Diffuse Uptake of 68Ga-Pentixafor in the Breasts During the Ovulatory Phase in a Patient With SAPHO Syndrome.

ABSTRACT: We report a case of a woman with SAPHO syndrome who exhibited increased tracer uptake in the sternal angle on a 99mTc-MDP bone scan. This patient was enrolled in a 68Ga-pentixafor PET/CT trial for inflammatory diseases. The PET/CT showed no abnormal tracer uptake in the sternal angle. Unexpectedly, diffuse uptake of 68Ga-pentixafor was observed in both breasts, which might be due to hormonal stimulation because the woman underwent the 68Ga-pentixafor PET/CT scan during the ovulatory phase.

Mechanisms of Berberine in anti-pancreatic ductal adenocarcinoma revealed by integrated multi-omics profiling.

This study integrates pharmacology databases with bulk RNA-seq and scRNA-seq to reveal the latent anti-PDAC capacities of BBR. Target genes of BBR were sifted through TargetNet, CTD, SwissTargetPrediction, and Binding Database. Based on the GSE183795 dataset, DEG analysis, GSEA, and WGCNA were sequentially run to build a disease network. Through sub-network filtration acquired PDAC-related hub genes. A PPI network was established using the shared genes. Degree algorithm from cytoHubba screened the key cluster in the network. Analysis of differential mRNA expression and ROC curves gauged the diagnostic performance of clustered genes. CYBERSORT uncovered the potential role of the key cluster on PDAC immunomodulation. ScRNA-seq analysis evaluated the distribution and expression profile of the key cluster at the single-cell level, assessing enrichment within annotated cell subpopulations to delineate the target distribution of BBR in PDAC. We identified 425 drug target genes and 771 disease target genes, using 57 intersecting genes to construct the PPI network. CytoHubba anchored the top 10 highest contributing genes to be the key cluster. mRNA expression levels and ROC curves confirmed that these genes showed good robustness for PDAC. CYBERSORT revealed that the key cluster influenced immune pathways predominantly associated with Macrophages M0, CD8 T cells, and naïve B cells. ScRNA-seq analysis clarified that BBR mainly acted on epithelial cells and macrophages in PDAC tissues. BBR potentially targets CDK1, CCNB1, CTNNB1, CDK2, TOP2A, MCM2, RUNX2, MYC, PLK1, and AURKA to exert therapeutic effects on PDAC. The mechanisms of action appear to significantly involve macrophage polarization-related immunological responses.

Cesarean hysterectomy in pregnancies complicated with placenta previa accreta: a retrospective hospital-based study.

BACKGROUND: Placenta previa accreta (PPA) is a severe obstetric condition that can cause massive postpartum hemorrhage and transfusion. Cesarean hysterectomy is necessary in some severe cases of PPA to stop the life-threatening bleeding, but cesarean hysterectomy can be associated with significant surgical blood loss and major complications. The current study is conducted to investigate the potential risk factors of excessive blood loss during cesarean hysterectomy in women with PPA. METHODS: This is a retrospective study including singleton pregnancies after 28 weeks of gestation in women with placenta previa and pathologically confirmed placenta accreta spectrum who received hysterectomy during cesarean sections. A total of 199 women from January 2012 to August 2023 were included in this study and were divided into Group 1 (estimated surgical blood loss (EBL) ≤ 3500 mL, n = 103) and Group 2 (EBL > 3500 mL, n = 96). The primary outcome was defined as an EBL over 3500 mL. Baseline characteristics and surgical outcomes were compared between the two groups. A multivariate logistic regression model was applied to find potential risk factors of the primary outcome. RESULTS: Massive surgical blood loss was prevalent in our study group, with a median EBL of 3500 mL. The multivariate logistic analysis showed that emergency surgery (OR 2.18, 95% CI 1.08-4.41, p = 0.029), cervical invasion of the placenta (OR 2.70, 95% CI 1.43-5.10, p = 0.002), and intraoperative bladder injury (OR 5.18, 95% CI 2.02-13.28, p = 0.001) were all associated with the primary outcome. Bilateral internal iliac arteries balloon occlusion (OR 0.57, 95% CI 0.34-0.97) and abdominal aortic balloon occlusion (OR 0.33, 95% CI 0.19-0.56) were negatively associated with the primary outcome. CONCLUSIONS: Emergency surgery, cervical invasion of the placenta, and intraoperative bladder injury were potential risk factors for additional EBL during cesarean hysterectomy in women with PPA. Future prospective studies are needed to confirm the effect of intra-arterial balloon occlusion in cesarean hysterectomy of PPA.

