HiMul-LGG: A hierarchical decision fusion-based local-global graph neural network for multimodal emotion recognition in conversation.

Emotion recognition in conversation (ERC) is a vital task that requires deciphering human emotions through analysis of contextual and multimodal information. However, extant research on ERC concentrates predominantly on investigating multimodal fusion while overlooking the model's constraints in dealing with unimodal representation discrepancy and speaker dependencies. To address the aforementioned problems, this paper proposes a Hierarchical decision fusion-based Local-Global Graph Neural Network for multimodal ERC (HiMul-LGG). HiMul-LGG employs a hierarchical decision fusion strategy to ensure feature alignment across modalities. Moreover, HiMul-LGG also adopts a local-global graph neural network architecture to reinforce inter-modality and intra-modality speaker dependency. Additionally, HiMul-LGG utilizes a cross-modal multi-head attention mechanism to promote interplay between modalities. We evaluate HiMul-LGG on two emotion recognition datasets, IEMOCAP and MELD, where HiMul-LGG outperforms existing methods. The results of the ablation study also imply the effectiveness of the proposed hierarchical decision fusion strategy and local-global structure of Graph construction.

Characterization of undifferentiated carcinomas of the pancreas with and without osteoclast-like giant cells.

BACKGROUND: Undifferentiated carcinoma (UC) is a rare subtype of pancreatic cancer differentiated from UC with osteoclast-like giant cells (UC-OGC) in 2019, impacting interpretation of literature that does not distinguish these subtypes. We sought to identify translationally relevant differences between these two variants and as compared to pancreatic ductal adenocarcinoma (PDAC). METHODS: We characterized clinical and multiomic differences between UC (n = 32) and UC-OGC (n = 15) using DNA-sequencing (seq), RNA-seq, and multiplex immunofluorescence (mIF) and compared these findings to PDAC. RESULTS: Characteristics at diagnosis were similar between UC and UC-OGC, though UC-OGC was more resectable (p = .009). Across all stages, median overall survival (OS) was shorter for UC than UC-OGC (0.4 vs 10.8 years, respectively; p = .003). This shorter survival was retained after stratification by resection, albeit without statistical significance (1.8 vs 11.9 years, respectively; p = .08). In a subset of patients with available tissue, the genomic landscape was similar between UC (n = 9), UC-OGC (n = 5), and PDAC (n = 159). Bulk RNA-seq was deconvoluted and, along with mIF in UC (n = 13), UC-OGC (n = 5), and PDAC (n = 16), demonstrated statistically significantly increased antigen-presenting cells (APCs), including M2 macrophages and NK cells, and decreased cytotoxic and regulatory T cells (Tregs) in UC and UC-OGC vs PDAC. Findings were similar between UC and UC-OGC except decreased Tregs in UC-OGC (p = .04). CONCLUSIONS: In this series, UC is more aggressive than UC-OGC with these variants having more APCs and fewer Tregs than PDAC, suggesting potential for immune-modulating therapies in treatment of these pancreatic cancer subtypes.

Metabolic landscape of the healthy pancreas and pancreatic tumor microenvironment.

Pancreatic cancer, one of the deadliest human malignancies, is characterized by a fibro-inflammatory tumor microenvironment and wide array of metabolic alterations. To comprehensively map metabolism in a cell type-specific manner, we harnessed a unique single-cell RNA-sequencing dataset of normal human pancreata. This was compared with human pancreatic cancer samples using a computational pipeline optimized for this study. In the cancer cells we observed enhanced biosynthetic programs. We identified downregulation of mitochondrial programs in several immune populations, relative to their normal counterparts in healthy pancreas. Although granulocytes, B cells, and CD8+ T cells all downregulated oxidative phosphorylation, the mechanisms by which this occurred were cell type specific. In fact, the expression pattern of the electron transport chain complexes was sufficient to identify immune cell types without the use of lineage markers. We also observed changes in tumor-associated macrophage (TAM) lipid metabolism, with increased expression of enzymes mediating unsaturated fatty acid synthesis and upregulation in cholesterol export. Concurrently, cancer cells exhibited upregulation of lipid/cholesterol receptor import. We thus identified a potential crosstalk whereby TAMs provide cholesterol to cancer cells. We suggest that this may be a new mechanism boosting cancer cell growth and a therapeutic target in the future.

