Fn-OMV potentiates ZBP1-mediated PANoptosis triggered by oncolytic HSV-1 to fuel antitumor immunity.

Oncolytic viruses (OVs) show promise as a cancer treatment by selectively replicating in tumor cells and promoting antitumor immunity. However, the current immunogenicity induced by OVs for tumor treatment is relatively weak, necessitating a thorough investigation of the mechanisms underlying its induction of antitumor immunity. Here, we show that HSV-1-based OVs (oHSVs) trigger ZBP1-mediated PANoptosis (a unique innate immune inflammatory cell death modality), resulting in augmented antitumor immune effects. Mechanistically, oHSV enhances the expression of interferon-stimulated genes, leading to the accumulation of endogenous Z-RNA and subsequent activation of ZBP1. To further enhance the antitumor potential of oHSV, we conduct a screening and identify Fusobacterium nucleatum outer membrane vesicle (Fn-OMV) that can increase the expression of PANoptosis execution proteins. The combination of Fn-OMV and oHSV demonstrates potent antitumor immunogenicity. Taken together, our study provides a deeper understanding of oHSV-induced antitumor immunity, and demonstrates a promising strategy that combines oHSV with Fn-OMV.

Sniping Cancer Stem Cells with Nanomaterials.

Cancer stem cells (CSCs) drive tumor initiation, progression, and therapeutic resistance due to their self-renewal and differentiation capabilities. Despite encouraging progress in cancer treatment, conventional approaches often fail to eliminate CSCs, necessitating the development of precise targeted strategies. Recent advances in materials science and nanotechnology have enabled promising CSC-targeted approaches, harnessing the power of tailoring nanomaterials in diverse therapeutic applications. This review provides an update on the current landscape of nanobased precision targeting approaches against CSCs. We elucidate the nuanced application of organic, inorganic, and bioinspired nanomaterials across a spectrum of therapeutic paradigms, encompassing targeted therapy, immunotherapy, and multimodal synergistic therapies. By examining the accomplishments and challenges in this potential field, we aim to inform future efforts to advance nanomaterial-based therapies toward more effective "sniping" of CSCs and tumor clearance.

Cancer stem cell-immune cell collusion in immunotherapy.

Immunotherapy has pioneered a new era of tumor treatment, in which the immune checkpoint blockade (ICB) exerts significant superiority in overcoming tumor immune escape. However, the formation of an immune-suppressive tumor microenvironment (TME) and the lack of effective activation of the immune response have become major obstacles limiting its development. Emerging reports indicate that cancer stem cells (CSCs) potentially play important roles in treatment resistance and progressive relapse, while current research is usually focused on CSCs themselves. In this review, we mainly emphasize the collusions between CSCs and tumor-infiltrating immune cells. We focus on the summary of CSC-immune cell crosstalk signaling pathways in ICB resistance and highlight the application of targeted drugs to improve the ICB response.

Integrative Analysis Identified MCT4 as an Independent Prognostic Factor for Bladder Cancer.

BACKGROUND: Bladder cancer is the 10th most common cancer and most common urothelial malignancy worldwide. Prognostic biomarkers for bladder cancer patients are required for individualized treatment. Monocarboxylate transporter 4 (MCT4), encoded by SLC16A3 gene, is a potential biomarker for bladder cancer because of its crucial role in the lactate efflux in the aerobic glycolysis process. We aimed to study the association between MCT4 expression and the overall survival (OS) of bladder cancer patients. METHODS: The published single-cell RNA sequencing data of 49,869 bladder cancer cells and 15,827 normal bladder mucosa cells and The Cancer Genome Atlas (TCGA) bladder cancer cohort data were used to explore the mRNA expression of SLC16A3 in bladder cancer. Eighty-nine consecutive bladder cancer patients who had undergone radical cystectomy were enrolled as a validation cohort. The expression of MCT4 proteins in bladder cancer specimens was detected using immunohistochemistry staining. The Kaplan-Meier survival analysis and Cox regression were performed to analyze the association between MCT4 protein expression and OS in bladder cancer patients. RESULTS: SLC16A3 mRNA was upregulated in bladder cancer cells. The upregulated genes in SLC16A3-positive epithelial cells were enriched in the glycolysis process pathway and monocarboxylic acid metabolic process pathway. Patients with high SLC16A3 mRNA expression showed significantly poor OS (p = 0.016). High MCT4 protein expression was also found to be an independent predictor for poor OS in bladder cancer patients (HR: 2.462; 95% CI: 1.202~5.042, p = 0.014). A nomogram was built based on the results of the multivariate Cox analysis. CONCLUSION: Bladder cancer with high SLC16A3 mRNA expression has a poor OS. High MCT4 protein expression is an independent prognostic factor for bladder cancer patients who had undergone radical cystectomy.

