Antegrade and Retrograde Approaches with a Mechanical Thrombectomy Device for the Treatment of Acute Lower Limb Deep Vein Thrombosis.

OBJECTIVE: To examine the efficacy of antegrade and retrograde approaches with the AngioJet thrombectomy device for the treatment of acute lower limb deep vein thrombosis (DVT) and to evaluate the necessity of filter placement. METHODS: The clinical data of patients with acute lower limb DVT treated with the AngioJet device from January 2021 to June 2023 were retrospectively analyzed. The patients were divided into the antegrade and retrograde treatment groups according to the surgical approach and the direction of valve opening. The thrombosis interception rate of the filter, incidence of pulmonary embolism (PE), thrombectomy effectiveness, venous obstruction rate, and thrombosis recurrence rate of each treatment group were evaluated. In addition, factors affecting patency were analyzed. RESULTS: AngioJet was employed for 84 patients with acute lower limb DVT, treating a total of 88 limbs. The thrombosis interception rate of the filter was 35.7% (30 patients). The incidence of new PE or PE exacerbation was 6.0% (5 patients), and a filter retrieval rate of 97.6% (82 patients) was detected. Thrombus removal of grade III occurred in 35 (64.8%) of the 54 limbs (61.4%) in the antegrade treatment group versus 13 (38.2%) of the 34 limbs (38.6%) in the retrograde treatment group (P < 0.05). At 3 months, venous patency and bleeding events involved 52 (96.3%) and 4 (7.4%) limbs in the antegrade treatment group, respectively, versus 29 (85.3%) and 2 (5.9%) in the retrograde treatment group, respectively (P > 0.05). Regression analysis was performed to determine factors that may affect 3-month patency in both groups. Statistically significant linear relationships were found between 3-month patency and thrombus removal rate [odds ratio [OR] = 0.546 (0.326, 0.916)], thrombus formation time [OR = 1.018 (1.002, 1.036)], and preoperative thrombosis score [OR = 1.012 (1.002, 1.022)] in the antegrade treatment group, as well as thrombus removal rate [0.473 (0.229, 0.977)] in the retrograde treatment group. In regression analysis of factors affecting patency in both groups and the venous clinical severity score/Villalta score, a statistically significant linear relationship was found between thrombus formation time and the venous clinical severity score in the antegrade treatment group [0.576 (0.467, 0.710)]. CONCLUSIONS: Both antegrade and retrograde approaches are safe and effective for the treatment of acute lower limb DVT. There are no differences in 3-month deep vein patency and post-thrombotic syndrome (PTS) incidence rates. Individuals with acute lower limb DVT are at high risk of thrombus shedding after treatment with AngioJet thrombectomy, and placement of a vena cava filter (VCF) is recommended for effective interception.

Efficacy and safety of surufatinib plus toripalimab, a chemotherapy-free regimen, in patients with advanced gastric/gastroesophageal junction adenocarcinoma, esophageal squamous cell carcinoma, or biliary tract cancer.

BACKGROUND: The programmed death 1 inhibitor toripalimab plus the angio-immuno kinase inhibitor surufatinib showed a tolerable safety profile and preliminary efficacy in patients with advanced solid tumors in a phase I study. METHODS: This open-label, multi-cohort study in China enrolled patients with advanced solid tumors who had failed or were intolerable to standard treatment into tumor-specific cohorts. Patients received surufatinib (250 mg orally, once daily) plus toripalimab (240 mg intravenously, once every three weeks). Results for three cohorts (gastric/gastroesophageal junction [GC/GEJ] adenocarcinoma, esophageal squamous cell carcinoma [ESCC], and biliary tract carcinoma [BTC]) are reported here. The primary endpoint was investigator-assessed objective response rate (ORR) per Response Evaluation criteria in Solid Tumors version 1.1. RESULTS: Between December 17, 2019, and January 29, 2021, 60 patients were enrolled (GC/GEJ, n = 20; ESCC, n = 20; BTC, n = 20). At data cutoff (February 28, 2023), ORRs were 31.6%, 30.0%, and 11.1%, respectively. Median progression-free survival was 4.1, 2.7, and 2.9 months, respectively. Median overall survival was 13.7, 10.4, and 7.0 months, respectively. Overall, grade ≥ 3 treatment-related adverse events occurred in 28 (46.7%) patients. CONCLUSIONS: Surufatinib plus toripalimab showed promising antitumor activity and a tolerable safety profile in immunotherapy-naïve patients with GC/GEJ adenocarcinoma, ESCC, or BTC. These findings warrant further study in larger randomized trials comparing surufatinib plus toripalimab with standard therapies in these tumors. CLINICALTRIALS: gov NCT04169672.

