Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) improve overall survival rate in patients with EGFR mutated non-small cell lung cancers (NSCLC). However, treatment with third-generation EGFR TKIs (osimertinib) develops C797S resistance in 20-30 % of the patients. To date, there is no approved drug for third-generation resistant EGFR-mutant NSCLC patients. There is an urgent unmet medical need to develop fourth-generation EGFR TKIs targeting C797S containing mutations. Extensive structure-activity relationship (SAR) studies led to the discovery of BBT-176 as a "first-in-class" reversible fourth-generation EGFR TKI. BBT-176 shows promising results of potent anti-cancer efficacy in osimertinib-resistant cell lines. In patient-derived cell (PDC) models, BBT-176 exhibits tumor regression once-daily oral 100 mg/kg dose as a single agent in day 25.

The rapid evolution of viruses poses a significant threat to global health, as evidenced by recent pandemics. Umifenovir (Arbidol®), a broad-spectrum antiviral drug, has demonstrated potential in treating various viral infections. This study aimed to assess the antiviral mechanism of umifenovir against influenza A virus (IAV), specifically its interaction with hemagglutinin (HA), using umifenovir-modified gold nanoparticles (umi-GNPs). Umi-GNPs have been applied to various IAV subtypes, including H1N1, H3N2, H4N6, H6N8, and H9N2. Our results demonstrate that umifenovir effectively inhibits viral replication in all tested subtypes at a viral titer of 104.5 50 % egg infective dose (EID50)/mL. Additionally, the aggregation of umi-GNPs with viruses pre-bound to umifenovir was suppressed, indicating that umi-GNPs bind to a specific region of the viral protein. These findings indicate that umi-GNPs can serve as novel agents for visually determining umifenovir resistance in IAV.

Abstract Background: Biliary tract cancer constitutes a heterogeneous group of diseases with a limited understanding of its molecular characteristics and prognostic/predictive biomarkers. We performed prespecified exploratory analyses of the STAMP trial, a multicenter randomized phase 2 trial of adjuvant capecitabine (CAP) or gemcitabine plus cisplatin (GemCis) for patients with resected extrahepatic cholangiocarcinoma (EH-CCA) with regional lymph node metastasis. Methods: Among 101 patients included in the intention-to-treat population of the STAMP trial, a total of 89 patients (45 in the GemCis group and 44 in the CAP group) were included in the current biomarker analysis after excluding 12 patients without available tissue and blood samples. Whole exome sequencing and proteomics were performed using surgical specimens. Results: TP53 (63%), SMAD4 (20%), and KRAS (18%) mutations were the most frequent in the pooled population. Somatic mutations in homologous recombination deficient (HRD) genes were present in 20% of patients, while one patient (1%) had a germline ATM mutation. The prevalence of microsatellite instability was 1%. Somatic mutations in known targetable genes were observed in 54 patients (60.7%) and proteogenomic integrative analysis revealed significant HER2 pathway alteration with HER2 amplification in 4 patients (7%). The characteristics of prognostic biomarkers varied by the adjuvant regimen used. In the adjuvant GemCis group, somatic mutations were associated with poor disease-free survival (DFS) and overall survival (OS), including KRAS (log-rank p=0.004 for DFS and p=0.003 for OS), FBXW7 (p=0.021 for DFS and p=0.011 for OS), and PIK3CA (p<0.001 for DFS and p=0.042 for OS) mutations. In the adjuvant CAP group, copy number alterations (CNAs) such as 8q24.21 amplification (p=0.006 for DFS and p=0.707 for OS) and 3q26.1 amplification (p=0.020 for DFS and p=0.026 for OS) were associated with poor survival, while 11q13.3 amplification (p=0.017 for DFS and p=0.099 for OS) was associated with improved survival. Additionally, a higher HRD score showed a tendency toward better DFS and OS in the GemCis group, but not in the CAP group, although it did not reach statistical significance in both groups (p>0.05). Non-negative matrix clustering of proteomics data classified patients into 4 clusters. Among those, cluster 2, which showed alterations in the metabolism pathway, was associated with higher CNA level, higher tendency of HRD scores, and favorable survival with GemCis (p=0.039 for DFS and p=0.100 for OS) but not with CAP. Conclusions: Comprehensive proteogenomic analyses enable the identification of prognostic biomarkers and may guide the selection of adjuvant chemotherapy in resected EH-CCA. Citation Format: Hyehyun Jeong, Ji-Hye Oh, Hee-Sung Ahn, Baek-Yeol Ryoo, Kyu-pyo Kim, Jae Ho Jeong, Inkeun Park, Seung-Mo Hong, Jinho Shin, Chae Won Park, Yoo Sook Cho, Kyunggon Kim, Chang Ohk Sung, Changhoon Yoo. Comprehensive proteogenomic profiling and biomarker analyses in resected extrahepatic cholangiocarcinoma: A prespecified exploratory analysis of the phase 2 STAMP trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6422.

