Dual-tracer PET/CT in the management of hepatocellular carcinoma.

Background & Aims: Combined 18F-fluorodeoxyglucose (FDG) and 11C-acetate (dual-tracer) positron-emission tomography/computed tomography (PET/CT) is being increasingly performed for the management of hepatocellular carcinoma (HCC), although its role is not well defined. Therefore, we evaluated its effectiveness in (i) staging, (ii) characterization of indeterminate lesions on conventional imaging, and (iii) detection of HCC in patients with unexplained elevations in serum alpha-fetoprotein (AFP) levels. Methods: We retrospectively assessed 525 consecutive patients from three tertiary centers between 2014 and 2020. For staging, we recorded new lesion detection rates, changes in the Barcelona Clinic Liver Cancer (BCLC) classification, and treatment allocation due to dual-tracer PET/CT. To characterize indeterminate lesions and unexplained elevation of serum AFP levels, the sensitivity and specificity of dual-tracer PET/CT in diagnosing HCC were evaluated. A multidisciplinary external review and a cost-benefit analysis of patients for metastatic screening were also performed. Results: Dual-tracer PET/CT identified new lesions in 14.3% of 273 staging patients, resulting in BCLC upstaging in 11.7% and treatment modifications in 7.7%. It upstaged 8.1% of 260 patients undergoing metastatic screening, with estimated savings of US$495 per patient. It had a sensitivity and specificity of 80.7% (95% CI 71.2-88.6%) and 94.8% (95% CI 90.4-98.6%), respectively, for diagnosing HCC in 201 indeterminate lesions. It detected HCC in 45.1% of 51 patients with unexplained elevations in serum AFP concentrations. External review revealed substantial agreement between local and external image interpretation and patient assessment (n = 273, κ = 0.822; 95% CI 0.803-0.864). Conclusions: Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP. Impact and implications: Compared to CT or MRI, dual-tracer positron-emission tomography/computed tomography (PET/CT) led to upstaging in 12% of patients with hepatocellular carcinoma (HCC) undergoing staging, resulting in treatment modification in 8% of cases and a cost saving of US$495 per patient. It also accurately detected HCC in high-risk cases where CT or MRI were equivocal or normal. Dual-tracer PET/CT provides added value beyond conventional imaging in patients with HCC by improving staging, confirming HCC diagnosis with high accuracy in patients with indeterminate lesions, and detecting HCC in patients with unexplained elevation of serum AFP.

Activation of 5-HT6 Receptors in the Ventrolateral Orbital Cortex Produces Anti-Anxiodepressive Effects in a Rat Model of Neuropathic Pain.

The comorbidity of anxiety and depression frequently occurs in patients with neuropathic pain. The ventrolateral orbital cortex (VLO) plays a critical role in mediating neuropathic pain and anxiodepression in rodents. Previous studies suggested that 5-HT6 receptors in the VLO are involved in neuropathic pain. Strong evidence supports a close link between 5-HT6 receptors and affective disorders such as depression and anxiety disorders. However, it remains unclear whether the 5-HT6 receptors in the VLO are involved in neuropathic pain-induced anxiodepression. Using a rat neuropathic pain model of spared nerve injury (SNI), we demonstrated that rats exhibited significant anxiodepression-like behaviors and the expression of VLO 5-HT6 receptors obviously decreased four weeks after SNI surgery. Microinjection of the 5-HT6 receptor agonist EMD-386088 into the VLO or overexpression of VLO 5-HT6 receptors alleviated anxiodepression-like behaviors. These effects were blocked by pre-microinjection of a selective 5-HT6 receptor antagonist (SB-258585) or inhibitors of AC (SQ-22536), PKA (H89), and MEK1/2 (U0126) respectively. Meanwhile, the expression of p-ERK, p-CREB, and BDNF in the VLO decreased four weeks after SNI surgery. Furthermore, administration of EMD-386088 upregulated the expression of BDNF, p-ERK, and p-CREB in the VLO of SNI rats, which were reversed by pre-injection of SB-258585. These findings suggest that activating 5-HT6 receptors in the VLO has anti-anxiodepressive effects in rats with neuropathic pain via activating AC-cAMP-PKA-MERK-CREB-BDNF signaling pathway. Accordingly, 5-HT6 receptor in the VLO could be a potential target for the treatment of the comorbidity of neuropathic pain and anxiodepression.