Quality diversity of three calcium-rich Primulina vegetables: A comprehensive analysis of calcium content, metabolite profiles, taste characteristics, and medicinal potential.

Primulina plants native to karst regions are exceptionally rich in calcium and have been developed into high­calcium leafy vegetables. However, limited knowledge of their metabolites, taste characteristics, and potential medicinal value restricts further genetic improvements. This study conducted a comprehensive analysis on three breeding species of Primulina vegetables. Common garden experiment demonstrated significant calcium enrichment capability, with calcium content ranging from 204.45 to 391.52 mg/100 g. Through widely-targeted metabolomics, 1121 metabolites were identified within these Primulina vegetables. Furthermore, comparative analysis identified 976 differentially accumulated metabolites across nine comparison groups, driven mainly by flavonoids, phenolic acids, and lipids. Integration of electronic tongue analysis and metabolomics revealed taste profiles and identified 17 key candidate compounds related to taste. Based on network pharmacology analysis, 32 active ingredients were found in Primulina vegetables, which highlighted potential medicinal value. These findings provide a data-driven foundation for breeding programs aimed at enhancing nutritional and flavor traits.

HDAC inhibitor SAHA enhances antitumor immunity via the HDAC1/JAK1/FGL1 axis in lung adenocarcinoma.

BACKGROUND: Histone deacetylase (HDAC), a kind of protease that regulates gene expression by modifying protein acetylation levels, is usually aberrantly activated in tumors. The approved pan-HDAC inhibitors (HDACi) have exhibited clinical benefits for hematopoietic malignancies. Recently, HDACis have emerged as enhancers of antitumor immunity. However, the effect of HDACs on the tumor immune microenvironment of lung adenocarcinoma (LUAD) and the underlying mechanism is largely unknown. METHODS: C57BL/6J and BALB/c nude mice with subcutaneous tumors were used for in vivo therapeutic effects and mechanistic investigations. Flow cytometry was used to measure the toxicity and exhaustion of human CD8+T cells after co-culturing with tumor cells and to determine the immunophenotype of tumor-infiltrating CD8+T cells. A series of experimental techniques, including RNA sequencing, quantitative PCR, western blot, ELISA, mass spectrometry, co-immunoprecipitation, chromatin immunoprecipitation and immunohistochemistry, were used to explore the underlying molecular mechanism. RESULTS: The pan-HDACi vorinostat (SAHA) promoted CD8+T cell infiltration and effector function in LUAD through suppressing FGL1, a newly identified major ligand of LAG-3. Mechanistically, SAHA inhibited the activity of HDAC1, an essential deacetylase of JAK1. This increased the acetylation level of JAK1 at lysine 1109, thus promoting its proteasomal degradation and subsequently reducing STAT3-driven FGL1 transcription. The combination regimen of SAHA and anti-LAG-3 therapy was further explored in an immunocompetent LUAD mouse model. Compared with those receiving control or single agent treatments, mice receiving combination therapy exhibited a lower tumor burden and superior CD8+T-cell-killing activity. CONCLUSIONS: Our results revealed a novel mechanism by which the HDACi SAHA potentiates CD8+T-cell-mediated antitumor activity through the HDAC1/JAK1/FGL1 axis, providing a rationale for the combined use of HDACis and immunotherapy.

Ninth Version of the AJCC and UICC Nasopharyngeal Cancer TNM Staging Classification.