Considering the urgent demand for reliable and rapid detection of infectious respiratory viruses during unpredictable pandemics, an innovative ultrasensitive colorimetric immunoassay for influenza A (H1N1) virus detection is developed herein. The proposed approach leverages dual amplification by combining layer‐by‐layer interactions with the nanozyme effect of biotinylated gold nanoparticles (BGNPs). BGNPs assemble around the target via repeated incubation cycles under optimized conditions, resulting in a layered structure that increases optical density, producing a more intense signal proportional to the viral titer. Additionally, the nanozyme effect of the layered BGNPs induces oxidation of 3,3',5,5'‐tetramethylbenzidine, which further enhances the visible signal detectable by the naked eye. This synergetic nanoprobe‐based system demonstrates remarkable sensitivity, with a limit of detection of 10 1.29 EID 50 mL −1 , which is 2500‐fold higher than that of commercial rapid kits and conventional enzyme‐linked immunosorbent assays, within a rapid 55 min timeframe. Furthermore, the anti‐interference capability and portability of the developed system reinforce its practicality, making it a promising tool for field diagnostic tests that offers advanced, ultrasensitive, and early detection of respiratory viruses.

The rapid transmission and numerous re-emerging human influenza virus variants that spread via the respiratory system have led to severe global damage, emphasizing the need for detection tools that can recognize active and intact virions with infectivity. Here, this work presents a plasmonic vesicle-mediated fusogenic immunoassay (PVFIA) comprising gold nanoparticle (GNP) encapsulating fusogenic polymeric vesicles (plasmonic vesicles; PVs) for the label-free and colorimetric detection of influenza A virus (IAV). The PVFIA combines two sequential assays: a biochip-based immunoassay for target-specific capture and a PV-induced fusion assay for color change upon the IAV-PV fusion complex formation. The PVFIA demonstrates excellent specificity in capturing the target IAV, while the fusion conditions and GNP induce a significant color change, enabling visual detection. The integration of two consecutive assays results in a low detection limit (100.7919 EID50 mL-1 ) and good reliability (0.9901), indicating sensitivity that is 104.208 times higher than conventional immunoassay. Leveraging the PV viral membrane fusion activity renders the PVFIA promising for point-of-care diagnostics through colorimetric detection. The innovative approach addresses the critical need for detecting active and intact virions with infectivity, providing a valuable tool with which to combat the spread of the virus.