Relationship between circulating thrombospondin-1 messenger ribonucleic acid and microribonucleic acid-194 levels in Chinese patients with type 2 diabetic kidney disease: The outcomes of a case-control study.

AIMS/INTRODUCTION: We investigated the relationship of circulating TSP-1 mRNA and miR-194 with diabetic kidney disease's degree. MATERIALS AND METHODS: We enrolled 167 hospitalized type 2 diabetes patients in the endocrinology department. Patients were split into three groups according to urinary microalbumin: A, B and C. The control group comprised healthy outpatients (n = 163). The quantities of microribonucleic acid (miR)-194 and thrombospondin-1 (TSP-1) messenger ribonucleic acid (mRNA) in the participants' circulation were measured using a quantitative real-time polymerase chain reaction. RESULTS: Circulating TSP-1 mRNA (P = 0.024) and miR-194 (P = 0.029) expressions significantly increased in type 2 diabetes patients. Circulating TSP-1 mRNA (P = 0.040) and miR-194 (P = 0.007) expression levels differed significantly among the three groups; circulating TSP-1 mRNA expression increased with urinary microalbumin. However, miR-194 declined in group B and increased in group C. Circulating TSP-1 mRNA was positively correlated with cystatin-c (r = 0.281; P = 0.021) and microalbumin/creatinine ratio (UmALB/Cr; r = 0.317; P = 0.009); miR-194 was positively correlated with UmALB/Cr (r = 0.405; P = 0.003). Stepwise multivariate linear regression analysis showed cystatin-c (ß = 0.578; P = 0.021) and UmALB/Cr (ß = 0.001; P = 0.009) as independent factors for TSP-1 mRNA; UmALB/Cr (ß = 0.005; P = 0.028) as an independent factor for miR194. Areas under the curve for circulating TSP-1 mRNA and miR194 were 0.756 (95% confidence interval 0.620-0.893; sensitivity 0.69 and specificity 0.71, P < 0.01) and 0.584 (95% confidence interval 0.421-0.748; sensitivity 0.54 and specificity 0.52, P < 0.01), respectively. CONCLUSIONS: Circulating TSP-1 mRNA and miR-194 expressions significantly increased in type 2 diabetes patients. The microalbumin group had lower levels of miR-194 (a risk factor that is valuable for type 2 diabetes kidney disease evaluation).

In vitro modulation the Notch pathway by piperine: A therapeutic strategy for docetaxel-resistant and non-resistant prostate cancer.

Docetaxel (DTX) resistance poses a significant challenge in the treatment of prostate cancer (PCa), often leading to chemotherapy failure. This study investigates the ability of piperine, a compound derived from black pepper, to enhance the sensitivity of PCa cells to DTX and elucidates its underlying mechanism. We established a DTX-resistant PCa cell line, DU145/DTX, to conduct our experiments. Through a series of assays, including MTT for cell viability, flow cytometry for apoptosis, Transwell for cell migration and invasion, and western blot for protein expression analysis, we assessed the effects of piperine on these cellular functions and on the Notch signaling pathway components. Our results demonstrated that we successfully established the DTX-resistant PCa cell line DU145/DTX. Piperine effectively decreased the viability of both DU145 and its DTX-resistant counterpart, DU145/DTX, in a concentration and time-dependent manner when used alone and in combination with DTX. Notably, piperine also induced apoptosis and reduced the migration and invasion capabilities of these cells. At the molecular level, piperine down-regulated the Notch pathway by inhibiting Notch1 and Jagged1 signaling, as well as reducing the expression of downstream effectors Hey1 and hes family bHLH transcription factor 1. The study concludes that piperine's ability to modulate the Notch signaling pathway and induce apoptosis highlights its potential as a complementary treatment for DTX-resistant PCa, paving the way for the use of traditional Chinese medicinal compounds in modern oncology treatment strategies.

Plexin domain-containing 1 may be a biomarker of poor prognosis in hepatocellular carcinoma patients, may mediate immune evasion.

