Mechanobiology studies of bladder tumor cells using laterally squeezing microfluidic flow cytometry.

The deformability and uptake capability of cells are critical indicators of their biomechanical properties and functional behaviors, particularly in tumor heterogeneity and cancer research. Here, we introduce a microfluidic flow cytometry platform integrated with a laterally adjustable squeezing structure for the characterization of bladder tumor cells (including 5637 and EJ cell lines) and uroepithelial cells (SV-HUC-1 cell line). The deformability of these cell types under varying channel width conditions was clearly assessed using this platform. The results demonstrated that tumor cells exhibited higher deformability compared to uroepithelial cells, with the EJ cell line exhibiting the greatest difference. Furthermore, the relationship between the malignancy, deformability, and uptake capability of bladder cells was explored through co-cultivation experiments with 2 µm particles. As the malignancy increased, the cells became more deformable and exhibited stronger phagocytic capability with particles. Subsequently, the heterogeneity of tumor cells was investigated by analyzing the deformability of phagocytic and non-phagocytic subpopulations within EJ cells. The developed microfluidic platform offers a promising high-throughput method to assess the biomechanical and phagocytic characteristics of cells, providing valuable insights into tumor cell biology, and potentially improving clinical status of urinary cytology examinations for bladder cancer.

Causal associations of MICB, CTSA, and MMP9 proteins with oral cancer: Mendelian randomization study.

Oral cancer (ORCA) is the most prevalent histological subtype of oral malignancies in which immune modulation is relevant. The goal of this work was to employ Mendelian randomization (MR) to investigate the causal connection between the immune-related proteins MICB, CTSA, MMP9, and ORCA. The Open GWAS database of the Integrative Epidemiology Unit (IEU) was accessed to collect GWAS data for ORCA (ieu-b-4961), MICB (prot-a-1898), CTSA (prot-a-717) and MMP9 (prot-a-1921). From 372,373 samples, the ORCA dataset comprises 7,723,107 single nucleotide polymorphisms (SNPs). MICB, CTSA, and MMP9 all have 10,534,735 SNPs and 3,301 sample sizes. Then, the primary SVMR implementation approaches were weighted mode, simple mode, inverse variance weighted (IVW), weighted median, and MR-Egger. IVW was the most effective technique. A sensitivity study was also carried out to assess the correctness of SVMR data, with special focus devoted to heterogeneity, horizontal pleiotropy, and Leave-One-Out (LOO). MVMR was eventually implemented as well. A Mendelian randomization analysis of the three exposure factors in the dataset (ieu-b-94, ebi-a-GCST012237) was also performed to validate the study results. According to the SVMR results, there was a noteworthy causal interaction between ORCA and MICB (P = 0.0014), MMP9 (P = 0.0343), and CTSA (P = 0.0003). Furthermore, odds ratios (ORs) values revealed that MMP9 (OR = 1.0005) was an ORCA risk factor, whereas MICB (OR = 0.9994) and CTSA (OR = 0.9993) were security factors. The robustness of the SVMR findings was confirmed by the p-values of the heterogeneity and horizontal pleiotropy, both of which were greater than 0.05. The MVMR result did not affect any of the safety or hazard features of these three exposure factors. However, the P value for MMP9 was greater than 0.05, implying that MICB and CTSA may have a greater influence on ORCA than MMP9. The validation outcomes in both datasets harmonized with the findings from previous research, thereby solidifying the reliability of results. Our investigation provided a crucial resource for further research on the subject by demonstrating a causal relationship between ORCA and MICB, CTSA, and MMP9.

Associations between Changes in Exposure to Air Pollutants due to Relocation and the Incidence of 14 Major Disease Categories and All-Cause Mortality: A Natural Experiment Study.