Multimodal Peri-articular Injection with Tranexamic Acid can reduce postoperative blood loss versus Intravenous Tranexamic Acid in Total Knee Arthroplasty: A Randomized Controlled Trial.

BACKGROUND: Tranexamic acid (TXA) has shown significant reductions in blood loss and transfusion rates in total knee arthroplasty (TKA). However, the optimal administration route continues to be debated. The aim of this trial was to compare the effectiveness of intravenous (IV) versus peri-articular injection (PAI) application of tranexamic acid in patients undergoing total knee arthroplasty. METHODS: We conducted a randomized controlled, double-blinded study. A total of 93 patients undergoing primary unilateral TKA were randomly distributed between 2 groups: the IV group (47 cases; 1 g TXA IV) and the PAI group (46 cases; 1 g TXA injected peri-articularly). The amount of total and hidden blood loss (HBL), drainage, transfusion rate, hemoglobin and hematocrit drift, and complications were recorded. RESULTS: Peri-articular injection of TXA reduced total blood loss (P < 0.001) and HBL more than IV use of TXA (P < 0.001). No patients in either group received a transfusion. No symptomatic deep venous thrombosis or other severe complications occurred. CONCLUSION: Peri-articular injection of TXA significantly reduced total blood loss and hidden blood loss to a greater degree than IV injection in total knee arthroplasty without reduction of drainage volume. TRIAL REGISTRATION: Chinese Clinical Trial Registry, ChiCTR-INR-16010270 . Date of registration: December 27, 2016.

Value of Preoperative Neutrophil-to-Lymphocyte Ratio in Predicting Prognosis of Surgically Resectable Urinary Cancers: Systematic Review and Meta-Analysis.

Objective Accumulated evidence has suggested that there is a close association between preoperative neutrophil-to-lymphocyte ratio (NLR) and prognosis of various malignant tumors. However, the relationship between NLR and surgically resectable urinary cancers remains contradictory. Therefore, we performed this systematic review and meta-analysis to explore whether preoperative NLR could predict the prognosis of surgically resectable urinary cancers. Methods After searching the Embase, PubMed/MEDLINE and Cochrane databases and screening the articles, we finally included 25 studies involving 15950 patients. Hazard ratios (HRs) and their 95% confidence intervals (CIs) were extracted to assess the association between preoperative NLR and the overall survival (OS) and cancer-specific survival (CSS) of surgically resectable urinary cancers. Results The pooled results revealed that an elevated preoperative NLR could predict a worse OS (HR=1.40, 95%CI: 1.26-1.54, P<0.001) and CSS (HR=1.43, 95%CI: 1.27-1.59, P<0.001) in urinary cancers. In addition, our analyses also suggested that high preoperative NLR was associated with worse prognosis in renal cell carcinoma (OS: HR=2.06, 95%CI: 1.54-2.76, P=0.131; CSS: HR=2.46, 95%CI: 1.46-4.16, P=0.178), upper tract urothelial carcinoma (OS: HR=1.91, 95%CI: 1.50-2.42, P=0.616; CSS: HR=1.84, 95%CI: 1.41-2.39, P=0.001), bladder cancer (OS: HR=1.09, 95%CI: 1.02-1.17, P<0.001; CSS: HR=1.05, 95%CI: 1.01-1.09, P=0.163) and prostate cancer (OS: HR=1.69, 95%CI: 1.19-2.41, P=0.714). Regardless of the participants' race or the cutoff value of the preoperative NLR, the results remained valid. Conclusion Elevated preoperative NLR could predict a worse prognosis in surgically resectable urinary cancers, namely, renal cell carcinoma, bladder cancer, prostate cancer and upper tract urothelial carcinoma.