Monitoring drug efficacy is significant in the current concept of companion diagnostics in metastatic breast cancer. Trastuzumab, a drug targeting human epidermal growth factor receptor 2 (HER2), is an effective treatment for metastatic breast cancer. However, some patients develop resistance to this therapy; therefore, monitoring its efficacy is essential. Here, we describe a deep learning-assisted monitoring of trastuzumab efficacy based on a surface-enhanced Raman spectroscopy (SERS) immunoassay against HER2-overexpressing mouse urinary exosomes. Individual Raman reporters bearing the desired SERS tag and exosome capture substrate were prepared for the SERS immunoassay; SERS tag signals were collected to prepare deep learning training data. Using this deep learning algorithm, various complicated mixtures of SERS tags were successfully quantified and classified. Exosomal antigen levels of five types of cell-derived exosomes were determined using SERS-deep learning analysis and compared with those obtained via quantitative reverse transcription polymerase chain reaction and western blot analysis. Finally, drug efficacy was monitored via SERS-deep learning analysis using urinary exosomes from trastuzumab-treated mice. Use of this monitoring system should allow proactive responses to any treatment-resistant issues.

Molecular-profiling-based cancer diagnosis has significant implications for predicting disease prognosis and selecting targeted therapeutic interventions. The analysis of cancer-derived extracellular vesicles (EVs) provides a noninvasive and sequential method to assess the molecular landscape of cancer. Here, we developed an all-in-one fusogenic nanoreactor (FNR) encapsulating DNA-fueled molecular machines (DMMs) for the rapid and direct detection of EV-associated microRNAs (EV miRNAs) in a single step. This platform was strategically designed to interact selectively with EVs and induce membrane fusion under a specific trigger. After fusion, the DMMs recognized the target miRNA and initiated nonenzymatic signal amplification within a well-defined reaction volume, thus producing an amplified fluorescent signal within 30 min. We used the FNRs to analyze the unique expression levels of three EV miRNAs in various biofluids, including cell culture, urine, and plasma, and obtained an accuracy of 86.7% in the classification of three major breast cancer (BC) cell lines and a diagnostic accuracy of 86.4% in the distinction between patients with cancer and healthy donors. Notably, a linear discriminant analysis revealed that increasing the number of miRNAs from one to three improved the accuracy of BC patient discrimination from 78.8 to 95.4%. Therefore, this all-in-one diagnostic platform performs nondestructive EV processing and signal amplification in one step, providing a straightforward, accurate, and effective individual EV miRNA analysis strategy for personalized BC treatment.

Breast cancer (BC) is a major global health problem, with ≈20-25% of patients overexpressing human epidermal growth factor receptor 2 (HER2), an aggressive marker, yet access to early detection and treatment varies across countries. A low-cost, equipment-free, and easy-to-use polydiacetylene (PDA)-based colorimetric sensor is developed for HER2-overexpressing cancer detection, designed for use in low- and middle-income countries (LMICs). PDA nanoparticles are first prepared through thin-film hydration. Subsequently, hydrophilic magnetic nanoparticles and HER2 antibodies are sequentially conjugated to them. The synthesized HER2-MPDA can be concentrated and separated by a magnetic field while inheriting the optical characteristics of PDA. The specific binding of HER2 antibody in HER2-MPDA to HER2 receptor in HER2-overexpressing exosomes causes a blue-to-red color change by altering the molecular structure of the PDA backbone. This colorimetric sensor can simultaneously separate and detect HER2-overexpressing exosomes. HER2-MPDA can detect HER2-overexpressing exosomes in the culture medium of HER2-overexpressing BC cells and in mouse urine samples from a HER2-overexpressing BC mouse model. It can selectively isolate and detect only HER2-overexpressing exosomes through magnetic separation, and its detection limit is found to be 8.5 × 108 particles mL-1. This colorimetric sensor can be used for point-of-care diagnosis of HER2-overexpressing BC in LMICs.

Colorimetric Detection In article number 2307262, Eun-Kyung Lim, Seungjoo Haam, and co-workers illustrate that blue HER2-MPDA combines with HER2 overexpressing exosomes, changes color to red, and is captured and separated by a magnet. Magnetically concentrated red HER2-MPDA can be seen with the naked eye. The left side is colored red to distinguish it from the blue right side.