BACKGROUND: Though observational studies have widely linked air pollution exposure to various chronic diseases, evidence comparing different exposures in the same people is limited. This study examined associations between changes in air pollution exposure due to relocation and the incidence and mortality of 14 major diseases. METHODS: We included 50,522 participants enrolled in the UK Biobank from 2006 to 2010. Exposures to particulate matter with a diameter ≤2.5µm (PM2.5), particulate matter with a diameter ≤10µm (PM10), nitrogen oxides (NOx), nitrogen dioxide (NO2), and sulfur dioxide (SO2) were estimated for each participant based on their residential address and relocation experience during the follow-up. Nine exposure groups were classified based on changes in long-term exposures due to residential mobility. Incidence and mortality of 14 major diseases were identified through linkages to hospital inpatient records and death registries. Cox proportional hazard models were used to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for incidence and mortality of the 14 diseases of interest. RESULTS: During a median follow-up of 12.6 years, 29,869 participants were diagnosed with any disease of interest, and 3,144 died. Significantly increased risk of disease and all-cause mortality was observed among individuals who moved from a lower to higher air polluted area. Compared with constantly low exposure, moving from low to moderate PM2.5 exposure was associated with increased risk of all 14 diseases but not for all-cause mortality, with adjusted HRs (95% CIs) ranging from 1.18 (1.05, 1.33) to 1.48 (1.30, 1.69); moving from low to high PM2.5 areas increased risk of all 14 diseases: infections [1.37 (1.19, 1.58)], blood diseases [1.57 (1.34, 1.84)], endocrine diseases [1.77 (1.50, 2.09)], mental and behavioral disorders [1.93 (1.68, 2.21)], nervous system diseases [1.51 (1.32, 1.74)], ocular diseases [1.76 (1.56, 1.98)], ear disorders [1.58 (1.35, 1.86)], circulatory diseases [1.59 (1.42, 1.78)], respiratory diseases [1.51 (1.33, 1.72)], digestive diseases [1.74 (1.58, 1.92)], skin diseases [1.39 (1.22, 1.58)], musculoskeletal diseases [1.62 (1.45, 1.81)], genitourinary diseases [1.54 (1.36, 1.74)] and cancer [1.42 (1.24, 1.63)]. We observed similar associations for PM10 and SO2 with 14 diseases (but not with all-cause mortality); increases in NO2 and NOx were positively associated with 14 diseases and all-cause mortality. CONCLUSIONS: This study supports potential associations between ambient air pollution exposure and morbidity as well as mortality. Findings also emphasize the importance of maintaining consistently low levels of air pollution to protect the public's health. https://doi.org/10.1289/EHP14367.

Risk factors for acute pancreatitis post percutaneous transhepatic biliary stenting in patients with distal malignant obstruction.

Background: Percutaneous transhepatic biliary stenting (PTBS) is an effective treatment for distal malignant biliary obstruction (MBO). Postoperative acute pancreatitis (AP) is a dangerous complication of this procedure. This study sought to investigate the risk factors for AP after PTBS. Methods: A total of 463 patients who underwent PTBS to treat suspected MBO from October 2012 to October 2021 were enrolled in this retrospective study. Among them, 26 individuals met the diagnostic criteria for postoperative pancreatitis following PTBS. The incidence of AP at 1 month postoperatively was recorded and analyzed. Several risk factors for AP were analyzed, and the odds ratios (ORs) were calculated by univariate and multivariate logistic analyses. Results: The incidence of AP after PTBS was 10.88% (26/239). The results of the multivariate analyses showed that repeated bile duct hemorrhage (OR =14.370, P=0.0001), intraoperative dilation (OR =7.848, P=0.0003), an operation time >50 min (OR =5.783, P=0.0009), and previous endoscopic intervention (OR =5.468, P=0.0021) were correlated with a high incidence of AP, while sex, age, time to biliary obstruction, body mass index, Eastern Cooperative Oncology Group score, previous anticancer treatments, forceps biopsy, obstruction length, stent size, contrast volume, operators, 125I strand placement, and blood parameters were not significantly correlated with AP (all P>0.05). Conclusions: A long operation time, intraoperative dilation, repeated bile duct hemorrhage, and previous endoscopic intervention were independent risk factors for AP. These factors should be considered by clinicians in future practice.