Importance: Accurate staging is a fundamental step in treating patients with nasopharyngeal carcinoma (NPC) worldwide; this is crucial not only for prognostication, but also for guiding treatment decisions. The American Joint Committee on Cancer (AJCC)/Union for International Cancer Control (UICC) tumor-node-metastasis (TNM) system is the global language for clinicians, researchers, and cancer registries. Continual improvement that aligns with contemporary pattern of care is essential. Objective: To improve the prognostic accuracy and clinical applicability of the eighth edition (TNM-8) for NPC. Design, Setting, and Participants: This multicenter study analyzed patients with NPC with detailed tumor features during January 2014 and December 2015 and was reviewed by experienced radiologists. The data analysis was completed in December 2023. The findings were further confirmed with internal and external validation. Statistical analyses and clinical considerations were reviewed by the AJCC/UICC multidisciplinary head and neck panels and attained consensus. The recommendations were evaluated by the AJCC Evidence-Based Medicine Committee before final endorsement as the ninth version (TNM-9). Main Outcomes and Measures: The primary end point was overall survival. Adjusted hazard ratios of different subgroups were then assessed for confirmation of optimal stage grouping. Results: Of the 4914 patients analyzed, 1264 (25.7%) were female and 3650 (74.3%) were male; the median (SD) age was 48.1 (12.0) years. Advanced radiological extranodal extension (with involvement of adjacent muscles, skin, and/or neurovascular bundles) was identified as an independent adverse factor for all end points: this was added as a criterion for N3. Patients with nonmetastatic disease were regrouped into stages I to III instead of TNM-8 stages I to IVA. Significant hazard discrimination was achieved by grouping T1-2N0-1 as stage I, T3/N2 as stage II, and T4/N3 as stage III. Although the T1-2N0-1 subgroups had comparable 5-year overall survival, subdivisions into IA (T1-T2N0) and IB (T1-T2N1) were recommended due to the distinction in adjusted hazard ratios following adjustment for chemotherapy use. Metastatic disease was exclusively classified as stage IV, and prognostication was further refined by subdivision into IVA (M1a, ≤3 lesions) and IVB (M1b, >3 lesions). TNM-9 demonstrated superiority compared with TNM-8 in major statistical aspects. Conclusion and Relevance: The results of this diagnostic study suggest that the ninth version of TNM staging for NPC, based on robust analyses and a comprehensive review by the AJCC/UICC staging committees, provides an improved staging system for global application and a framework for future incorporation of nonanatomical factors. This will be launched for global application in January 2025.

Efficacy of Shugan Hewei formula combined with rabeprazole in refractory gastroesophageal reflux disease: randomized, double-blind, placebo-controlled trial.

OBJECTIVES: To assess the efficacy of the Chinese herbal medication Shugan Hewei formula (SHF) combined with rabeprazole in patients with refractory gastroesophageal reflux disease (rGERD). METHOD: A total of 264 participants were randomly assigned to the treatment group (n = 132) receiving SHF granules (20 mg) combined with rabeprazole (10 mg) and the control group (n = 132) receiving placebo SHF granules (20 mg) combined with rabeprazole (20 mg). Both groups undergo 8 weeks of treatment and 2 weeks of follow-up. RESULTS: The treatment group showed higher total clinical symptom efficacy and lower total symptom scores compared to the control group. The treatment group was superior to the control group in reducing rGERD major symptom scores, including heartburn, retrosternal pain, regurgitation and belching, and acid regurgitation. Additionally, treatment group (Z = 8.169, P < 0.001) and control group (Z = 9.800, P < 0.001) treatments were all significantly attenuated esophageal inflammation, demonstrating comparable efficacy. Patients with esophagitis grade A decreased from 40.34% to 17.23%, and those with grade B decreased from 11.76% to 3.78% in the treatment group. The results of the SF-36 scale showed that combination therapy was more effective in improving role limitations due to physical health, vitality, general health, total somato-physical health, and psychiatric mental health. CONCLUSION: Our study reveals that the combined treatment of SHF with rabeprazole is more efficacious in managing patients with rGERD when contrasted with sole rabeprazole treatment.

Case Report: Misdiagnosis of a lipofibromatosis-like neural tumor of the dorsal skin as dermatofibrosarcoma protuberans.