Proteomic and metabolomic features in patients with HCC responding to lenvatinib and anti-PD1 therapy.

Combination therapy (lenvatinib/programmed death-1 inhibitor) is effective for treating unresectable hepatocellular carcinoma (uHCC). We reveal that responders have better overall and progression-free survival, as well as high tumor mutation burden and special somatic variants. We analyze the proteome and metabolome of 82 plasma samples from patients with hepatocellular carcinoma (HCC; n = 51) and normal controls (n = 15), revealing that individual differences outweigh treatment differences. Responders exhibit enhanced activity in the alternative/lectin complement pathway and higher levels of lysophosphatidylcholines (LysoPCs), predicting a favorable prognosis. Non-responders are enriched for immunoglobulins, predicting worse outcomes. Compared to normal controls, HCC plasma proteins show acute inflammatory response and platelet activation, while LysoPCs decrease. Combination therapy increases LysoPCs/phosphocholines in responders. Logistic regression/random forest models using metabolomic features achieve good performance in the prediction of responders. Proteomic analysis of cancer tissues unveils molecular features that are associated with side effects in responders receiving combination therapy. In conclusion, our analysis identifies plasma features associated with uHCC responders to combination therapy.

Enhancing Targeted Therapy in Hepatocellular Carcinoma through a pH-Responsive Delivery System: Folic Acid-Modified Polydopamine-Paclitaxel-Loaded Poly(3-hydroxybutyrate-co-3-hydroxyvalerate) Nanoparticles.

Currently, there is an inherent contradiction between the multifunctionality and excellent biocompatibility of anticancer drug nanocarriers, which limits their application. Therefore, to overcome this limitation, we aimed to develop a biocompatible drug delivery system for the treatment of hepatocellular carcinoma (HCC). In this study, we employed poly(3-hydroxybutyrate-co-3-hydroxyvalerate) (PHBV) as the fundamental framework of the nanocarrier and utilized the emulsion solvent evaporation method to fabricate nanoparticles loaded with paclitaxel (PTX), known as PTX-PHBV NPs. To enhance the tumor-targeting capability, a dopamine self-polymerization strategy was employed to form a pH-sensitive coating on the surface of the nanoparticles. Then, folic acid (FA)-targeting HCC was conjugated to the nanoparticles with a polydopamine (PDA) coating by using the Michael addition reaction, resulting in the formation of HCC-targeted nanoparticles (PTX-PHBV@PDA-FA NPs). The PTX-PHBV@PDA-FA NPs were characterized and analyzed by using dynamic light scattering, scanning electron microscopy, fourier-transform infrared spectroscopy, X-ray diffraction, differential scanning calorimetry, and thermogravimetric analysis. Encouragingly, PTX-PHBV@PDA-FA NPs exhibited remarkable anticancer efficacy in an HCC xenograft mouse model. Furthermore, compared to raw PTX, PTX-PHBV@PDA-FA NPs showed less toxicity in vivo. In conclusion, these results demonstrate the potential of PTX-PHBV@PDA-FA NPs for HCC treatment and biocompatibility.

Modified interproximal tunneling technique with customized sub-epithelial connective tissue graft for gingival papilla reconstruction: report of three cases with a cutback incision on the palatal side.