Radiofrequency-responsive black phosphorus nanogel crosslinked with cisplatin for precise synergy in multi-modal tumor therapies.

Radiofrequency-responsive nanoparticles (RFNPs) have drawn increasingly attentions as RF energy absorbing antenna to enhance antitumor efficacy of radiofrequency ablation (RFA). However, it remains a huge challenge for inorganic RFNPs to precisely synergize RFA with other antitumor modes in a clinically acceptable way on bio-safety and bio-compatibility. In this work, RF-responsive black phosphorus (BP) nanogel (BP-Pt@PNA) was successfully fabricated by crosslinking coordination of cisplatin with BP and temperature sensitive polymer PNA. BP-Pt@PNA exhibited strong RF-heating effect and RF-induced pulsatile release of cisplatin. Under RF irradiation, BP-Pt@PNA exhibited cytotoxic enhancement on 4T1 cells. By the synergistic effect of BP and cisplatin, BP-Pt@PNA achieved RF-stimulated systemic immune effect, thus induced enhance suppression on tumor growth and metastasis. Moreover, BP-Pt@PNA realized long-term drug retention in tumor and favorable embolization to tumor-feeding arteries. With high drug loading capacity and favorable bio-safety and bio-degradability, BP-Pt@PNA is expected as an ideal RFNP for precisely synergizing RFA with other antitumor modes in clinical application.

Effects of epidural anesthesia and analgesia on the incidence of chronic pain after thoracoscopic lung surgery: A retrospective cohort study.

Objective: Chronic postoperative pain (CPSP) is common after thoracic surgery, even after the less invasive video-assisted thoracoscopic surgery (VATS). This study investigated the effect of thoracic epidural anesthesia (TEA) on the development of CPSP. Materials: We retrospectively analyzed the data of patients who underwent VATS at our center between 2020 and 2022. The enrolled patients were divided into the epidural block (EPI) and patient-controlled intravenous analgesia (PCIA) groups. A telephone questionnaire was used to collect information regarding CPSP, which was defined as a numerical rating scale (VAS) score ≥1 at 3 or 6 months postoperatively. Additionally, statistical analyses were performed to identify the risk factors for CPSP in the two groups. Results: Overall, 894 patients completed the follow-up interviews at 3 and 6 months, with 325 and 569 patients in the PCIA and EPI groups, respectively. The incidence rates of CPSP in the PCIA group at 3 and 6 months were 16.9 % (95 % confidence interval [CI]: 9.3-32.7 %) and 13.5 % (95 % CI: 8.7-33.4 %), and 10.3 % (95 % CI: 8.1-30.5 %) and 3.6 % (95 % CI: 3.5-21.5 %) in EPI group, respectively. The incidence of CPSP at 3 months (P = 0.0048) and 6 months (P < 0.005) was statistically significant in both groups. Age and lymph node dissection were significantly associated with CPSP. Conclusions: Compared to PCIA, TEA was associated with a lower incidence of CPSP after VATS, and should be considered an important part of the analgesia regimen for patients with VATS.

Efficacy and Safety of TACE Combined with Regorafenib versus TACE Combined with Camrelizumab in Hepatocellular Carcinoma With Untreatable Progression After TACE Combined with Sorafenib Therapy: A Case Control Study.