Infectious diseases pose persistent threats to public health, demanding advanced vaccine technologies. Nanomaterial-based delivery systems offer promising solutions to enhance immunogenicity while minimizing reactogenicity. We introduce a self-assembled vaccine (SAV) platform employing antigen-polymer conjugates designed to facilitate robust immune responses. The SAVs exhibit efficient cellular uptake by dendritic cells (DCs) and macrophages, which are crucial players in the innate immune system. The high-density antigen presentation of this SAV platform enhances the affinity for DCs through multivalent recognition, significantly augmenting humoral immunity. SAV induced high levels of immunoglobulin G (IgG), IgG1, and IgG2a, suggesting that mature DCs efficiently induced B cell activation through multivalent antigen recognition. Universality was confirmed by applying it to respiratory viruses, showcasing its potential as a versatile vaccine platform. Furthermore, we have also demonstrated strong protection against influenza A virus infection with SAV containing hemagglutinin, which is used in influenza A virus subunit vaccines. The efficacy and adaptability of this nanostructured vaccine present potential utility in combating infectious diseases.

Park et al . (2023) in a article published in Scientific Reports newly defined the Haengmae Formation of the Jeongseon-type Joseon Supergroup in the Taebaeksan Basin as follows. r It is a Pebble -bearing Fine Sand -sized Clastic rock (PBSC) that uncomfortably covers the lower carbonate rock (Jeongseon Limestone), formed during the Ordovician -Silurian Transition (OST). d Based on this definition, Park et al . (2023) further developed the detailed geological map provided by Kim et al . (2020), who designated the Haengmae Formation as a litho-stratigraphic unit of clastic sedimentary rocks, and presented the following new evidence: (1) At the boundary between the underlying Jeongseon Limestone and the Haengmae Formation, angular unconformity outcrop and continuous karst erosion structures on the upper surface of the Jeongseon Limestone were found. (2) U-Pb dating of detrital zircons from the Haengmae Formation indicated the latest Ordovician age. (3) In -situ 8 18 O quartz and 87 Sr/ 86 Sr carbonates isotope analyses showed anomalies in the Haengmae Formation. The paper by Park et al . (2023) has significant geological importance for two main reasons: (1) It provides a reconfirmation chrono-stratigraphically and litho-stratigraphically that the Hoedongri Formation is of the Silurian period. (2) It finds firstly the presence of the clastic sedimentary unit at the Ordovician -Silurian Transition (OST) period with a global distribution, on the Korean Peninsula. Furthermore, by demonstrating that the Haengmae Formation serves as a stratigraphic marker indicating the Ordovician -Silurian Transition period, it has secured the essential reference layer required for stratigraphic correlations between the Jeongseon-type Joseon Supergroup and the Joseon Supergroups of other regions. Therefore, this comment aims to share the geological significance of the paper by Park et al . (2023).

A major question in geodynamic evolution of the Earth is whether the continental keel evolved geochemically or were delaminated and replaced by a new mantle. Here we present direct evidence for the geochemical evolution of continental keel from lherzolite xenoliths preserved in the Cenozoic alkali basalts from Jeju Island, Korea. Our findings, using detailed petrography and geochemical methods, reveal distinct textures and compositional changes (represented by olivine with magnesium number 91–87, 86–61 respectively) of two stages of geochemical alteration. The first stage involved a parental kimberlite melt that penetrated during the Paleozoic, and the second was caused by alkali basalt during Cenozoic. Our findings suggest that the Archean depleted harzburgitic upper mantle partially evolved to lherzolitic through interaction with melts/fluids that originated from the deep mantle, implying no wholesale delamination of the upper mantle root of East Asian continents.