BACKGROUND: For the first time, we investigated the oncological role of plexin domain-containing 1 (PLXDC1), also known as tumor endothelial marker 7 (TEM7), in hepatocellular carcinoma (HCC). AIM: To investigate the oncological profile of PLXDC1 in HCC. METHODS: Based on The Cancer Genome Atlas database, we analyzed the expression of PLXDC1 in HCC. Using immunohistochemistry, quantitative real-time polymerase chain reaction (qRT-PCR), and Western blotting, we validated our results. The prognostic value of PLXDC1 in HCC was analyzed by assessing its correlation with clinicopathological features, such as patient survival, methylation level, tumor immune microenvironment features, and immune cell surface checkpoint expression. Finally, to assess the immune evasion potential of PLXDC1 in HCC, we used the tumor immune dysfunction and exclusion (TIDE) website and immunohistochemical staining assays. RESULTS: Based on immunohistochemistry, qRT-PCR, and Western blot assays, overexpression of PLXDC1 in HCC was associated with poor prognosis. Univariate and multivariate Cox analyses indicated that PLXDC1 might be an independent prognostic factor. In HCC patients with high methylation levels, the prognosis was worse than in patients with low methylation levels. Pathway enrichment analysis of HCC tissues indicated that genes upregulated in the high-PLXDC1 subgroup were enriched in mesenchymal and immune activation signaling, and TIDE assessment showed that the risk of immune evasion was significantly higher in the high-PLXDC1 subgroup compared to the low-PLXDC1 subgroup. The high-risk group had a significantly lower immune evasion rate as well as a poor prognosis, and PLXDC1-related risk scores were also associated with a poor prognosis. CONCLUSION: As a result of this study analyzing PLXDC1 from multiple biological perspectives, it was revealed that it is a biomarker of poor prognosis for HCC patients, and that it plays a role in determining immune evasion status.

Delayed metastatic endometrial carcinoma mimicking primary colon adenocarcinoma: A surprise histopathological finding.

Key Clinical Message: Colorectal cancer is the third most common malignancy worldwide, with an increasing incidence. Colonic metastasis is a rare occurrence; thus, misdiagnosis is common. Immunohistochemistry facilitates accurate diagnosis and subsequent management. Abstract: Most cancers in the colon are primary colorectal cancers, however metastasis from another primary is possible, albeit rare. Endometrial cancer metastasis to the colon is a rare occurrence and is only described in a handful of cases. We describe a rare case of metastatic endometrial cancer in the colon presenting 5 years post radical hysterectomy and adjuvant radiotherapy in a 62-year-old female. She presented with a 1-week history of right upper quadrant pain, with no other associated symptoms. She was presumed to have a primary colorectal cancer based on her colonoscopy and CT findings; later proven otherwise by immunohistochemistry (IHC). Endometrial cancer metastasis to the colon is rare, thus misdiagnosis can easily occur. Currently, there are 6 similar cases reported in the literature, all occurring in the absence of colorectal endometriosis. This case illustrates the relative importance of considering colon as a potential site for metastasis of endometrial cancer and the utility of IHC in aiding diagnosis and guiding further management.

Evaluating effectiveness and safety of combined percutaneous transhepatic gallbladder drainage and laparoscopic cholecystectomy in acute cholecystitis patients: Meta-analysis.

BACKGROUND: Acute cholecystitis (AC) is a common disease in general surgery. Laparoscopic cholecystectomy (LC) is widely recognized as the "gold standard" surgical procedure for treating AC. For low-risk patients without complications, LC is the recommended treatment plan, but there is still controversy regarding the treatment strategy for moderate AC patients, which relies more on the surgeon's experience and the medical platform of the visiting unit. Percutaneous transhepatic gallbladder puncture drainage (PTGBD) can effectively alleviate gallbladder inflammation, reduce gallbladder wall edema and adhesion around the gallbladder, and create a "time window" for elective surgery. AIM: To compare the clinical efficacy and safety of LC or PTGBD combined with LC for treating AC patients, providing a theoretical basis for choosing reasonable surgical methods for AC patients. METHODS: In this study, we conducted a clinical investigation regarding the combined use of PTGBD tubes for the treatment of gastric cancer patients with AC. We performed searches in the following databases: PubMed, Web of Science, EMBASE, Cochrane Library, China National Knowledge Infrastructure, and Wanfang Database. The search encompassed literature published from the inception of these databases to the present. Subsequently, relevant data were extracted, and a meta-analysis was conducted using RevMan 5.3 software. RESULTS: A comprehensive analysis was conducted, encompassing 24 studies involving a total of 2564 patients. These patients were categorized into two groups: 1371 in the LC group and 1193 in the PTGBD + LC group. The outcomes of the meta-analysis revealed noteworthy disparities between the PTGBD + LC group and the LC group in multiple dimensions: (1) Operative time: Mean difference (MD) = 17.51, 95%CI: 9.53-25.49, P < 0.01; (2) Conversion to open surgery rate: Odds ratio (OR) = 2.95, 95%CI: 1.90-4.58, P < 0.01; (3) Intraoperative bleeding loss: MD = 32.27, 95%CI: 23.03-41.50, P < 0.01; (4) Postoperative hospital stay: MD = 1.44, 95%CI: 0.14-2.73, P = 0.03; (5) Overall postoperative complication rate: OR = 1.88, 95%CI: 1.45-2.43, P < 0.01; (6) Bile duct injury: OR = 2.17, 95%CI: 1.30-3.64, P = 0.003; (7) Intra-abdominal hemorrhage: OR = 2.45, 95%CI: 1.06-5.64, P = 0.004; and (8) Wound infection: OR = 0. These findings consistently favored the PTGBD + LC group over the LC group. There were no significant differences in the total duration of hospitalization [MD = -1.85, 95%CI: -4.86-1.16, P = 0.23] or bile leakage [OR = 1.33, 95%CI: 0.81-2.18, P = 0.26] between the two groups. CONCLUSION: The combination of PTGBD tubes with LC for AC treatment demonstrated superior clinical efficacy and enhanced safety, suggesting its broader application value in clinical practice.