A network-based predictive gene expression signature for recurrence risks in stage II colorectal cancer.

The current criteria for defining the recurrence risks of stage II colorectal cancer (CRC) are not robust; therefore, we aimed to explore novel gene signatures to predict recurrence risks and to reveal the underlying mechanisms of stage II CRC. First, the gene expression profiles of 124 patients with stage II CRC from The Cancer Genome Atlas (TCGA) database were obtained to screen differentially expressed genes (DEGs). A total of 202 DEGs, including 128 upregulated and 74 downregulated, were identified in the recurrence group (n = 24) compared to the nonrecurrence group (n = 100). Furthermore, the top 5 DEGs (ZNF561, WFS1, SLC2A1, MFI2, and PTGR1) were identified by random forest variable hunting, and four (ZNF561, WFS1, SLC2A1, and PTGR1) were selected to create a four-gene recurrent model (GRM), with an area under the curve (AUC) of 0.882 according to the receiver operating characteristic curve, and the robust diagnostic effectiveness of the GRM was further validated with another gene expression profiling dataset (GSE12032), with an AUC of 0.943. The diagnostic effectiveness of the GRM regarding recurrence was associated with poor disease-free survival in all stages of CRC. In addition, gene ontology functional annotation and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses revealed 18 enriched functions and 6 enriched pathways. Four genes, ABCG2, CACNA1F, CYP19A1, and TF, were identified as hub genes by the protein-protein interaction network, which further validated that these genes were correlated with a poor pathologic stage and overall survival in all stages of CRC. In conclusion, the GRM can effectively classify stage II CRC into groups of high and low risks of recurrence, thereby making up for the prognostic value of the traditional clinicopathological risk factors defined by the National Comprehensive Cancer Network guidelines. The hub genes may be useful therapeutic targets for recurrence. Thus, the GRM and hub genes could offer clinical value in directing individualized and precision therapeutic regimens for stage II CRC patients.

A complicated case of innominate and right common arterial aneurysms due to Takayasu's arteritis.

BACKGROUND: Innominate artery aneurysms (IAAs) are relatively rare. Endovascular therapy has been an alternative to open surgery in some IAA cases, but open repair is still necessary in complicated cases. CASE SUMMARY: We report a 35-year-old female who suffered from Takayasu's arteritis. The patient did not get regular treatment, and IAA and right common carotid artery aneurysm developed, which complicated with occlusion of the left carotid artery, subclavian artery, and the initial part of the left vertebral artery. The patient also had moderate aortic valve insufficiency. With inflammation being controlled well, the patient received the surgery for arterial aneurysms of innominate and right common carotid arteries and aortic valve insufficiency. The shunts for cerebral blood supply were designed to protect the brain and the surgery was conducted successfully under extracorporeal circulation. CONCLUSION: The case illustrates that open surgery may be appropriate for some complicated IAAs, and brain protection is important.

Huge brown tumor of the rib in an unlocatable hyperparathyroidism patient with "self-recovered" serum calcium and parathyroid hormone: A case report.

BACKGROUND: The brown tumor is a kind of complication of hyperparathyroidism (HPT). The ultimate therapy usually is the resolution of HPT. We herein report an unlocatable HPT patient who received resection of a huge brown tumor of the rib, and experienced "self-recovery" of serum calcium and parathyroid hormone. CASE SUMMARY: A 34-year-old female patient who suffered from a gradually increasing mass of the left chest wall since 2007 came to our hospital for treatment. The patient had a history of serum Ca and parathyroid hormone (PTH) increasing since June 2015 and received zoledronic acid treatment for 17 mo. When she came to our hospital in November 2017 after discontinuing medical treatment for 3 mo, the serum Ca and PTH levels were within normal ranges. The patient had no imaging abnormalities of parathyroid ultrasound or 99mTc-methoxyisobutyl isonitrile. Enhanced computed tomography revealed a local soft tissue mass of 96 mm × 113 mm with bone erosion of the left 8th rib, and the mass presented irregular enhancement with an unclear boundary between the mass and spleen. The mass was thought to likely be caused by HPT, but a malignancy could not be ruled out. Resection of the mass was performed, and the pathology proved that the mass was a brown tumor. A diagnosis of unlocatable HPT was considered. Since the serum Ca and PTH levels were both normal pre- and post-operation, the patient did not receive exploratory surgery for HPT, and received regular follow-up. CONCLUSION: The huge brown tumor of the rib and "self-recovered" serum PTH and Ca levels are relatively rare in HPT patients. An exploratory operation may be deferred for these patients, and long-term follow-up should be performed.