Sensory processing sensitivity and compassion fatigue in intensive care unit nurses: A chain mediation model.

BACKGROUND: Compassion among intensive care unit (ICU) nurses is an essential component of humanistic care in the ICU However, the enormous pressures of the job and the lack of social support have led to persistently severe compassion fatigue. Sensory processing sensitivity, as a personality trait for individuals to perceive external factors, has underlying significance for compassion fatigue. AIMS: This study aims to investigate the internal and external environmental factors and the underlying mechanisms that influence the impact of sensory processing sensitivity among ICU nurses on the development of compassion fatigue. STUDY DESIGN: A cross-sectional descriptive study was conducted with 290 nurses from various hospitals in five cities in China. METHOD: A self-designed demographic questionnaire, the Chinese version of the Professional Quality of Life Scale, the Chinese version of the Highly Sensitive Person Scale, the Chinese version of the Perceived Social Support Scale, and the Chinese version of the Perceived Stress Scale were used to survey 290 ICU nurses. The mediating roles of perceived social support and perceived stress between sensory processing sensitivity and compassion fatigue were tested. RESULTS: The research results indicate that the total effect of sensory processing sensitivity on compassion fatigue is significant (0.245 [0.093, 1.160]), whereas the direct effect of sensory processing sensitivity on compassion fatigue is not significant (-0.43 [-0.402, 0.247]). Perceived social support and perceived stress exhibit serial mediating effects between sensory processing sensitivity and compassion fatigue (-0.065 [-0.142, -0.013]). CONCLUSION: Our results revealed, for the first time, the underlying mechanism between sensory processing sensitivity and compassion fatigue among ICU nurses. Providing necessary stress-relief condition and abundant social support are important measures for nursing managers to reduce compassion fatigue and improve the quality of critical care humanistic nursing services.

Targeted therapies and conventional care for the treatment of ankylosing spondylitis in China: a cost-effectiveness analysis based on the network-meta analysis.

OBJECTIVE: This study aimed to evaluate the long-term cost-effectiveness of conventional care (CC) and seven first-line targeted therapies marketed in China for the treatment of patients with ankylosing spondylitis (AS)-namely secukinumab, ixekizumab, infliximab, etanercept, adalimumab and golimumab and tofacitinib-from the perspective of the Chinese health care system. METHODS: The York model was structured as a 12-week decision tree leading into two Markov models. This study set 1 year as a recurring cycle and a lifetime timeframe for the model. Primary model outcomes included the costs in Chinese yuan (CNY), health outcomes in quality-adjusted life-years (QALYs) and the incremental cost-effectiveness ratio (ICER) under a willingness-to-pay threshold of ¥89,358 (equal to the per capita gross domestic product in China in 2023) per QALY. Parameters in the York model were captured from network meta-analyses and literature including treatment response, short-term disease progression, patient functioning and long-term structural disease progression. Utilities are dependent on indicators such as the BASDAI score, the BASFI score, gender and age. Drug prices were analysed using the median price of the Chinese market from YAOZH net in the basic analysis. Costs and outcomes were discounted at 5.0%. We performed deterministic and probabilistic sensitivity analyses to investigate the robustness of the results. The prices of original drugs and generic drugs were used in the scenario analysis. RESULTS: Compared with CC, the ICER of golimumab was ¥104,217.4/QALY, which is between 1 and 3 times the GDP per capita, while the ICERs of the other six targeted therapies were less than ¥89,358/QALY. The specific economic rank of the targeted therapy was as follows: secukinumab > ixekizumab > tofacitinib > infliximab > etanercept > adalimumab > golimumab. Treatment response rates such as the BASDAI50, changes in the BASDAI/BASFI scores and the discounting rate were key model drivers. According to the scenario analysis, IL-17 inhibitors were still the most economical intervention when original drugs and generic drugs were used. CONCLUSION: Targeted therapies are cost-effective treatments for AS. Overall, IL-17 inhibitors were the dominant treatment. The choice of the brand-new prices or generic drug prices can greatly affect economics.