PURPOSE: To evaluate the efficacy and safety of transarterial chemoembolization (TACE) combined with regorafenib (hereafter, TACE-regorafenib) or camrelizumab (hereafter, TACE-camrelizumab) for treating hepatocellular carcinoma (HCC) with untreatable progression after TACE and sorafenib therapy. METHODS: The medical records of patients with HCC who received TACE-regorafenib or TACE-camrelizumab between September 2018 and December 2023 were retrospectively evaluated. Therapeutic response, overall survival (OS), progression-free survival (PFS), and adverse events (AEs) were compared between the two groups. RESULTS: A total of 76 patients were enrolled in this study, with 41 and 35 patients in the TACE-regorafenib and TACE-camrelizumab groups, respectively. The objective response rates in the TACE-regorafenib and TACE-camrelizumab groups were 9.8% and 8.6%, respectively, with no statistically significant difference between the two groups (P = 0.859). Similarly, there was no statistically significant difference in disease control rates between the two groups (61.0% vs 68.6%, P = 0.838). The median OS was 11 months in the TACE-regorafenib group and 10 months in the TACE-camrelizumab group, with no significant difference between the two groups (P = 0.348). The TACE-regorafenib group had a median PFS of 7 months, which was significantly longer than that of the TACE-camrelizumab group (4 months, P = 0.004). There was no significant difference in the incidence of AEs between the two groups (P = 0.544). CONCLUSIONS: TACE-regorafenib was safe, well-tolerated, and showed promising efficacy in patients with sorafenib-refractory advanced HCC, whereas TACE-camrelizumab demonstrated similar survival benefits.

Coixol mitigates Toxoplasma gondii infection-induced liver injury by inhibiting the Toxoplasma gondii HSP70/TLR4/NF-κB signaling pathway in hepatic macrophages.

ETHNOPHARMACOLOGICAL RELEVANCE: Coix seed, the dry mature seed kernel of the gramineous plant coix (Coix lacryma-jobi L. var. ma-yuen Stapf), is widely consumed as a traditional Chinese medicine and functional food in China and South Korea. We have previously demonstrated the protective effect of coixol, a polyphenolic compound extracted from coix, against Toxoplasma gondii (T. gondii) infection-induced lung injury. However, the protective effect of coixol on hepatic injury induced by T. gondii infection have not yet been elucidated. AIM OF THE STUDY: This study explores the impact of coixol on T. gondii infection-induced liver injury and elucidates the underlying molecular mechanisms. MATERIALS AND METHODS: Female BALB/c mice and Kupffer cells (KCs) were employed to establish an acute T. gondii infection model in vivo and an inflammation model in vitro. The study examined coixol's influence on the T. gondii-derived heat shock protein 70 (T.g.HSP70)/toll-like receptor 4 (TLR4)/nuclear factor (NF)-κB signaling pathway in T. gondii-infected liver macrophages. Furthermore, a co-culture system of KCs and NCTC-1469 hepatocytes was developed to observe the impact of liver macrophages infected with T. gondii on hepatocyte injury. RESULTS: Coixol notably inhibited the proliferation of tachyzoites and the expression of T.g.HSP70 in mouse liver and KCs, and attenuated pathological liver injury. Moreover, coixol decreased the production of high mobility group box 1, tumor necrosis factor-α, and inducible nitric oxide synthase by suppressing the TLR4/NF-κB signaling pathway in vitro and in vivo. Coixol also mitigated KCs-mediated hepatocyte injury. CONCLUSIONS: Coixol protects against liver injury caused by T. gondii infection, potentially by diminishing hepatocyte injury through the suppression of the inflammatory cascade mediated by the T.g.HSP70/TLR4/NF-κB signaling pathway in KCs. These findings offer new perspectives for developing coixol as a lead compound for anti-T. gondii drugs.

Structural basis for the ligand recognition and G protein subtype selectivity of kisspeptin receptor.

Kisspeptin receptor (KISS1R), belonging to the class A peptide-GPCR family, plays a key role in the regulation of reproductive physiology after stimulation by kisspeptin and is regarded as an attractive drug target for reproductive diseases. Here, we demonstrated that KISS1R can couple to the Gi/o pathway besides the well-known Gq/11 pathway. We further resolved the cryo-electron microscopy (cryo-EM) structure of KISS1R-Gq and KISS1R-Gi complexes bound to the synthetic agonist TAK448 and structure of KISS1R-Gq complex bound to the endogenous agonist KP54. The high-resolution structures provided clear insights into mechanism of KISS1R recognition by its ligand and can facilitate the design of targeted drugs with high affinity to improve treatment effects. Moreover, the structural and functional analyses indicated that conformational differences in the extracellular loops (ECLs), intracellular loops (ICLs) of the receptor, and the "wavy hook" of the Gα subunit may account for the specificity of G protein coupling for KISS1R signaling.