Background: Lipofibromatosis-like neural tumors (LPF-NT), which have only recently been established, are intermediate soft tissue tumors with neurotrophic tropomyosin receptor kinase 1 (NTRK1) gene alterations and are typically misdiagnosed as dermatofibrosarcoma protuberans, low-grade malignant peripheral nerve sheath tumors, or spindle cell lipoma due to their histopathological and immunohistochemical expression of CD34 and S-100. Case presentation: The patient was admitted to our hospital with a painless back mass that had appeared more than 4 years prior to admission. Physical examination revealed a subcutaneous mass on the back, approximately 1.5 cm in diameter and protruding into the skin, with clear boundaries and no tenderness. The tumor was surgically resected. The postoperative pathological results suggested a spindle cell soft tissue tumor, and dermatofibrosarcoma protuberan was initially considered. After consultation at a provincial hospital, the patient was diagnosed with a cutaneous lipofibromatosis-like neural tumor of the back. A second extended resection was then performed. Intraoperative rapid freezing examination revealed negative incision margins. Conclusion: Histological and immunohistochemical detections aid in the differential diagnosis of LPF-NTs. Complete surgical resection is the preferred treatment for LPF-NTs.

Tissue Kallikrein supplementation in ischemic phase protects the neurovascular unit and attenuates reperfusion-induced injury in ischemic stroke.

Tissue kallikrein (TK) has emerged as a potential neuroprotective agent in ischemic stroke (IS), yet the optimal timing and mechanisms of TK therapy remain unclear. Here, we established a causal link between lower baseline TK levels and an increased risk of stroke through a retrospective, multicenter cohort study involving 2115 initially non-stroke subjects monitored for 5 years. Sequentially, we observed a notable increase in bradykinin receptor 2 (B2R) levels during the ischemic phase of the IS model, while levels of TK and bradykinin receptor 1 (B1R) remained stable. Intriguingly, both B1R and B2R exhibited a significant elevation 24 h after reperfusion. Further investigations in preclinical models demonstrated that TK supplementation activates the PI3K/AKT signaling pathway via enhanced B2R expression during the ischemic phase, leading to nuclear translocation of Hif-1α. This activation enhances the expression of VEGF and eNOS, thereby fortifying the neurovascular unit. Moreover, it suppresses the activation of the kallikrein-kinin system induced by reperfusion injury, effectively reducing inflammation, ROS production, apoptosis, and endothelial barrier dysfunction. Thus, our findings highlight the significance of TK supplementation during the ischemic phase in attenuating reperfusion-induced injury in IS, providing a mechanistic rationale for determining the optimal timing for TK supplementation therapy.

Unraveling the toxicity mechanisms of nanoplastics with various surface modifications on Skeletonema costatum: Cellular and molecular perspectives.

Nanoplastics are ubiquitous in marine environments, exhibiting high bioavailability and potential toxicity to marine organisms. However, the impacts of nanoplastics with various surface modifications on marine microalgae remain largely unexplored. This study explored the toxicity mechanisms of two nanoplastic types-polystyrene (PS) and polymethyl methacrylate (PMMA)-with distinct surface modifications on Skeletonema costatum at cellular and molecular levels. Results showed that nanoplastics significantly impaired the growth of microalgae, particularly PS-NH2, which caused the most pronounced growth inhibition, reaching 56.99 % after a 96-h exposure at 50 mg/L. Transcriptomic profiling revealed that nanoplastics disrupted the expression of genes predominantly involved in ribosome biogenesis, aminoacyl-tRNA biosynthesis, amino acid metabolism, and carbohydrate metabolism pathways. The integrated biochemical and transcriptomic evidence highlighted that PS-NH2 nanoplastics had the most adverse impact on microalgae, affecting fundamental pathways such as ribosome biogenesis, energy metabolism, photosynthesis, and oxidative stress. Our findings underscore the influence of surface-modified nanoplastics on algal growth and contribute new understanding to the toxicity mechanisms of these nanoplastics in marine microalgae, offering critical information for assessing the risks of emerging pollutants.

Interpretative structural modeling method: An analysis of influencing factors analysis on the adverse experiences of cardiac surgery patients in the intensive care units.

Objective: To construct an interpretation structure model of adverse experiences of cardiac surgery patients in intensive care unit, so as to provide a reference for optimizing the experience of critical patients step by step. Methods: Literature review, semi-structured interviews, questionnaires and Delphi method were used to summarize and analyze the influencing factors of intensive care experience in cardiac surgery. The explanatory structural model was used to divide the influencing factors into levels and construct the explanatory structural model of adverse experience of cardiac surgery patients in intensive care. Results: A hierarchical structure model containing 34 elements and 15 levels was constructed, which were divided into Surface level, middle level and root level. Conclusion: The intensive care experience of patients in cardiac surgery department is mainly affected by 34 factors. There are direct or indirect correlations between the influencing factors, and different levels have different effects.