Oncogenic KRAS-Dependent Stromal Interleukin-33 Directs the Pancreatic Microenvironment to Promote Tumor Growth.

Pancreatic cancer is characterized by an extensive fibroinflammatory microenvironment. During carcinogenesis, normal stromal cells are converted to cytokine-high cancer-associated fibroblasts (CAF). The mechanisms underlying this conversion, including the regulation and function of fibroblast-derived cytokines, are poorly understood. Thus, efforts to therapeutically target CAFs have so far failed. Herein, we show that signals from epithelial cells expressing oncogenic KRAS-a hallmark pancreatic cancer mutation-activate fibroblast autocrine signaling, which drives the expression of the cytokine IL33. Stromal IL33 expression remains high and dependent on epithelial KRAS throughout carcinogenesis; in turn, environmental stress induces interleukin-33 (IL33) secretion. Using compartment-specific IL33 knockout mice, we observed that lack of stromal IL33 leads to profound reprogramming of multiple components of the pancreatic tumor microenvironment, including CAFs, myeloid cells, and lymphocytes. Notably, loss of stromal IL33 leads to an increase in CD8+ T-cell infiltration and activation and, ultimately, reduced tumor growth. Significance: This study provides new insights into the mechanisms underlying the programming of CAFs and shows that during this process, expression of the cytokine IL33 is induced. CAF-derived IL33 has pleiotropic effects on the tumor microenvironment, supporting its potential as a therapeutic target.

Identification of symptom clusters and change trajectories in patients with acute exacerbation of chronic obstructive pulmonary disease.

Aim and objectives: This study aimed to identify symptom cluster (SC) patterns and change trajectories in patients with acute exacerbation of chronic obstructive pulmonary disease (AECOPD), the correlation of the SCs with laboratory and imaging indicators, and the intrinsic association of the SCs with prognostic outcomes and disease burden. Method: Symptom information was collected using a digital evaluation scoring system at the time of admission, on the third day after admission, and upon discharge. Laboratory and imaging examination data were compiled simultaneously. Exploratory factor analysis was used to identify the AECOPD SCs. The number of factors (clusters) was determined by examining factors with eigenvalues ≥1.0, using 0.50 for factor loadings as the minimum cut-off value. Spearman's correlation analysis was used to explore the link between the SCs and laboratory and imaging indicators, as well as the relationship between the severity of the symptoms in different clusters, prognostic outcomes, and disease burden. Results: This study included 148 patients. Three SCs were identified: activity-nutrition SC, breath-sleep SC and respiratory SC. Correlation analysis indicated a connection between the activity-nutrition SC and the white blood cell count, and serum sodium and potassium levels, whereas the breath-sleep SC was correlated with white blood cells and eosinophil counts, serum potassium level, and pleural effusion. Additionally, the respiratory SC was associated with serum calcium and magnesium levels, the partial pressure of carbon dioxide, and C-reactive protein (CRP) level. There was a positive correlation between the activity-nutrition SC and hospitalization cost, as well as between the breath-sleep SC and both the hospitalization length and cost. Conclusion: Patients with AECOPD presented three SCs that affected the length and cost of hospitalization. Concurrently, the severity of the symptoms in the clusters was related to white blood cell and eosinophil counts; serum sodium, potassium, calcium, and magnesium levels; CRP level; the partial pressure of carbon dioxide; and pleural effusion, indicating that the symptoms in each clusters may share related physiological mechanisms. An in-depth exploration of the pathogenesis and intervention paths of health problems is of great significance for promoting precision nursing.

Insights into the mechanisms driven by H3K4 KMTs in pancreatic cancer.