Tertiary lymphoid structures as potential biomarkers for cancer prediction and prognosis.

Tertiary lymphoid structures (TLSs) are ectopic lymphocyte aggregates formed in non-lymphoid tissues, including cancers, and are loci for the generation of in situ anti-tumor immune responses, which play a crucial role in cancer control. The state of TLS presence in cancer and its composition can significantly impact the treatment response and prognosis of patients. TLSs have the potential to serve as predictive and prognostic biomarkers for cancer. However, the mechanisms underlying TLS formation in cancer and how the essential components of TLSs affect cancer are not fully understood. In this review, we summarized TLS formation in cancer, the value of the TLS in different states of existence, and its key constituents for cancer prediction and prognosis. Finally, we discussed the impact of cancer treatment on TLSs.

Long-term prognosis in patients with thymoma combined with myasthenia gravis: a propensity score-matching analysis.

Introduction: We aimed to assess the impact of myasthenia gravis (MG) on the long-term prognosis in patients with thymoma after surgery and identify related prognostic factors or predictors. Methods: This retrospective observational study included 509 patients with thymoma (thymoma combined with MG [MG group] and thymoma alone [non-MG group]). Propensity score matching was performed to obtain comparable subsets of 96 patients in each group. A comparative analysis was conducted on various parameters. Results: Before matching, the 10-year survival and recurrence-free survival rates in both groups were 93.8 and 98.4%, and 85.9 and 93.4%, respectively, with no statistically significant difference observed in the survival curves between the groups (p > 0.05). After propensity score matching, 96 matched pairs of patients from both groups were created. The 10-year survival and recurrence-free survival rates in these matched pairs were 96.9 and 97.7%, and 86.9 and 91.1%, respectively, with no statistical significance in the survival curves between the groups (p > 0.05). Univariate analysis of patients with thymoma postoperatively revealed that the World Health Organization histopathological classification, Masaoka-Koga stage, Tumor Node Metastasis stage, resection status, and postoperative adjuvant therapy were potentially associated with tumor recurrence after thymoma surgery. Multivariate analysis demonstrated that the Masaoka-Koga stage and postoperative adjuvant therapy independently predicted the risk of recurrence in patients with thymoma after surgery. Conclusion: There was no difference in prognosis in patients with thymoma with or without MG. The Masaoka-Koga stage has emerged as an independent prognostic factor affecting recurrence-free survival in patients with thymoma, while postoperative adjuvant therapy represents a poor prognostic factor.

Golgi Protein 73 Promotes Angiogenesis in Hepatocellular Carcinoma.

Golgi protein 73 (GP73), a resident protein of the Golgi apparatus, is notably elevated in hepatocellular carcinoma (HCC). While its critical role in remodeling the tumor microenvironment (TME) is recognized, the intricate mechanisms are not fully understood. This study reveals that GP73 in HCC cells interacts with prolyl hydroxylase-2 (PHD-2) in a competitive manner, thereby impeding the hydroxylation of hypoxia-induced factor-1α (HIF-1α). The effect above promotes the production and secretion of vascular endothelial growth factor A (VEGFA). Moreover, exosomal GP73 derived from HCC cells can be internalized by human umbilical vein endothelial cells (HUVECs) and competitively interact with HECTD1, an E3 ubiquitin ligase targeting growth factor receptor-bound protein 2 (GRB2). This interaction stabilizes GRB2, thereby activating the Ras-mitogen-activated protein kinase (MAPK) signaling pathway. Consequently, escalated levels of GP73 intensify VEGF production in HCC cells and potentiate mitogenic signaling in vascular endothelial cells, fostering angiogenesis in the TME. Our findings propose that GP73 might serve as a novel target for anti-angiogenic therapy in HCC.