Alectinib Versus Crizotinib in Asian Patients With Treatment-Naïve Advanced ALK-Positive NSCLC: Five-Year Update From the Phase 3 ALESIA Study.

Introduction: Previous results from the phase 3 ALESIA study (NCT02838420) revealed that alectinib (a central nervous system [CNS]-active, ALK inhibitor) had clinical benefits in treatment-naïve Asian patients with advanced ALK-positive NSCLC, consistent with the global ALEX study. We present updated data after more than or equal to 5 years of follow-up from the "last patient in" date. Methods: Adult patients with treatment-naïve, advanced ALK-positive NSCLC from mainland China, South Korea, and Thailand were randomized 2:1 to receive twice-daily 600 mg alectinib (n = 125) or 250 mg crizotinib (n = 62). The primary endpoint was investigator-assessed progression-free survival. Secondary or exploratory endpoints included overall survival, objective response rate, time to CNS progression, and safety. Results: At the data cutoff (May 16, 2022), the median survival follow-up was 61 and 51 months in the alectinib and crizotinib arms, respectively. Median progression-free survival was 41.6 months with alectinib versus 11.1 months with crizotinib (stratified hazard ratio = 0.33, 95% confidence interval: 0.23-0.49). Overall survival data remain immature; 5-year overall survival rates were 66.4% (alectinib arm) versus 56.1% (crizotinib arm). Objective response rate was 91.2% versus 77.4% with alectinib and crizotinib, respectively. CNS progression was delayed with alectinib versus crizotinib (cause-specific hazard ratio = 0.16, 95% confidence interval: 0.08-0.32). Median treatment duration was longer with alectinib versus crizotinib (42.3 versus 12.6 mo). No new safety signals were observed. Conclusions: With four additional years of follow-up, these updated results confirm the clinical benefit and manageable safety of alectinib in Asian patients with advanced ALK-positive NSCLC, and confirm alectinib as a standard-of-care treatment for patients with advanced ALK-positive NSCLC.

Integrating NiSe2-MoSe2 heterojunctions with N-doped porous carbon substrate architecture for an enhanced electrocatalytic water splitting device.

The development of sustainable energy technologies relies on the exploitation of efficient and durable electrocatalysts for water splitting at high current densities. Our work presents a novel bifunctional catalyst, denoted as NM@NC/CC, which combines the benefits of NiSe2-MoSe2 heterojunctions with nitrogen-enriched porous carbon derived from metal-organic frameworks (MOFs). The integration of these components is designed to harness their combined advantages, which include enhanced electron transfer, improved mass and gas evolution dynamics, and an increased number of catalytically active sites. These features collectively optimize the energetics for both the hydrogen evolution reaction (HER) and oxygen evolution reaction (OER). As a result, the catalyst facilitates rapid kinetics for the overall water-splitting process. The NM@NC/CC demonstrates low overpotentials, requiring only 91 mV for the HER and 280 mV for the OER to reach a current density of 10 mA cm-2. Even at higher current densities of 100 mA cm-2 for HER and 50 mA cm-2 for OER, the overpotentials are only 159 mV and 350 mV, respectively. Additionally, a two-electrode setup using this catalyst achieves a current density of 10 mA cm-2 with a minimal cell voltage of 1.56 V. The insights gained from this study will contribute to the advancement of electrocatalysts for energy conversion technologies.

Properties of Skin Collagen from Southern Catfish (Silurus meridionalis) Fed with Raw and Cooked Food.

The southern catfish (Silurus meridionalis) is an economically important carnivorous freshwater fish in China. In this study, we compared the properties of skin collagen from southern catfish fed with raw food (RF) and cooked food (CF). The skin collagen yield in the RF group (8.66 ± 0.11%) was significantly higher than that of the CF group (8.00 ± 0.27%). SDS-PAGE, circular dichroism spectroscopy, and FTIR analyses revealed that the collagen extracted from southern catfish skin in both groups was type I collagen, with a unique triple helix structure and high purity. The thermal denaturation temperature of collagen in the RF group (35.20 ± 0.11 °C) was significantly higher than that of the CF group (34.51 ± 0.25 °C). The DPPH free radical scavenging rates were 68.30 ± 2.41% in the RF collagen and 61.78 ± 3.91% in the CF collagen, which was higher than that found in most fish collagen. Both the RF and CF groups had high ability to form fibrils in vitro. Under the same conditions, the CF group exhibited faster fibril formation and a thicker fibril diameter (p < 0.05). In addition, the RF group exhibited significantly higher expression of col1a1 compared to the CF group. These results indicated that feeding southern catfish raw food contributed to collagen production, and the collagen from these fish may have potential in biomaterial applications.