Pancreatic cancer is a malignancy arising from the endocrine or exocrine compartment of this organ. Tumors from exocrine origin comprise over 90% of all pancreatic cancers diagnosed. Of these, pancreatic ductal adenocarcinoma (PDAC) is the most common histological subtype. The five-year survival rate for PDAC ranged between 5 and 9% for over four decades, and only recently saw a modest increase to ∼12-13%, making this a severe and lethal disease. Like other cancers, PDAC initiation stems from genetic changes. However, therapeutic targeting of PDAC genetic drivers has remained relatively unsuccessful, thus the focus in recent years has expanded to the non-genetic factors underlying the disease pathogenesis. Specifically, it has been proposed that dynamic changes in the epigenetic landscape promote tumor growth and metastasis. Emphasis has been given to the re-organization of enhancers, essential regulatory elements controlling oncogenic gene expression, commonly marked my histone 3 lysine 4 monomethylation (H3K4me1). H3K4me1 is typically deposited by histone lysine methyltransferases (KMTs). While well characterized as oncogenes in other cancer types, recent work has expanded the role of KMTs as tumor suppressor in pancreatic cancer. Here, we review the role and translational significance for PDAC development and therapeutics of KMTs.

Cell-drug conjugates.

By combining living cells with therapeutics, cell-drug conjugates can potentiate the functions of both components, particularly for applications in drug delivery and therapy. The conjugates can be designed to persist in the bloodstream, undergo chemotaxis, evade surveillance by the immune system, proliferate, or maintain or transform their cellular phenotypes. In this Review, we discuss strategies for the design of cell-drug conjugates with specific functions, the techniques for their preparation, and their applications in the treatment of cancers, autoimmune diseases and other pathologies. We also discuss the translational challenges and opportunities of this class of drug-delivery systems and therapeutics.

DeepCBA: A deep learning framework for gene expression prediction in maize based on DNA sequences and chromatin interactions.

Chromatin interactions create spatial proximity between distal regulatory elements and target genes in the genome, which has an important impact on gene expression, transcriptional regulation, and phenotypic traits. To date, several methods have been developed for predicting gene expression. However, existing methods do not take into consideration the effect of chromatin interactions on target gene expression, thus potentially reducing the accuracy of gene expression prediction and mining of important regulatory elements. In this study, we developed a highly accurate deep learning-based gene expression prediction model (DeepCBA) based on maize chromatin interaction data. Compared with existing models, DeepCBA exhibits higher accuracy in expression classification and expression value prediction. The average Pearson correlation coefficients (PCCs) for predicting gene expression using gene promoter proximal interactions, proximal-distal interactions, and both proximal and distal interactions were 0.818, 0.625, and 0.929, respectively, representing an increase of 0.357, 0.16, and 0.469 over the PCCs obtained with traditional methods that use only gene proximal sequences. Some important motifs were identified through DeepCBA; they were enriched in open chromatin regions and expression quantitative trait loci and showed clear tissue specificity. Importantly, experimental results for the maize flowering-related gene ZmRap2.7 and the tillering-related gene ZmTb1 demonstrated the feasibility of DeepCBA for exploration of regulatory elements that affect gene expression. Moreover, promoter editing and verification of two reported genes (ZmCLE7 and ZmVTE4) demonstrated the utility of DeepCBA for the precise design of gene expression and even for future intelligent breeding. DeepCBA is available at http://www.deepcba.com/ or http://124.220.197.196/.

Cost-effectiveness analysis of Anaprazole versus Ilaprazole for the treatment of duodenal ulcers in China.

Objective: Anaprazole, an innovative drug, has shown promise in initial clinical trials for patients with duodenal ulcers (DU) in China. This study aimed to evaluate the potential effects, safety, and cost-effectiveness of Anaprazole compared to Ilaprazole in the treatment of DU and the budgetary impact on the healthcare system. Methods: Two multicentre, randomized controlled trials were used as data sources. The efficacy and safety of Anaprazole and Ilaprazole were compared using an anchored matching-adjusted indirect comparison (MAIC). A cost-utility analysis (CUA) was performed using a Markov model. A budget impact analysis (BIA) was conducted to evaluate the impact on the expenditure of the Chinese healthcare system. Deterministic and probabilistic sensitivity analyses were undertaken to test the uncertainty. Results: The study findings indicated that Anaprazole and Ilaprazole have similar efficacy and safety in treating DU (OR = 1.05; 95% CI, 0.94-1.01; p = 0.35; OR = 0.63; 95% CI, 0.39-1.08; p = 0.12). The ICUR was 2,995.41¥/QALY, which is below the WTP threshold. The CUA results showed that Anaprazole is a cost-effective intervention with a probability of 85% at a given threshold. The results demonstrated strong robustness in the sensitivity analysis. Anaprazole imposed a low burden on the Chinese healthcare budget in the BIA. Conclusion: Compared with Ilaprazole, Anaprazole has similar efficacy, safety, and high cost-effectiveness, while also impacting the total expenditure of the healthcare system. Clinical Trial Registration: ClinicalTrials.gov, identifier NCT04215653 and NCT02847455.