PPARγ agonist rosiglitazone alters the temporal and spatial distribution of inflammation during abdominal aortic aneurysm formation.

Research into inflammation during abdominal aortic aneurysm (AAA) formation remains inconclusive. The present study aimed to demonstrate the temporal and spatial distribution of inflammatory cytokines, and to confirm the effect of peroxisome proliferator­activated receptor γ (PPARγ) on the incidence of AAA formation and the distribution of inflammation in the disease process. Male apolipoprotein E­/­ mice were randomly divided into eight groups: Angiotensin II (Ang­II)­only 7, 14, 21, 28 and 42 days groups, Ang­II with rosiglitazone (RGZ) 28 and 42 days groups, and the saline control 42 days group. The early stage was defined as between 7 and 21 days, and the late stage as between 28 and 42 days. Incidences of early rupture and late rupture, aneurysm formation and the maximum diameters of the aorta were recorded. Suprarenal abdominal aortic tissues were collected for histological analysis, and western blotting was performed to reveal the distribution of inflammation. Treatment with Ang­II caused a significant dilation of the aorta in the late stage; however, this was not observed in the early stage. RGZ reduced the maximum diameters in the late stage. With the pathological process alterations, the inflammatory type shifted. Regarding temporal distribution, the tumor necrosis factor (TNF)­α expression level was increased over time, and the interleukin (IL)­10 expression level significantly decreased. When considering the spatial distribution, TNF­α was expressed dominantly in the aneurysmal body and IL­10 was dominant in the aneurysmal neck in the late stage. The PPARγ agonist RGZ may reduce the expression of TNF­α in the late stage and increase the expression level of IL­10, maintaining the TNF­α or IL­10 expression levels at the same levels as in the early stage. Aortic inflammation during AAA formation is dynamic. Protective anti­inflammatory cytokines are upregulated in the early 'compensatory stage'; however, pro­inflammatory cytokines are dominant in the late 'decompensatory stage'. PPARγ is likely to continue to upregulate the expression of anti­inflammatory cytokines, extend the 'compensatory stage', and decelerate the process of AAA development and rupture.

A siphonous morphology affects light-harvesting modulation in the intertidal green macroalga Bryopsis corticulans (Ulvophyceae).

MAIN CONCLUSION: The macroalga Bryopsis corticulans relies on a sustained protective NPQ and a peculiar body architecture to efficiently adapt to the extreme light changes of intertidal shores. During low tides, intertidal algae experience prolonged high light stress. Efficient dissipation of excess light energy, measured as non-photochemical quenching (NPQ) of chlorophyll fluorescence, is therefore required to avoid photodamage. Light-harvesting regulation was studied in the intertidal macroalga Bryopsis corticulans, during high light and air exposure. Photosynthetic capacity and NPQ kinetics were assessed in different filament layers of the algal tufts and in intact chloroplasts to unravel the nature of NPQ in this siphonous green alga. We found that the morphology and pigment composition of the B. corticulans body provides functional segregation between surface sunlit filaments (protective state) and those that are underneath and undergo severe light attenuation (light-harvesting state). In the surface filaments, very high and sustained NPQ gradually formed. NPQ induction was triggered by the formation of transthylakoid proton gradient and independent of the xanthophyll cycle. PsbS and LHCSR proteins seem not to be active in the NPQ mechanism activated by this alga. Our results show that B. corticulans endures excess light energy pressure through a sustained protective NPQ, not related to photodamage, as revealed by the unusually quick restoration of photosystem II (PSII) function in the dark. This might suggest either the occurrence of transient PSII photoinactivation or a fast rate of PSII repair cycle.

The Diagnostic and Prognostic Role of Interleukin 12B and Interleukin 6R Gene Polymorphism in Patients With Ankylosing Spondylitis.