B-Myb deficiency boosts bortezomib-induced immunogenic cell death in colorectal cancer.

B-Myb has received considerable attention for its critical tumorigenic function of supporting DNA repair. However, its modulatory effects on chemotherapy and immunotherapy have rarely been reported in colorectal cancer. Bortezomib (BTZ) is a novel compound with chemotherapeutic and immunotherapeutic effects, but it fails to work in colorectal cancer with high B-Myb expression. The present study was designed to investigate whether B-Myb deletion in colorectal cancer could potentiate the immune efficacy of BTZ against colorectal cancer and to clarify the underlying mechanism. Stable B-Myb knockdown was induced in colorectal cancer cells, which increased apoptosis of the cancer cells relative to the control group in vitro and in vivo. We found that BTZ exhibited more favourable efficacy in B-Myb-defective colorectal cancer cells and tumor-bearing mice. BTZ treatment led to differential expression of genes enriched in the p53 signaling pathway promoted more powerful downstream DNA damage, and arrested cell cycle in B-Myb-defective colorectal cancer. In contrast, recovery of B-Myb in B-Myb-defective colorectal cancer cells abated BTZ-related DNA damage, cell cycle arrest, and anticancer efficacy. Moreover, BTZ promoted DNA damage-associated enhancement of immunogenicity, as indicated by potentiated expression of HMGB1 and HSP90 in B-Myb-defective cells, thereby driving M1 polarization of macrophages. Collectively, B-Myb deletion in colorectal cancer facilitates the immunogenic death of cancer cells, thereby further promoting the immune efficacy of BTZ by amplifying DNA damage. The present work provides an effective molecular target for colorectal cancer immunotherapy with BTZ.

Hierarchically Biomimetic Scaffolds with Anisotropic Micropores and Nanotopological Patterns to Promote Bone Regeneration via Geometric Modulation.

Structural engineering is an appealing means to modulate osteogenesis without the intervention of exogenous cells or therapeutic agents. In this work, a novel 3D scaffold with anisotropic micropores and nanotopographical patterns is developed. Scaffolds with oriented pores are fabricated via the selective extraction of water-soluble polyethylene oxide from its poly(ε-caprolactone) co-continuous mixture and uniaxial stretching. The plate apatite-like lamellae are subsequently hatched on the pore walls through surface-induced epitaxial crystallization. Such a unique geometric architecture yields a synergistic effect on the osteogenic capability. The prepared scaffold leads to a 19.2% and 128.0% increase in the alkaline phosphatase activity of rat bone mesenchymal stem cells compared to that of the scaffolds with only oriented pores and only nanotopographical patterns, respectively. It also induces the greatest upregulation of osteogenic-related gene expression in vitro. The cranial defect repair results demonstrate that the prepared scaffold effectively promotes new bone regeneration, as indicated by a 350% increase in collagen I expression in vivo compared to the isotropic porous scaffold without surface nanotopology after implantation for 14 weeks. Overall, this work provides geometric motifs for the transduction of biophysical cues in 3D porous scaffolds, which is a promising option for tissue engineering applications.