MR radiomics unveils neoadjuvant chemo-responsiveness with insights into selective treatment de-intensification in HPV-positive oropharyngeal carcinoma.

BACKGROUND: Accurate prediction of neoadjuvant chemotherapy (NAC) response allows for NAC-guided personalized treatment de-intensification in HPV-positive oropharyngeal squamous cell carcinoma (OPSCC). In this study, we aimed to apply baseline MR radiomic features to predict NAC response to help select NAC-guided de-intensification candidates, and to explore biological underpinnings of response-oriented radiomics. METHODS: Pre-treatment MR images and clinical data of 131 patients with HPV-positive OPSCC were retrieved from Fudan University Shanghai Cancer Center. Patients were divided into training cohort (n = 47), validation cohort 1 (n = 49) from NAC response-adapted de-intensification trial (IChoice-01, NCT04012502) and real-world validation cohort 2 (n = 35). NAC prediction model using linear support vector machine (SVM) was built and validated. Subsequent nomograms combined radiomics and clinical characteristics were established to predict survival outcomes. RNA-seq and proteomic data were compared to interpret the molecular features underlying radiomic signatures with differential NAC response. FINDINGS: For NAC response prediction, the fusion model with both oropharyngeal and nodal signatures achieved encouraging performance to predict good responders in the training cohort (AUC 0·89, 95% CI, 0·79-0·95) and validation cohort 1 (AUC 0·71, 95% CI, 0·59-0·83). For prognosis prediction, radiomics-based nomograms exhibited satisfactory discriminative ability between low-risk and high-risk patients (PFS, C-index 0·85, 0·76 and 0·83; OS, C-index 0·79, 0·76 and 0·87, respectively) in three cohorts. Expression analysis unveiled NAC poor responders had predominantly enhanced keratinization while good responders were featured by upregulated immune response and oxidative stress. INTERPRETATION: The MR-based radiomic models and prognostic models efficiently discriminate among patients with different NAC response and survival risk, which help candidate selection in HPV-positive OPSCC with regard to personalized treatment de-intensification.

Anti-infective properties of mung bean (Vigna radiata (L.)R. Wilczek) coat extract on Pseudomonas aeruginosa-infected Caenorhabditis elegans: Transcriptomics and pathway analysis.

ETHNOPHARMACOLOGICAL RELEVANCE: Mung bean coat has long been known for its wide-ranging health benefits, including antibacterial, anti-inflammatory, and immune-modulatory properties. For many years in China, mung beans have been employed in the therapeutic management of inflammation induced by pathogenic bacteria infection, yet the precise underlying protective mechanisms remain to be comprehensively elucidated. AIM OF THE STUDY: Given the growing concern over antibiotic resistance, there is a necessity to explore new anti-infective agents. Here, the anti-infective properties of Mung bean coat extract (MBCE) were investigated using a model of Pseudomonas aeruginosa-infected nematodes. MATERIALS AND METHODS: The protective effects of MBCE on Pseudomonas aeruginosa (PA14) infected nematodes were assessed by lifespan assay, reactive oxygen species (ROS) levels, transcriptomics, and Quantitative real-time PCR (qRT-PCR). RESULTS: MBCE significantly improved the survival rates and reduced ROS levels in infected worms. Transcriptomic profiling disclosed predominant KEGG pathway enrichments in immune responses, energy metabolism processes such as oxidative phosphorylation and the tricarboxylic acid cycle, alongside aging-related neurodegenerative diseases and longevity regulatory pathways like PI3K-AKT, MAPK, mTOR, and FOXO. qRT-PCR validation showed that MBCE upregulated antimicrobial peptides (spp-3, lys-1, lys-7, abf-2, cnc-2, nlp-33, clec-85), gram-negative responses (irg-3, src-2, grd-3, col-179), and mitochondrial function (mev-1) gene expressions, while downregulated insulin signaling-related (age-1, akt-1, akt-2, daf-15) gene expressions. Mutant strains lifespan analysis indicated that the nsy-1, sek-1, pmk-1, daf-2, aak-2, sir-2.1, and skn-1 were necessary for lifespan extension mediated by MBCE under PA14 infection, but not clk-1, isp-1, mev-1, or daf-16. CONCLUSION: Collectively, our findings suggested that MBCE increased the survival rates of PA14-infected worms by activating downstream antimicrobial and antioxidant gene expressions through modulation of MAPK, daf-2, aak-2, sir-2.1, and skn-1 pathways. The research underscored the potential of natural plant compounds to strengthen the body's defenses against infections, potentially mitigating harmful ROS levels and improving survival. Additionally, these findings elucidated the mechanisms by which these plant-derived compounds enhance the immune system, implying their potential utility as dietary supplements or as an alternative to conventional antibiotics.