PONV Management in Adult Patients: Evidence-based Summary.

PURPOSE: To summarize the evidence on perioperative nausea and vomiting management in adult patients worldwide. DESIGN: This is a summary of the best evidence on postoperative nausea and vomiting in adults. METHODS: Databases such as British Medical Journal Best Practice, Cochrane Library, Joanna Briggs Institute, National Institute for Health and Care Excellence, Scottish Intercollegiate Guidelines Network, National Guideline Clearing House, Guidelines International Network, American Society of Anesthesiologists (ASA), Association of periOperative Registered Nurses (AORN), Registered Nurses Association of Ontario, PubMed, Cumulative Index to Nursing and Allied Health Literature, Embase, Yimaitong Clinical Guidelines, China Anesthesia Official website, SinoMed, China National Knowledge Infrastructure, Wanfang, and VIP were searched to collect the relevant guidelines for clinical decision-making, best practices, systematic review, evidence summary, and expert consensus about perioperative nausea and vomiting management. The retrieval time was from the establishment of the database to January 2022. Two authors independently evaluated the quality of the included literature and extracted and summarized the evidence that met the quality criteria. FINDINGS: A total of 22 studies, including 1 best practice, 2 clinical decision-making articles, 7 evidence summaries, 1 clinical guideline, 9 systematic reviews, and 2 expert consensuses, were included. The summary of 37 pieces of evidence from 7 aspects: risk factors, assessment methods, multimodal prevention strategy, health education, nondrug intervention, drug prevention, postoperative analgesia management strategy, and organization management. CONCLUSIONS: The health care team should select the best evidence according to the characteristics of the department and clinical practice, scientifically manage perioperative nausea and vomiting of patients, reduce the incidence and severity of nausea and vomiting, and promote the accelerated rehabilitation of patients.

Rapid summer Russian Arctic sea-ice loss enhances the risk of recent Eastern Siberian wildfires.

In recent decades boreal wildfires have occurred frequently over eastern Siberia, leading to increased emissions of carbon dioxide and pollutants. However, it is unclear what factors have contributed to recent increases in these wildfires. Here, using the data we show that background eastern Siberian Arctic warming (BAW) related to summer Russian Arctic sea-ice decline accounts for ~79% of the increase in summer vapor pressure deficit (VPD) that controls wildfires over eastern Siberia over 2004-2021 with the remaining ~21% related to internal atmospheric variability associated with changes in Siberian blocking events. We further demonstrate that Siberian blocking events are occurring at higher latitudes, are more persistent and have larger zonal scales and slower decay due to smaller meridional potential vorticity gradients caused by stronger BAW under lower sea-ice. These changes lead to more persistent, widespread and intense high-latitude warming and VPD, thus contributing to recent increases in eastern Siberian high-latitude wildfires.

[Progress on the involvement of HDAC11 in the regulation of mammalian oocyte maturation and early embryonic development].

Oocyte maturation and early embryonic development are key steps in the reproductive physiology of female mammals, and any error in this process can adversely affect reproductive development. Recent studies have shown that epigenetic modifications of histones play important roles in the regulation of oocyte meiosis and quality assurance of early embryonic development. Histone deacetylase 11 (HDAC11) is the smallest known member of the histone deacetylases (HDACs) family, and inhibition of HDAC11 activity significantly suppresses the rate of oocyte maturation, as well as the development of 8-cell and blastocyst embryos at the embryonic stage. This paper focuses on recent progress on the important role of HDAC11 in the regulation of mammalian oocyte maturation and early embryonic development, hoping to gain insights into the key roles played by epitope-modifying proteins represented by HDAC11 in the regulation of mammalian reproduction and their molecular mechanisms.