Prolonged oral intake of green tea polyphenols attenuates delirium-like behaviors in mice induced by anesthesia/surgery.

Postoperative delirium (POD) is a severe postoperative complication characterized by delirium-like symptoms. So far, no effective preventable strategy for POD prevention has been identified. Reports show that the consumption of green tea polyphenols (GTP) is associated with better cognitive function by modulating the composition of gut microbiota. Whether GTP also play a role in alleviating POD through gut microbiota is unknown. Herein, we studied the effect of prolonged (eight weeks) GTP intake on postoperative delirium in C57BL/6 mice with laparotomies under isoflurane anesthesia (anesthesia/surgery). We subsequently investigated anesthesia/surgery caused behavioral changes and increased the expression of malondialdehyde (MAD), an oxidative stress marker, and the activities of superoxide dismutase (SOD), an antioxidant marker, in the mice at 6 h after anesthesia/surgery. However, GTP administration reversed these changes and alleviated anesthesia/surgery-induced decrease in the abundance of gut bacterial genera, Roseburia. Further, fecal microbiota transplant demonstrated that compared with mice in the control group, treatment of C57BL/6 mice with feces from GTP-treated mice had a slight effect on the behavioral changes of mice. These data suggest that daily consumption of GTP could protect against anesthesia/surgery-induced behavioral changes, which is closely associated with gut microbiota modification by GTP.

Prognostic PET [11C]-acetate uptake is associated with hypoxia gene expression in patients with late-stage hepatocellular carcinoma - a bench to bed study.

BACKGROUND: Positron Emission Tomography (PET) with combined [18F]-FDG and [11C]-acetate (dual-tracer) is used for the management of hepatocellular carcinoma (HCC) patients, although its prognostic value and underlying molecular mechanism remain poorly understood. We hypothesized that radiotracer uptake might be associated with tumor hypoxia and validated our findings in public and local human HCC cohorts. METHODS: Twelve orthotopic HCC xenografts were established using MHCC97L cells in female nude mice, with 5 having undergone hepatic artery ligation (HAL) to create tumor hypoxia in vivo. Tumors in both Control and HAL-treated xenografts were imaged with [11C]-acetate and [18F]-FDG PET-MR and RNA sequencing was performed on the resected tumors. Semiquantitative analysis of PET findings was then performed, and the findings were then validated on the Cancer Genome Atlas Liver Hepatocellular Carcinoma (TCGA-LIHC) cohort and patients from our institution. RESULTS: HAL-treated mice showed lower [11C]-acetate (HAL-treated vs. Control, tumor-to-liver SUV ratio (SUVTLR): 2.14[2.05-2.21] vs 3.11[2.75-5.43], p = 0.02) but not [18F]-FDG (HAL-treated vs. Control, SUVTLR: 3.73[3.12-4.35] vs 3.86[3.7-5.29], p = 0.83) tumor uptakes. Gene expression analysis showed the PET phenotype is associated with upregulation of hallmark hypoxia signature. The prognostic value of the hypoxia gene signature was tested on the TCGA-LIHC cohort with upregulation of hypoxia gene signature associated with poorer overall survival (OS) in late-stage (stage III and IV) HCC patients (n = 66, OS 2.05 vs 1.67 years, p = 0.046). Using a local cohort of late-stage HCC patients who underwent dual-tracer PET-CT, tumors without [11C]-acetate uptake are associated with poorer prognosis (n = 51, OS 0.25 versus 1.21 years, p < 0.0001) and multivariable analyses showed [11C]-acetate tumor uptake as an independent predictor of OS (HR 0.17 95%C 0.06-0.42, p < 0.0001). CONCLUSIONS: [11C]-acetate uptake is associated with alteration of tumor hypoxia gene expression and poorer prognosis in patients with advanced HCC.

Tick cysteine protease inhibitors suppress immune responses in mannan-induced psoriasis-like inflammation.