African swine fever virus (ASFV) is a severe and persistent threat to the global swine industry. As there are no vaccines against ASFV, there is an immense need to develop easy-to-use, cost-effective, and rapid point-of-care (POC) diagnostic platforms to detect and prevent ASFV outbreaks. Here, a novel POC diagnostic system based on affinity column chromatography for the optical detection of ASFV is presented. This system employs an on-particle hairpin chain reaction to sensitize magnetic nanoclusters with long DNA strands in a target-selective manner, which is subsequently fed into a column chromatography device to produce quantitatively readable and colorimetric signals. The detection approach does not require expensive analytical apparatus or immobile instrumentation. The system can detect five genes constituting the ASFV whole genome with a detection limit of ≈19.8 pm in swine serum within 30 min at laboratory room temperature. With an additional pre-amplification step using polymerase chain reaction (PCR), the assay is successfully applied to detect the presence of ASFV in 30 suspected swine samples with 100% sensitivity and specificity, similar to quantitative PCR. Thus, this simple, inexpensive, portable, robust, and customizable platform for the early detection of ASFV can facilitate the timely surveillance and implementation of control measures.

We introduce a new 'image-mapping' in-situ U-Pb dating method using LA-ICP-MS, proposed by Drost et al. (2018), and show the characteristics and usability of this method through several examples of absolute age results determined by first applying it to samples from the Joseon Supergroup of the Early Paleozoic Era in Korea. Unlike the previous in-situ spot analysis, this in-situ U-Pb dating method for carbonate minerals can determine the absolute age with high reliability by applying the 'image-mapping' method of micro -sized domains based on micro-textural observation, as well as determine the absolute age of multiple geological 'events' that occurred after deposition. This was confirmed in the case of determining the syn-depositional age and the multiple post-depositional ages from carbonate minerals of the Makgol and the Daegi Formations. Therefore, if the 'image-mapping' in-situ U-Pb dating method is applied to determine the absolute age of various types of carbonate minerals that exist in various geological environments throughout the geologic era, it will be possible to secure new geological age information.

Lung cancer is one of the most common malignant tumors worldwide and is characterized by high morbidity and mortality rates and a poor prognosis. It is the leading cause of cancer-related death in the United States and worldwide. Most patients with lung cancer are treated with chemotherapy, radiotherapy, or surgery; however, effective treatment options remain limited. In this review, we aim to provide an overview of clinical trials, ranging from Phase I to III, conducted on drug delivery systems for lung cancer treatment. The trials included oral, inhaled, and intravenous administration of therapeutics. Furthermore, the study also talks about the evolving paradigm of targeted therapy and immunotherapy providing promising directions for personalized treatment. In addition, we summarize the best results and limitations of these drug delivery systems and discuss the potential capacity of nanomedicine.

Accurate diagnosis of Alzheimer’s disease (AD) in its earliest stage can prevent the disease and delay the symptoms. Therefore, more sensitive, non-invasive, and simple screening tools are required for the early diagnosis and monitoring of AD. Here, we design a self-assembled nanoparticle-mediated amplified fluorogenic immunoassay (SNAFIA) consisting of magnetic and fluorophore-loaded polymeric nanoparticles. Using a discovery cohort of 21 subjects, proteomic analysis identifies adenylyl cyclase-associated protein 1 (CAP1) as a potential tear biomarker. The SNAFIA demonstrates a low detection limit (236 aM), good reliability (R 2 = 0.991), and a wide analytical range (0.320–1000 fM) for CAP1 in tear fluid. Crucially, in the verification phase with 39 subjects, SNAFIA discriminates AD patients from healthy controls with 90% sensitivity and 100% specificity in under an hour. Utilizing tear fluid as a liquid biopsy, SNAFIA could potentially aid in long-term care planning, improve clinical trial efficiency, and accelerate therapeutic development for AD.

Clastic successions found in the carbonate platform of continental margin during the Ordovician–Silurian Transition (OST) period are archives for interpreting paleo-depositional systems. Here, we report in-situ δ 18 O quartz and 87 Sr/ 86 Sr carbonate isotope chemo-stratigraphy for an unconformable clastic unit from the Cathaysia terrane that rifted off the Gondwana Supercontinent in the Early Paleozoic Era. Our results suggest a depositional proxy and model for geological events attributed to rapid changes in the sedimentary environment during the OST period. Importantly, these results present crucial clues that infer the influence of Paleo-Tethys Sea opening, global eustatic regression, and rapid sedimentary provenance change. Our study provides insight into paleo-tracer that could be a key method for interpreting depositional system of carbonate platform based on in-situ mineral isotope chemo-stratigraphy that preserves the original value of provenance and geochemical condition.