Pan-immune-inflammation value: a new prognostic index in operative laryngeal and pharyngeal carcinomas.

PURPOSE: This study aimed to further evaluate the potential value of Pan-Immune-Inflammation Value (PIV) as a prognostic marker in patients with laryngeal and pharyngeal tumors. METHODS: A total of 545 patients with laryngeal and pharyngeal tumors who underwent surgery at Qilu Hospital of Shandong University were included. We determined the optimal cutoff of PIV and divided the patients into two groups. The relationship between PIV and clinicopathological features was explored by the chi-square test and the Mann-Whitney U test. Survival analysis and Cox regression analysis were used to evaluate the relationship between PIV and overall survival (OS) and disease-free survival (DFS). We also compared the prognostic predictive value of PIV with other inflammation-related markers. Finally, we developed a simple scoring prediction model based on several independent prognostic parameters. RESULTS: We found that PIV was statistically associated with clinicopathological features such as tumor stage (p < 0.001), node stage (p = 0.001), postoperative chemotherapy (p = 0.026), and vascular thrombosis (p = 0.027). Survival analysis demonstrated a significant correlation between elevated PIV and reduced OS and DFS (p < 0.0001). Multivariate Cox regression analysis further confirmed PIV as a prognostic indicator (HR 2.507; 95% CI 1.343-4.681; p = 0.004), which is superior to SII, NLR, MLR and PLR. Three of the independent prognostic factors screened by multivariate Cox regression analysis were selected to be used to create a scoring system with a concordance index of 0.756. CONCLUSIONS: Elevated PIV is associated with poor prognosis in patients with laryngeal and pharyngeal tumors, suggesting that PIV may be an important adjunctive indicator for assessing patient prognosis. REGISTRATION INFORMATION: Registration number: KYLL-202307-001, date: July 2023.

A Peel Test Method to Characterize the Decay Law of Prepreg Tape Tack at Different Temperatures.

The tack of prepreg is a key factor affecting the automatic tape laying process. During the manufacturing process of large composite parts, prepreg material may be stored at room temperature for several days, resulting in a decrease in its tack. In this study, a new tack test tool was designed, and the decay rate of prepreg tack at different temperatures was tested. We proposed a prepreg tack decay model, which assumes that the main factor in tack decay is the reduction in resin chain activity during storage. The maximum deviation between the model calculation results and the experimental results of the tack decay rate is 9.7%. This study also proposed a new statistical unit for prepreg tack, which can establish the relationship between the tack of prepreg and its remaining storage time and reduce prepreg management costs.

Stage-specificity of STING activation in intrahepatic cholangiocarcinoma determines the efficacy of its agonism.

Intrahepatic cholangiocarcinoma (iCCA) is an aggressive cancer with an extremely poor prognosis, and new treatment options are needed. Recently, immunotherapy has emerged as an efficient treatment against malignant tumors, but less effective in iCCA. Activation of stimulator of interferon genes (STING) signaling could reignite immunologically inert tumors, but the expression and role of STING in iCCA remains to be determined. Here, we show STING is expressed in iCCA, and patients with high expression of STING in early-stage iCCA have a longer overall survival than those have low expression. Increased immune cell infiltration in early-stage iCCA corresponds to elevated STING expression. In mice iCCA models, treatment with the STING agonist MSA-2 show stage-specific inhibitory effects on tumors, with beneficial effects in early-stage tumors but not with advanced-stage cancer. This discrepancy was associated with greater programmed cell death ligand 1 (PD-L1) expression in advanced-stage tumors. Combination therapy targeting PD-L1 and MSA-2 strikingly reduced tumor burden in such tumors compared to either monotherapy. Cumulatively, these data demonstrate that STING agonism monotherapy improves the immune landscape of the tumor microenvironment in early-stage iCCA, while combination therapy ameliorates advanced-stage iCCA.

Unveiling the Molecular Landscape of Pancreatic Ductal Adenocarcinoma: Insights into the Role of the COMPASS-like Complex.