Mature tertiary lymphoid structures: important contributors to anti-tumor immune efficacy.

Tertiary lymphoid structures (TLS) represent the ectopic aggregations of immune cells arising during chronic inflammation or tumor progression. In cancer, TLS are often associated with beneficial clinical outcomes in patients undergoing immunotherapy, underscoring their prognostic and predictive significance. Mature TLS, characterized by germinal centers and areas of T-cell and B-cell aggregation, are considered primary locations for activating and maintaining both humoral and cellular anti-tumor immune effects. Despite their recognized importance, the mechanisms driving the formation of mature TLS in cancer and their influence on the immune response within tumors remain insufficiently understood. Therefore, this review aims to comprehensively explore the structural composition, development mechanisms, maturity impact factors, immunological function, and innovative therapeutic strategies of mature TLS within the tumor microenvironment. The research summarized herein offers novel insights and considerations for therapeutic approaches to promote TLS generation and maturation in patients with cancer, representing a promising avenue for future cancer therapies.

Associations Between Dietary Intake of Tomato and Lycopene with All-Cause and Cancer-Specific Mortality in US Adults with Diabetes: Results From a Cohort Study.

This study aimed to explore the association between dietary intake of tomatoes and lycopene with all-cause and cancer mortality among US adults with diabetes. We hypothesized that a higher intake of tomato and lycopene is related to a reduced risk of all-cause and cancer mortality among adults with diabetes. This prospective study was conducted among 9213 US adults with diabetes using data from the National Health and Nutrition Examination Survey (NHANES) 2007-2016. Data on dietary intake of tomatoes and lycopene were obtained from two 24-h dietary recalls. Multivariate Cox proportional hazard models determined the associations between tomato/lycopene intake and mortality. A higher intake of tomatoes and lycopene was significantly associated with a lower risk of all-cause mortality (tomato: Q5 vs. Q1: HR = 0.68, 95% CI = 0.54-0.86, p = 0.001, p for trend = 0.001; lycopene: Q5 vs. Q1: HR = 0.78, 95% CI = 0.64-0.95, p = 0.013, p for trend = 0.006) after adjusting for all covariates. Compared with the lowest quintile of tomato and lycopene intake, the highest quintile was associated with a lower risk of cancer mortality (tomato: HR = 0.58, 95% CI = 0.35-0.96, p = 0.035; lycopene: HR = 0.63, 95% CI = 0.40-0.98, p = 0.043). Our study demonstrated that dietary intake of tomatoes and lycopene was significantly associated with a lower risk of all-cause mortality in US adults with diabetes. High consumption of tomatoes and lycopene was also related to reduced cancer mortality in US adults with diabetes.

Molecular basis of human noradrenaline transporter reuptake and inhibition.

Noradrenaline, also known as norepinephrine, has a wide range of activities and effects on most brain cell types1. Its reuptake from the synaptic cleft heavily relies on the noradrenaline transporter (NET) located in the presynaptic membrane2. Here we report the cryo-electron microscopy (cryo-EM) structures of the human NET in both its apo state and when bound to substrates or antidepressant drugs, with resolutions ranging from 2.5 Å to 3.5 Å. The two substrates, noradrenaline and dopamine, display a similar binding mode within the central substrate binding site (S1) and within a newly identified extracellular allosteric site (S2). Four distinct antidepressants, namely, atomoxetine, desipramine, bupropion and escitalopram, occupy the S1 site to obstruct substrate transport in distinct conformations. Moreover, a potassium ion was observed within sodium-binding site 1 in the structure of the NET bound to desipramine under the KCl condition. Complemented by structural-guided biochemical analyses, our studies reveal the mechanism of substrate recognition, the alternating access of NET, and elucidate the mode of action of the four antidepressants.

Temperature-sensitive nanogels combined with polyphosphate and cisplatin for the enhancement of tumor artery embolization by coagulation activation.