Protease inhibitors regulate various biological processes and prevent host tissue/organ damage. Specific inhibition/regulation of proteases is clinically valuable for treating several diseases. Psoriasis affects the skin in the limbs and scalp of the body, and the contribution of cysteine and serine proteases to the development of skin inflammation is well documented. Cysteine protease inhibitors from ticks have high specificity, selectivity, and affinity to their target proteases and are efficient immunomodulators. However, their potential therapeutic effect on psoriasis pathogenesis remains to be determined. Therefore, we tested four tick cystatins (Sialostatin L, Sialostatin L2, Iristatin, and Mialostatin) in the recently developed, innate immunity-dependent mannan-induced psoriasis model. We explored the effects of protease inhibitors on clinical symptoms and histological features. In addition, the number and percentage of immune cells (dendritic cells, neutrophils, macrophages, and γδT cells) by flow cytometry, immunofluorescence/immunohistochemistry and, the expression of pro-inflammatory cytokines (TNF-a, IL-6, IL-22, IL-23, and IL-17 family) by qPCR were analyzed using skin, spleen, and lymph node samples. Tick protease inhibitors have significantly decreased psoriasis symptoms and disease manifestations but had differential effects on inflammatory responses and immune cell populations, suggesting different modes of action of these inhibitors on psoriasis-like inflammation. Thus, our study demonstrates, for the first time, the usefulness of tick-derived protease inhibitors for treating skin inflammation in patients.

Discovery of new triterpenoids from Leptopus clarkei and their antiproliferative activity on cancer cells.

Two new triterpenoids (1-2), along with six known analogues (3-8) were obtained from the dried whole plant of Leptopus clarkei. Compound 1 is a 3,4-seco-lupane-type triterpenoid, and compound 2 is a phenylpropanoid-conjugated pentacyclic triterpenoid possessing trans-p-coumaroyl unit attached to oleanane-type skeleton. This is the first report on chemical investigation of the L. clarkei, and the triterpenoid derivatives were found in this plant for the first time. The structures of the new compounds were unequivocally elucidated by HRESIMS and 1D/2D NMR data. Additionally, the isolated compounds were evaluated for theircytotoxicities against four cancer cell lines including HepG2, MCF-7, A549 and HeLa. Notably, compound 2 exhibited the most significant antiproliferative activity with IC50 less than 20 µM for four cancer lines.

Establishment and application of three predictive models of anastomotic leakage after rectal cancer sphincter-preserving surgery.

BACKGROUND: Anastomotic leakage (AL) occurs frequently after sphincter-preserving surgery for rectal cancer and has a significant mortality rate. There are many factors that influence the incidence of AL, and each patient's unique circumstances add to this diversity. The early identification and prediction of AL after sphincter-preserving surgery are of great significance for the application of clinically targeted preventive measures. Developing an AL predictive model coincides with the aim of personalised healthcare, enhances clinical management techniques, and advances the medical industry along a more precise and intelligent path. AIM: To develop nomogram, decision tree, and random forest prediction models for AL following sphincter-preserving surgery for rectal cancer and to evaluate the predictive efficacy of the three models. METHODS: The clinical information of 497 patients with rectal cancer who underwent sphincter-preserving surgery at Jincheng People's Hospital of Shanxi Province between January 2017 and September 2022 was analyzed in this study. Patients were divided into two groups: AL and no AL. Using univariate and multivariate analyses, we identified factors influencing postoperative AL. These factors were used to establish nomogram, decision tree, and random forest models. The sensitivity, specificity, recall, accuracy, and area under the receiver operating characteristic curve (AUC) were compared between the three models. RESULTS: AL occurred in 10.26% of the 497 patients with rectal cancer. The nomogram model had an AUC of 0.922, sensitivity of 0.745, specificity of 0.966, accuracy of 0.936, recall of 0.987, and accuracy of 0.946. The above indices in the decision tree model were 0.919, 0.833, 0.862, 0.951, 0.994, and 0.955, respectively and in the random forest model were 1.000, 1.000, 1.000, 0.951, 0.994, and 0.955, respectively. The DeLong test revealed that the AUC value of the decision-tree model was lower than that of the random forest model (P < 0.05). CONCLUSION: The random forest model may be used to identify patients at high risk of AL after sphincter-preserving surgery for rectal cancer owing to its strong predictive effect and stability.

Systematically analysis of decompensated cirrhotic patients with spontaneous bacterial peritonitis to identify diagnostic and prognostic indexes.