Pancreatic ductal adenocarcinoma (PDAC) is poised to become the second leading cause of cancer-related death by 2030, necessitating innovative therapeutic strategies. Genetic and epigenetic alterations, including those involving the COMPASS-like complex genes, have emerged as critical drivers of PDAC progression. This review explores the genetic and epigenetic landscape of PDAC, focusing on the role of the COMPASS-like complex in regulating chromatin accessibility and gene expression. Specifically, we delve into the functions of key components such as KDM6A, KMT2D, KMT2C, KMT2A, and KMT2B, highlighting their significance as potential therapeutic targets. Furthermore, we discuss the implications of these findings for developing novel treatment modalities for PDAC.

Macrophage hitchhiking for systematic suppression in postablative multifocal HCC.

BACKGROUND AND AIMS: HCC, particularly the multifocal HCC, features aggressive invasion and dismal prognosis. Locoregional treatments were often refractory to eliminate tumor tissue, resulting in residual tumor cells persisting and subsequent progression. Owing to problematic delivery to the tumor tissue, systemic therapies, such as lenvatinib (LEN) therapy, show limited clinical benefit in preventing residual tumor progression. Therefore, more advanced strategies for postablative multifocal HCC are urgently needed. APPROACH AND RESULTS: Motivated by the chemotaxis in tumor penetration of macrophages, we report a strategy named microinvasive ablation-guided macrophage hitchhiking for the targeted therapy toward HCC. In this study, the strategy leverages the natural inflammatory gradient induced by ablation to guide LEN-loaded macrophages toward tumor targeting, which increased by ~10-fold the delivery efficiency of LEN in postablative HCC in vivo. Microinvasive ablation-guided macrophage hitchhiking has demonstrated significant antitumor activity in various HCC models, including the hydrodynamic tail vein injection multifocal HCC mouse model and the orthotopic xenograft HCC rabbit model, systematically inhibiting residual tumor progression after ablation and prolonging the median survival of tumor-bearing mice. The potential antitumor mechanism was explored using techniques such as flow cytometry, ELISA, and immunohistochemistry. We found that the strategy significantly suppressed tumor cell proliferation and neovascularization, and such enhanced delivery of LEN stimulated systemic immune responses and induced durable immune memory. CONCLUSIONS: The macrophage hitchhiking strategy demonstrates exceptional therapeutic efficacy and biosafety across various species, offering promising prospects for clinical translation in controlling residual tumor progression and improving outcomes following HCC ablation.

A FLOWERING LOCUS T ortholog is associated with photoperiod-insensitive flowering in hemp (Cannabis sativa L.).

Hemp (Cannabis sativa L.) is an extraordinarily versatile crop, with applications ranging from medicinal compounds to seed oil and fibre products. Cannabis sativa is a short-day plant, and its flowering is highly controlled by photoperiod. However, substantial genetic variation exists for photoperiod sensitivity in C. sativa, and photoperiod-insensitive ("autoflower") cultivars are available. Using a bi-parental mapping population and bulked segregant analysis, we identified Autoflower2, a 0.5 Mbp locus significantly associated with photoperiod-insensitive flowering in hemp. Autoflower2 contains an ortholog of the central flowering time regulator FLOWERING LOCUS T (FT) from Arabidopsis thaliana which we termed CsFT1. We identified extensive sequence divergence between alleles of CsFT1 from photoperiod-sensitive and insensitive cultivars of C. sativa, including a duplication of CsFT1 and sequence differences, especially in introns. Furthermore, we observed higher expression of one of the CsFT1 copies found in the photoperiod-insensitive cultivar. Genotyping of several mapping populations and a diversity panel confirmed a correlation between CsFT1 alleles and photoperiod response, affirming that at least two independent loci involved in the photoperiodic control of flowering, Autoflower1 and Autoflower2, exist in the C. sativa gene pool. This study reveals the multiple independent origins of photoperiod insensitivity in C. sativa, supporting the likelihood of a complex domestication history in this species. By integrating the genetic relaxation of photoperiod sensitivity into novel C. sativa cultivars, expansion to higher latitudes will be permitted, thus allowing the full potential of this versatile crop to be reached.