Transcatheter arterial chemoembolization (TACE) is the first-line therapy for hepatocellular carcinoma (HCC). However, the exacerbated hypoxia microenvironment induces tumor relapse and metastasis post-TACE. Here, temperature-sensitive block polymer complexed with polyphosphate-cisplatin (Pt-P@PND) was prepared for the enhancement of tumor artery embolization by coagulation activation. After supra-selective infusion into the tumor vessels, Pt-P@PND nanogels performed efficient embolization of tumor arteries by sol-gel transition at body temperature. Meanwhile, coagulation cascade was evoked to form blood clots in the peripheral arteries inaccessible to the nanogels by released PolyP. The blood clots-filled hydrogel networks composed of gel and clots showed a denser structure and higher modulus, thereby achieving long-term embolization of all levels of tumor arteries. Pt-P@PND nanogels efficiently inhibited tumor growth and reduced the expression of HIF-1α, VEGF, CD31, and MMP-9 on VX2 tumor-bearing rabbit model. The released Nitro-Pt stimulated the immunogenic cell death of tumor cells, thus enhancing the antitumor immune response to suppress tumor relapse and metastasis post-TACE. It is hoped that Pt-P@PND nanogels can be developed as a promising embolic agent with procoagulant activity for enhancing the antitumor immune response through a combination of embolism, coagulation, and chemotherapy. STATEMENT OF SIGNIFICANCE: Clinical embolic agents, such as Lipiodol and polyvinyl alcohol (PVA) microspheres, are limited by their rapid elimination or larger size, thus lead to incomplete embolization of trans-catheter arterial chemoembolization (TACE). Herein, temperature-sensitive Pt-P@PND nanogels were developed to achieve long-term embolization of all levels of tumor arteries by gel/clot generation. The released Nitro-Pt induced immunogenic cell death in tumor cells, which improved the antitumor immune microenvironment by the maturation of DCs and lymphocytic infiltration. Pt-P@PND nanogels successfully inhibited tumor growth and activated an antitumor immune response to curb the recurrence and metastasis of residual tumor cells both in VX2 tumor-bearing rabbit model and 4T1 tumor-bearing mouse model. These findings suggested that Pt-P@PND could be developed as an ideal embolic agent for clinical TACE treatment.

Hepatic arterial infusion chemotherapy combined with toripalimab and surufatinib for the treatment of advanced intrahepatic cholangiocarcinoma.

PURPOSE: The aim of the present study is to report the clinical results of patients with advanced intrahepatic cholangiocarcinoma (ICC) who received combination therapy of hepatic arterial infusion chemotherapy (HAIC), toripalimab and surufatinib. METHODS: The study cohort consisted of 28 patients with advanced ICC who were treated with HAIC (mFOLFOX6 regimen, Q3W) in combination with intravenous toripalimab (240 mg, Q3W) and oral surufatinib (150 mg, once daily). The cohort had 14 male and 14 female patients. The baseline characteristics of the study cohort were obtained. The tumor response and drug-associated toxicity were assessed and reported. RESULTS: During the follow-up period (median follow-up time: 11.3 months; range: 4-19 months), four patients died of tumor progression. The objective response rate and disease control rate were 58% and 79%, respectively. The mPFS was 9.5 months, and the overall survival rate was 83.3%. The most frequent adverse events were nausea and vomiting (100%) and abdominal pain (85.7%). Serious complications related to death were not observed. CONCLUSION: The combination treatment schedule for advanced ICC demonstrated positive efficacy and safety profiles. CLINICAL SIGNIFICANCE: This study provides promising clinical guidance for the treatment of advanced cholangiocarcinoma and is expected to modify the treatment strategy for this disease.

Mid-term outcomes of endoscopic vein harvesting in coronary artery bypass grafting: a retrospective cohort study.