The emergence of fatal viruses that pose continuous threats to global health has fueled the intense effort to develop direct, accurate, and high‐throughput virus detection platforms. Current diagnostic methods, including qPCR and rapid antigen tests, indicate how much of the virus is present, whether small fragments or whole viruses. However, these methods do not indicate the probability of the virus to be active, capable of interacting with host cells and initiating the infection cycle. Herein, a sialic acid‐presenting fusogenic liposome (sLipo–Chol) nanosensor with purposefully modulated membrane rigidity to rapidly detect the fusion‐competent influenza A virus (IAV) is developed. This nanosensor possesses virus‐specific features, including hemagglutinin (HA) binding and HA‐mediated membrane fusion. It is explored how the fusogenic capability of sLipo–Chol with different membrane rigidities impacts their sensing performance by integrating Förster resonance energy transfer (FRET) pairs into the bilayers. The addition of an intact virus led to instant FRET signal changes, thus enabling the direct detection of diverse IAV subtypes—even in avian fecal samples—within an hour at room temperature. Therefore, the sensing approach, with an understanding of the cellular pathogenesis of influenza viruses, will aid in developing bioinspired nanomaterials for evolution into nanosystems to detect infection‐competent viruses.

Two stages of illite mineralization are recognized in the hydrothermal alteration zone of the Hoam granite. These illites are formed as a result of pervasive alteration by re-equilibration with high water/rock in a brittle environment below <2 km; the mineralization timing is middle Oligocene (26–27 Ma), coinciding with the timing of crustal deformation related to the opening of the East Sea (Sea of Japan). The mineralogical and geochemical characteristics of the clearly distinguished illites at each site indicate that they were mineralized from different fluid injections in distinct geological environments. Illites at the site-1 alteration zone are characterized by high-K content [K0.84 per O10(OH)2], 2M1 polytype of 99 %, hexagonal plate shape, and coexistence with pyrite. These observations indicate that the illites were formed in a slow cooling system (>250 °C), high fS2, and a relatively acidic environment. The pseudomorphic replacement combined with matrix-filling texture indicates that the illites at the site-1 alteration zone recorded the changes in fluid conditions from low to high water-rock ratio. In contrast, the illites at the site-2 alteration zone show the coexistence of polytypes (2M1, 1M, and 1Md), high-K illites [(K0.83 per O10(OH)2]/low-K illites [K0.63 per O10(OH)2], platy/hairy shapes, and presence of magnetite. Furthermore, this alteration zone no longer exhibits primary textures because of pervasive alteration induced by the dissolution-precipitation process. These results indicate that they were formed in a rapid cooling system and were continuously under conditions of high water-rock ratio, as well as in a less acidic and fS2 environment than that observed at the site-1 alteration zone. The behavior of trace elements for each illite primarily depends on the constituents of the hydrothermal fluid, which reflect different degrees of fluid evolution. The enrichment of high field strength elements (Nb and Ta), large ion lithophile elements (B, Be, and Cs), rare earth elements, and actinide elements (U and Th) in illite at the site-2 alteration zone shows that these elements formed by a more evolved fluid than that of the illite at the site-1 alteration zone. In addition, negative Ce anomalies at the site-2 alteration zone indicate that these crystallized in a reducing environment. Considering the mineralogical and geochemical properties of illites at the site-1 and site-2 alteration zones, the illite mineralization in the Hoam granite was likely generated by at least two episodes of hydrothermal illite mineralization, which originated from episodic injections of fluids, rather than continuously evolved fluids.