OBJECTIVES: Interleukin 23 (IL-23) pathway and IL-1 cluster genes play prominent role in the etiopathology of ankylosing spondylitis (AS). The aim of this study was to investigate the diagnostic and prognostic role of 5 single-nucleotide polymorphisms related to IL-23 pathway and IL-1 cluster genes in AS patients. METHODS: Four hundred thirty-one patients with AS and 206 age- and sex-matched healthy controls were recruited in this prospective cohort study. Five potential single-nucleotide polymorphisms (IL-23R [rs11209026], IL-12B [rs6871626], TYK2 [rs6511701], IL-6R [rs4129267], and IL-1R2 [rs2192752]) related to IL-23 pathway and IL-1 cluster genes by analyzing previous studies were genotyped. Among 431 total AS patients, 198 active cases were treated and followed up for 24 weeks. RESULTS: Frequencies of IL-12B AA (rs6871626) and IL-6R TT (rs4129267) genotypes were increased in AS patients compared with healthy controls (both P < 0.001), and IL-12B A (rs6871626) as well as IL-6R T (rs4129267) allele increased the risk of AS independently (both P < 0.001). The Bath Ankylosing Spondylitis Disease Activity Index score was found to be elevated in AS patients with IL-12B AA (rs6871626) compared with patients with the CA and CC genotypes (P = 0.002 and P < 0.001, respectively), and the Bath Ankylosing Spondylitis Functional Index score was also increased in AS patents with IL-12B AA (rs6871626) than in those with the CA and CC genotypes (P = 0.001 and P < 0.001). In addition, IL-6R T (rs4129267) allele could predict a worse ASAS-20 (Assessment of SpondyloArthritis international Society) response at week 24 as an independent factor by multivariate logistic regression analysis with additive model (P = 0.011). CONCLUSIONS: Interleukin 12B (rs6871626) and IL-6R (rs4129267) gene polymorphisms could serve as promising biomarkers for diagnosis and prognosis in AS patients.

Role of CXCR4 and SDF1 as prognostic factors for survival and the association with clinicopathology in colorectal cancer: A systematic meta-analysis.

C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 were proven to play important roles in several types of cancer and in many biological processes connected with tumor growth, invasion, angiogenesis, and metastasis. However, the clinical significance of C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 expression in colorectal cancer remains inaccurate. The purpose of this systematic meta-analysis is to investigate the role of C-X-C chemokine receptor type 4 and stromal cell-derived factor-1 as prognostic factors for survival and the association between C-X-C chemokine receptor type 4/ stromal cell-derived factor-1 and clinicopathology in colorectal cancer. Databases including PubMed, EMBASE, and Cochrane Library were searched for relevant literatures updated till January 2017. Review Manager 5.3 was used for data analysis. In our meta-analysis, C-X-C chemokine receptor type 4 expression is related to tumor-node-metastasis stage, tumor differentiation, liver metastasis, lymph node metastasis, distant metastasis, and diagnosis, and no correlation of C-X-C chemokine receptor type 4 expression with tumor size, gender, preoperative carcinoembryonic antigen, age, or vascular invasion has been observed. Stromal cell-derived factor-1 expression has no relationship with tumor-node-metastasis stage, lymph node metastasis, vascular invasion, age, gender, distant metastasis, or diagnosis. The expression of stromal cell-derived factor-1 has association with tumor differentiation. Moreover, the pooled hazard ratio for disease-free survival/overall survival showed that overexpression of C-X-C chemokine receptor type 4/stromal cell-derived factor-1 reduced disease-free survival/overall survival in colorectal cancer. Therefore, High expression of C-X-C chemokine receptor type 4/stromal cell-derived factor-1 which is essential in tumor progression can predict poor survival that may provide more advance prognostic clues to colorectal cancer patients.

Prospective Randomized Study of Sarpogrelate Versus Clopidogrel-based Dual Antiplatelet Therapies in Patients Undergoing Femoropopliteal Arterial Endovascular Interventions: Preliminary Results.

