival data in SII-low groups on both RFS (P < 0.001) and OS (P < 0.001). The univariate and multivariate analyses revealed that higher level of SII was independently associated with both poorer RFS time and OS time. However, no significant result was shown on NLR, PLR, or LMR. Conclusion: SII is an effective prognostic factor for predicting the prognosis of ICC patient undergone curative hepatectomy, while NLR, PLR, and LMR are not associated with clinical outcomes of these patients. [ABSTRACT FROM AUTHOR]

Variable refrigerant flow (VRF) systems have gained much attention and been widely used in commercial and residential buildings benefitting from their competitive advantages. However, after long-term operation in a complex environment, various faults may occur in the VRF systems, resulting in failure to meet users comfort requirements and even unnecessary increase in energy consumption. This paper proposes a simulated annealing wrapped generic ensemble fault diagnosis strategy for typical faults of VRF systems, such as refrigerant charge amount (RCA) faults, valve faults, and compressor liquid return (LF) faults. The simulated annealing algorithm based on random forest (SA-RF) is first utilized to perform feature selection process on the three kinds of fault datasets to select the optimal variables that can well characterize the fault states, which can improve the modeling efficiency while reducing the data dimensionality. Then five component learners and the proposed ensemble model based on them are established adopting the optimal variables as input variables. Through visualizing the error evolution and margin of the boosting models built in the first stage of the integration process, it was found that the boosting models can effectively avoid overfitting and most samples are correctly classified with high confidence. By comparing with the five component learners, it is concluded that the boosting strategy in the first stage can improve the diagnostic performance of the models, and the weighted voting integration strategy in the second stage can further improve the diagnostic performance of the model. The final ensemble model can effectively compensate for the deficiencies of each component learners and its diagnostic accuracy for the three fault data sets is as high as 95.37%, 99.36% and 98.3%, respectively, indicating that the model can be applied to diagnose the three types of faults in VRF system at the same time, showing a high versatility. [ABSTRACT FROM AUTHOR]

In the original publication, the authors' contribution is missing in the acknowledgment section. The correct acknowledgement is provided in this correction. Also, in Fig. 4, the second (c) after figure (d) should be read as (e). In Fig. 5 (i), the Y-axis label “Current (μA)” should be read as “Voltage”. [ABSTRACT FROM AUTHOR]