OBJECTIVES: Endoscopic vein harvesting (EVH) is an alternative technique to obtain the saphenous vein for coronary artery bypass grafting (CABG) surgery. We aimed to evaluate the early and mid-term outcomes of patients with EVH in CABG. METHODS: This cohort study included consecutive isolated CABG patients in Nanjing First Hospital from July 2020 to December 2022 using propensity score matching methods. Patients were classified to EVH group and open vein harvesting (OVH) group according to the vein harvesting methods. The primary outcome was the all-cause death, and the secondary outcomes were major adverse cardiovascular events (MACEs) including cardiovascular death, heart failure, myocardial infarction and revascularization and asymptomatic survival in the follow-up. RESULTS: Totally 1247 patients were included in the study with 849 in OVH group and 398 in EVH group. Patients with EVH were more female, diabetes, higher body mass index, more multi-vessel and left main diseases. 308 pairs were formed after the matching. There was no significant difference in the rates of in-hospital death (EVH vs. OVH, 2.3% vs. 1.3%, P = 0.543). During the 3 years follow-up, EVH grafts were considered not inferior to OVH grafts, no differences were found in all-cause death [8.5% vs. 5.0%, hazard ratio (HR) 1.565, 95% confidence interval (CI): 0.77-3.17, P = 0.21], MACEs (8.1% vs. 7.1%, HR 1.165, 95CI: 0.51-2.69, P = 0.71) and asymptomatic survival (66.7% vs. 72.5%, HR 1.117, 95%CI: 0.65-1.92, P = 0.68). CONCLUSIONS: EVH grafts were considered comparable to OVH grafts in patients following CABG in the 3 years follow-up.

Limbal stem cells carried by a four-dimensional -printed chitosan-based scaffold for corneal epithelium injury in diabetic rabbits.

Methods: Herein, we obtained and characterized deltaN p63- and adenosine triphosphate-binding cassette subfamily G member 2-expressing limbal stem cells (LSCs). Chitosan and carboxymethyl chitosan (CTH) were cross-linked to be an in situ thermosensitive hydrogel (ACH), which was printed through four-dimensional (4D) printing to obtain a porous carrier with uniform pore diameter (4D-CTH). Rabbits were injected with alloxan to induce diabetes mellitus (DM). Following this, the LSC-carrying hydrogel was spread on the surface of the cornea of the diabetic rabbits to cure corneal epithelium injury. Results: Compared with the control group (LSCs only), rapid wound healing was observed in rabbits treated with LSC-carrying 4D-CTH. Furthermore, the test group also showed better corneal nerve repair ability. The results indicated the potential of LSC-carrying 4D-CTH in curing corneal epithelium injury. Conclusion: 4D-CTH holds potential as a useful tool for studying regenerative processes occurring during the treatment of various diabetic corneal epithelium pathologies with the use of stem cell-based technologies.

Slow-replicating leukemia cells represent a leukemia stem cell population with high cell-surface CD74 expression.

Persistence of quiescent leukemia stem cells (LSCs) after treatment most likely contributes to chemotherapy resistance and poor prognosis of leukemia patients. Identification of this quiescent cell population would facilitate eradicating LSCs. Here, using a cell-tracing PKH26 (PKH) dye that can be equally distributed to daughter cells following cell division in vivo, we identify a label-retaining slow-cycling leukemia cell population from AML1-ETO9a (AE9a) leukemic mice. We find that, compared with cells not maintaining PKH-staining, a higher proportion of PKH-retaining cells are in G0 phase, and PKH-retaining cells exhibit increased colony formation ability and leukemia initiation potential. In addition, PKH-retaining cells possess high chemo-resistance and are more likely to be localized to the endosteal bone marrow region. Based on the transcriptional signature, HLA class II histocompatibility antigen gamma chain (Cd74) is highly expressed in PKH-retaining leukemia cells. Furthermore, cell surface CD74 was identified to be highly expressed in LSCs of AE9a mice and CD34+ human leukemia cells. Compared to Lin-CD74- leukemia cells, Lin-CD74+ leukemia cells of AE9a mice exhibit higher stemness properties. Collectively, our findings reveal that the identified slow-cycling leukemia cell population represents an LSC population, and CD74+ leukemia cells possess stemness properties, suggesting that CD74 is a candidate LSC surface marker.