A comprehensive dataset for digital restoration of Dunhuang murals.

The MuralDH dataset is an invaluable digital resource developed for the conservation and restoration of Dunhuang murals, which are critical components of global cultural heritage facing threats from degradation. This dataset comprises over 5000 high-resolution images tailored to 512 × 512 pixels, emphasizing the preservation of mural integrity and detail. It includes 1000 images with pixel-level damage annotations for segmentation research and 500 images specially processed for super-resolution studies, catering to a wide range of digital restoration needs. While the primary focus of this work is the dataset itself, we also introduce a supportive digital restoration framework. This framework, which encompasses damage segmentation, inpainting, and super-resolution techniques, serves as a secondary validation of MuralDH's utility and versatility. Through MuralDH, technology revives ancient art, embodying the essence of interdisciplinary innovation. By facilitating advanced research in computer vision and artificial intelligence, MuralDH aims to revolutionize the digital preservation practices for murals and other cultural artifacts, demonstrating the critical role of interdisciplinary collaboration in safeguarding our cultural legacy.

Open-Source Throttling of CD8+ T Cells in Brain with Low-Intensity Focused Ultrasound-Guided Sequential Delivery of CXCL10, IL-2, and aPD-L1 for Glioblastoma Immunotherapy.

Improving clinical immunotherapy for glioblastoma (GBM) relies on addressing the immunosuppressive tumor microenvironment (TME). Enhancing CD8+ T cell infiltration and preventing its exhaustion holds promise for effective GBM immunotherapy. Here, a low-intensity focused ultrasound (LIFU)-guided sequential delivery strategy is developed to enhance CD8+ T cells infiltration and activity in the GBM region. The sequential delivery of CXC chemokine ligand 10 (CXCL10) to recruit CD8+ T cells and interleukin-2 (IL-2) to reduce their exhaustion is termed an "open-source throttling" strategy. Consequently, up to 3.39-fold of CD8+ T cells are observed with LIFU-guided sequential delivery of CXCL10, IL-2, and anti-programmed cell death 1 ligand 1 (aPD-L1), compared to the free aPD-L1 group. The immune checkpoint inhibitors (ICIs) therapeutic efficacy is substantially enhanced by the reversed immunosuppressive TME due to the expansion of CD8+ T cells, resulting in the elimination of tumor, prolonged survival time, and long-term immune memory establishment in orthotopic GBM mice. Overall, LIFU-guided sequential cytokine and ICIs delivery offers an "open-source throttling" strategy of CD8+ T cells, which may present a promising strategy for brain-tumor immunotherapy.

Novel potent molecular glue degraders against broad range of hematological cancer cell lines via multiple neosubstrates degradation.