BACKGROUND: Sarpogrelate is a selective 5-hydroxytryptamine (5-HT) receptor subtype 2A antagonist which blocks 5-HT induced platelet aggregation and proliferation of vascular smooth muscle cells. We compared the efficacy of sarpogrelate-based dual antiplatelet therapies for the prevention of restenosis and target lesion revascularization (TLR) rates comparing with that of clopidogrel after percutaneous endovascular interventions (EVIs) of femoropopliteal (FP) arterial lesions. METHODS: This prospective, multicenter, randomized clinical trial recruited a total of 120 patients with successful EVI of FP lesions at seven centers across China between January 2011 and June 2012. Patients were randomized to receive either sarpogrelate (100 mg trice daily for 6 months, n = 63) or clopidogrel (75 mg once daily for 6 months, n = 57). All patients also received oral aspirin (100 mg once daily for 12 months). Clinical follow-up was conducted up to 12 months postprocedure. RESULTS: There was no significant difference between the two groups in basic demographic data. The restenosis rate was higher in the clopidogrel group (22.80%) than in sarpogrelate group (17.50%), but there was no significant difference between these two groups (P = 0.465). The TLR rate, ipsilateral amputation rate, mortality in all-cause and bleeding rate were also similar in the two groups (P > 0.05). CONCLUSIONS: Aspirin plus sarpogrelate is a comparable antithrombotic regimen to aspirin plus clopidogrel after EVI of FP arterial lesions. Dual antiplatelet therapies might play an important role in preventing restenosis after successful EVI of FP lesions.

Treatment of advanced rectal cancer after renal transplantation.

Renal transplantation is a standard procedure for end-stage renal disease today. Due to immunosuppressive drugs and increasing survival time after renal transplantation, patients with transplanted kidneys carry an increased risk of developing malignant tumors. In this case report, 3 patients with advanced rectal cancer after renal transplantation for renal failure were treated with anterior resection or abdominoperineal resection plus total mesorectal excision, followed by adjuvant chemotherapy. One patient eventually died of metastasized cancer 31 mo after therapy, although his organ grafts functioned well until his death. The other 2 patients were well during the 8 and 21 mo follow-up periods after rectal resection. We therefore strongly argue that patients with advanced rectal cancer should receive standard oncology treatment, including operation and adjuvant treatment after renal transplantation. Colorectal cancer screening in such patients appears justified.

High-light induced superoxide radical formation in cytochrome b6f complex from Bryopsis corticulans as detected by EPR spectroscopy.

The generation of superoxide radical (O2·â») in Cyt b6f of Bryopsis corticulans under high light illumination was studied using electron paramagnetic resonance (EPR) spectroscopy. This could be evidenced by the addition of SOD which specifically reacted with O2·â». The generation of O2·â» was lost in the absence of oxygen and was found to be suppressed in the presence of NaN3 and be scavenged by extraneous antioxidants such as ascorbate, ß-carotene and glutathione which could also scavenged ¹O2*. These results indicated that O2·â» which produced under high light illumination in Cyt b6f of B. corticulans might rise from a reaction which ¹O2* could participated in. Also the photo-protection mechanism to Cyt b6f complex by antioxidants which might contain in thylakoid was speculated.

High-light induced singlet oxygen formation in cytochrome b(6)f complex from Bryopsis corticulans as detected by EPR spectroscopy.

Electron paramagnetic resonance (EPR) spectroscopy was used to detect the light-induced formation of singlet oxygen ((1)O(2)*) in the intact and the Rieske-depleted cytochrome b(6)f complexes (Cyt b(6)f) from Bryopsis corticulans, as well as in the isolated Rieske Fe-S protein. It is shown that, under white-light illumination and aerobic conditions, chlorophyll a (Chl a) bound in the intact Cyt b(6)f can be bleached by light-induced (1)O(2)*, and that the (1)O(2)* production can be promoted by D(2)O or scavenged by extraneous antioxidants such as l-histidine, ascorbate, beta-carotene and glutathione. Under similar experimental conditions, (1)O(2)* was also detected in the Rieske-depleted Cyt b(6)f complex, but not in the isolated Rieske Fe-S protein. The results prove that Chl a cofactor, rather than Rieske Fe-S protein, is the specific site of (1)O(2)* formation, a conclusion which draws further support from the generation of (1)O(2)* with selective excitation of Chl a using monocolor red light.