BACKGROUND: Spontaneous bacterial peritonitis (SBP) is a common complication in patients with cirrhosis. The diagnosis of SBP is still mostly based on ascites cultures and absolute ascites polymorphonuclear (PMN) cell count, which restricts the widely application in clinical settings. This study aimed to identify reliable and easy-to-use biomarkers for both diagnosis and prognosis of cirrhotic patients with SBP. METHODS: We conducted a retrospective study including 413 cirrhotic patients from March 2013 to July 2022 in the First Affiliated Hospital of Guangxi Medical University. Patients' clinical characteristics and laboratory indices were collected and analyzed. Two machine learning methods (Xgboost and LASSO algorithms) and a logistic regression analysis were adopted to screen and validate the indices associated with the risk of SBP. A predictive model was constructed and validated using the estimated area under curve (AUC). The indices related to the survival of cirrhotic patients were also analyzed. RESULTS: A total of 413 cirrhotic patients were enrolled in the study, of whom 329 were decompensated and 84 were compensated. 52 patients complicated and patients with SBP had a poorer Child-Pugh score (P < 0.05). Patients with SBP had a greater proportion of malignancies than those without SBP(P < 0.05). The majority of laboratory test indicators differed significantly between patients with and without SBP (P < 0.05). Albumin, neutrophil-to-lymphocyte ratio (NLR), and ferritin-to-neutrophil ratio (FNR) were found to be independently associated with SBP in decompensated cirrhotic patients using LASSO algorithms, and logistic regression analysis. The model established by the three indices showed a high predictive value with an AUC of 0.808. Furthermore, increased neutrophils, ALP, and C-reactive protein-to-albumin ratio (CAR) were associated with the shorter survival time of patients with decompensated cirrhosis, and the combination of these indices showed a greater predictive value for cirrhotic patients. CONCLUSIONS: The present study identified FNR as a novel index in the diagnosis of SBP in decompensated patients with cirrhosis. A model based on neutrophils, ALP and CAR showed high performance in predicting the prognosis of patients with decompensated cirrhosis.

Mesenchymal stem cell-regulated miRNA-mRNA landscape in acute-on-chronic liver failure.

BACKGROUND: Acute-on-chronic liver failure (ACLF) is a major challenge in the field of hepatology. While mesenchymal stem cell (MSC) therapy can improve the prognosis of patients with ACLF, the molecular mechanisms through which MSCs attenuate ACLF remain poorly understood. We performed global miRNA and mRNA expression profiling via next-generation sequencing of liver tissues from MSC-treated ACLF mice to identify important signaling pathways and major factors implicated in ACLF alleviation by MSCs. METHODS: Carbon tetrachloride-induced ACLF mice were treated with saline or mouse bone marrow-derived MSCs. Mouse livers were subjected to miRNA and mRNA sequencing. Related signal transduction pathways were obtained through Gene Set Enrichment Analysis. Functional enrichment, protein-protein interaction, and immune infiltration analyses were performed for the differentially expressed miRNA target genes (DETs). Hub miRNA and mRNA associated with liver injury were analyzed using LASSO regression. The expression levels of hub genes were subjected to Pearson's correlation analysis and verified using RT-qPCR. The biological functions of hub genes were verified in vitro. RESULTS: The tricarboxylic acid cycle and peroxisome proliferator-activated receptor pathways were activated in the MSC-treated groups. The proportions of liver-infiltrating NK resting cells, M2 macrophages, follicular helper T cells, and other immune cells were altered after MSC treatment. The expression levels of six miRNAs and 10 transcripts correlated with the degree of liver injury. miR-27a-5p was downregulated in the mouse liver after MSC treatment, while its target gene E2f2 was upregulated. miR-27a-5p inhibited E2F2 expression, suppressed G1/S phase transition and proliferation of hepatocytes, in addition to promoting their apoptosis. CONCLUSIONS: This is the first comprehensive analysis of miRNA and mRNA expression in the liver tissue of ACLF mice after MSC treatment. The results revealed global changes in hepatic pathways and immune subpopulations. The miR-27a-5p/E2F2 axis emerged as a central regulator of the MSC-induced attenuation of ACLF. The current findings improve our understanding of the molecular mechanisms through which MSCs alleviate ACLF.

Immunological characterization and diagnostic models of RNA N6-methyladenosine regulators in Alzheimer's disease.