BACKGROUND: Targeted protein degradation of neosubstrates plays a crucial role in hematological cancer treatment involving immunomodulatory imide drugs (IMiDs) therapy. Nevertheless, the persistence of inevitable drug resistance and hematological toxicities represents a significant obstacle to their clinical effectiveness. METHODS: Phenotypic profiling of a small molecule compounds library in multiple hematological cancer cell lines was conducted to screen for hit degraders. Molecular dynamic-based rational design and cell-based functional assays were conducted to develop more potent degraders. Multiple myeloma (MM) tumor xenograft models were employed to investigate the antitumor efficacy of the degraders as single or combined agents with standard of care agents. Unbiased proteomics was employed to identify multiple therapeutically relevant neosubstrates targeted by the degraders. MM patient-derived cell lines (PDCs) and a panel of solid cancer cell lines were utilized to investigate the effects of candidate degrader on different stage of MM cells and solid malignancies. Unbiased proteomics of IMiDs-resistant MM cells, cell-based functional assays and RT-PCR analysis of clinical MM specimens were utilized to explore the role of BRD9 associated with IMiDs resistance and MM progression. RESULTS: We identified a novel cereblon (CRBN)-dependent lead degrader with phthalazinone scaffold, MGD-4, which induced the degradation of Ikaros proteins. We further developed a novel potent candidate, MGD-28, significantly inhibited the growth of hematological cancer cells and induced the degradation of IKZF1/2/3 and CK1α with nanomolar potency via a Cullin-CRBN dependent pathway. Oral administration of MGD-4 and MGD-28 effectively inhibited MM tumor growth and exhibited significant synergistic effects with standard of care agents. MGD-28 exhibited preferentially profound cytotoxicity towards MM PDCs at different disease stages and broad antiproliferative activity in multiple solid malignancies. BRD9 modulated IMiDs resistance, and the expression of BRD9 was significant positively correlated with IKZF1/2/3 and CK1α in MM specimens at different stages. We also observed pronounced synergetic efficacy between the BRD9 inhibitor and MGD-28 for MM treatment. CONCLUSIONS: Our findings present a strategy for the multi-targeted degradation of Ikaros proteins and CK1α against hematological cancers, which may be expanded to additional targets and indications. This strategy may enhance efficacy treatment against multiple hematological cancers and solid tumors.

Phage-antibiotic synergy suppresses resistance emergence of Klebsiella pneumoniae by altering the evolutionary fitness.

Phage-antibiotic synergy (PAS) represents a superior treatment strategy for pathogen infections with less probability of resistance development. Here, we aim to understand the molecular mechanism by which PAS suppresses resistance in terms of population evolution. A novel hypervirulent Klebsiella pneumoniae (KP) phage H5 was genetically and structurally characterized. The combination of H5 and ceftazidime (CAZ) showed a robust synergistic effect in suppressing resistance emergence. Single-cell Raman analysis showed that the phage-CAZ combination suppressed bacterial metabolic activities, contrasting with the upregulation observed with phage alone. The altered population evolutionary trajectory was found to be responsible for the contrasting metabolic activities under different selective pressures, resulting in pleiotropic effects. A pre-existing wcaJ point mutation (wcaJG949A) was exclusively selected by H5, conferring a fitness advantage and up-regulated activity of carbohydrate metabolism, but also causing a trade-off between phage resistance and collateral sensitivity to CAZ. The wcaJ point mutation was counter-selected by H5-CAZ, inducing various mutations in galU that imposed evolutionary disadvantages with higher fitness costs, and suppressed carbohydrate metabolic activity. H5 and H5-CAZ treatments resulted in opposite effects on the transcriptional activity of the phosphotransferase system and the ascorbate and aldarate metabolism pathway, suggesting potential targets for phage resistance suppression. Our study reveals a novel mechanism of resistance suppression by PAS, highlighting how the complexity of bacterial adaptation to selective pressures drives treatment outcomes. IMPORTANCE: Phage-antibiotic synergy (PAS) has been recently proposed as a superior strategy for the treatment of multidrug-resistant pathogens to effectively reduce bacterial load and slow down both phage and antibiotic resistance. However, the underlying mechanisms of resistance suppression by PAS have been poorly and rarely been studied. In this study, we tried to understand how PAS suppresses the emergence of resistance using a hypervirulent Klebsiella pneumoniae (KP) strain and a novel phage H5 in combination with ceftazidime (CAZ) as a model. Our study reveals a novel mechanism by which PAS drives altered evolutionary trajectory of bacterial populations, leading to suppressed emergence of resistance. The findings advance our understanding of how PAS suppresses the emergence of resistance, and are imperative for optimizing the efficacy of phage-antibiotic therapy to further improve clinical outcomes.