Alzheimer's disease (AD) is the most prevalent form of dementia, and it displays both clinical and molecular variability. RNA N6-methyladenosine (m6A) regulators are involved in a wide range of essential cellular processes. In this study, we aimed to identify molecular signatures associated with m6A in Alzheimer's disease and use those signatures to develop a predictive model. We examined the expression patterns of m6A regulators and immune features in Alzheimer's disease using the GSE33000 dataset. We examined the immune cell infiltration and molecular groups based on m6A-related genes in 310 Alzheimer's disease samples. The WGCNA algorithm was utilized to determine differently expressed genes within each cluster. After evaluating the strengths and weaknesses of the random forest model, the support vector machine model, the generalized linear model, and eXtreme Gradient Boosting, the best machine model was selected. Methods such as nomograms, calibration curves, judgment curve analysis, and the use of independent data sets were used to verify the accuracy of the predictions made. Alzheimer's disease and non-disease Alzheimer's groups were compared to identify dysregulated m6A-related genes and activated immune responses. In Alzheimer's disease, two molecular clusters linked to m6A were identified. Immune infiltration analysis indicated substantial variation in protection between groups. Cluster 1 included processes like the Toll-like receptor signaling cascade, positive regulation of chromatin binding, and numerous malignancies; cluster 2 included processes like the cell cycle, mRNA transport, and ubiquitin-mediated proteolysis. With a lower residual and root mean square error and a larger area under the curve (AUC = 0.951), the Random forest machine model showed the greatest discriminative performance. The resulting random forest model was based on five genes, and it performed well (AUC = 0.894) on external validation datasets. Accuracy in predicting Alzheimer's disease subgroups was also shown by analyses of nomograms, calibration curves, and decision curves. In this research, we methodically outlined the tangled web of connections between m6A and AD and created a promising prediction model for gauging the correlation between m6A subtype risk and AD pathology.

Siglec-9 acts as an immune-checkpoint molecule on macrophages in glioblastoma, restricting T-cell priming and immunotherapy response.

Neoadjuvant immune-checkpoint blockade therapy only benefits a limited fraction of patients with glioblastoma multiforme (GBM). Thus, targeting other immunomodulators on myeloid cells is an attractive therapeutic option. Here, we performed single-cell RNA sequencing and spatial transcriptomics of patients with GBM treated with neoadjuvant anti-PD-1 therapy. We identified unique monocyte-derived tumor-associated macrophage subpopulations with functional plasticity that highly expressed the immunosuppressive SIGLEC9 gene and preferentially accumulated in the nonresponders to anti-PD-1 treatment. Deletion of Siglece (murine homolog) resulted in dramatically restrained tumor development and prolonged survival in mouse models. Mechanistically, targeting Siglece directly activated both CD4+ T cells and CD8+ T cells through antigen presentation, secreted chemokines and co-stimulatory factor interactions. Furthermore, Siglece deletion synergized with anti-PD-1/PD-L1 treatment to improve antitumor efficacy. Our data demonstrated that Siglec-9 is an immune-checkpoint molecule on macrophages that can be targeted to enhance anti-PD-1/PD-L1 therapeutic efficacy for GBM treatment.

Revascularization Surgery for Moyamoya Vasculopathy: An Australian Experience.

BACKGROUND: Moyamoya vasculopathy is a rare steno-occlusive cerebrovascular disorder presenting with ischemia or hemorrhage. There are racial and geographic differences in presentation and outcome. There is little information regarding moyamoya in Australia. METHODS: Moyamoya patients undergoing surgery from 2001 to 2022 were studied retrospectively. The outcomes of revascularization surgery in adult and pediatric patients, with ischemic and hemorrhagic disease were analyzed, including functional outcomes, postoperative complications, bypass patency, and long-term rates of ischemic and hemorrhagic events. RESULTS: A total of 68 patients with 122 revascularized hemispheres and 8 posterior circulation revascularizations were included in this study. Eighteen patients were of Asian descent and 46 were of Caucasian origin. Presentation was with ischemia in 124 hemispheres and hemorrhage in six hemispheres. There were 92 direct, 34 indirect, and 4 combined revascularization surgeries performed. Early postoperative complications occurred in 3.1% (n = 4) of operations and delayed complications (infection, subdural hematoma) occurred after 4.6% (n = 6) of operations. Mean follow-up was 6.5 years (3-252 months). There was 100% patency of direct grafts at last follow-up. There were no hemorrhagic events following surgery and 1 new ischemic event 2 years after surgery. There was significant improvement in physical health functional outcomes at most recent follow-up (P < 0.05); mental health outcomes were not different between preoperative and postoperative assessments. CONCLUSIONS: The majority of Australian moyamoya patients are Caucasian and the most common clinical presentation is ischemia. Revascularization surgery had excellent outcomes with very low rates of ischemia and hemorrhage, comparing favorably to the natural history of moyamoya vasculopathy.