BACKGROUND: Gingival papilla defects, which cause an unpleasant appearance and involve the upper anterior teeth, may be triggered by several factors. Several noninvasive and invasive techniques have been proposed for gingival papilla reconstruction. The combination of interproximal tunneling and customized connective tissue grafts (CTGs) has shown promise in papilla augmentation. However, due to the narrowness and limited blood supply of the gingival papilla, the long-term outcomes of these techniques remain unpredictable. Therefore, achieving tension-free coronal advancement of the interdental papilla and proper placement of the CTG is crucial for successful long-term outcomes and could provide widely applicable methods for papilla augmentation. CASE REPORT: In this study, we enrolled three patients with gingival papilla defects in the maxillary anterior teeth. For reconstruction, we proposed a modified interproximal tunneling (MIPT) technique combined with a CTG. A crucial modification based on previous studies involved adding a cutback incision to the base of the palatal vertical incision, resulting in tension-free healing. Additionally, the CTG was sutured upright to further enhance the height of the gingiva papilla. To evaluate the efficacy of the MIPT technique, the clinical parameters-including the Jemt papilla index and the distance from the tip of the papilla to the interproximal contact point-were examined using a periodontal probe (UNC15, Hu-friedy) at baseline and 12 months after surgery. All three patients achieved satisfactory papilla reconstruction 12 months after the surgery. These three cases were used to evaluate the efficacy of the MIPT technique combined with the customized CTG. An average increase in the Jemt papilla score from 1.6 to 2.8 and a reduction in the distance from the papilla tip to the contact point of adjacent teeth from 2 mm to 0.08 mm were observed 12 months after surgery. CONCLUSION: The preliminary results confirmed that this technique holds promise for gingival papilla augmentation between tooth/tooth or tooth/implant.

Effectiveness and safety of human type 5 recombinant adenovirus (H101) in malignant tumor with malignant pleural effusion and ascites: A multicenter, observational, real-world study.

BACKGROUND: The aim of this study was to analyze the effectiveness and safety of H101 in Chinese patients with malignant pleural effusion and ascites (MPE/MA) in the real world. METHODS: This multicenter, observational, real-world study recruited patients with MPE/MA caused by malignant tumor receiving H101-containing treatment between January 2020 and June 2022. Effectiveness was evaluated by overall remission rate (ORR), and safety was evaluated based on adverse events (AEs). Subgroup analysis was performed on patients grouped according to tumor type, the volume of MPE and MA, and dosage of H101. RESULTS: A total of 643 eligible patients were enrolled, and 467 received H101 monotherapy and 176 received H101 combined with chemotherapy. The ORR of total patients was60.3% with 388 case of PR. In the H101 monotherapy group, the decrease of MPE or MA was achieved in 282 (60.4%, PR) patients, 176 (37.7%, NC) patients showed no change in volume of MPE or MA, and nine (1.9%, PD) patients showed an increase, yielding an ORR of 60.4% (282/467). The ORR for the combination therapy group was 60.2% (106/176), with 106 cases of PR, 69 cases of NC and one case of PD. Subgroup analyses based on tumor type, volume of MPE and MA, and dosage of H101 all showed high ORR, approximately 60%. The main AEs associated with H101-containing regimens were fever, nausea and vomiting. No serious AEs occurred in both groups. CONCLUSION: Encouraging clinical benefits and manageable toxicity of H101 against MPE/MA were preliminarily observed in the real-world clinical setting, indicating that the H101-containing regimen is reliable, safe, and feasible, providing a novel and effective option for the treatment of this disease.

Analysis of the anatomical and biomechanical characteristics of the pelvic floor in cystocele.

INTRODUCTION: Stress urinary incontinence (SUI) occurs due to disruption of the pelvic floor anatomy; however, the complexity of the pelvic floor support structures and individual patient differences make it difficult to identify the weak points in the pelvic floor support that cause SUI to occur, develop, and recur. This study aimed to analyze the pelvic floor anatomy, structural features, and biomechanics of cystoceles to develop more effective treatment plans with individualized and precise healthcare. MATERIAL AND METHODS: In this observational case-controlled study (clinical trial identifier BOJI201855L), 102 women with normal pelvic floor function and 273 patients diagnosed with cystocele degrees I-III were identified at Shanghai General Hospital from October 2016 to December 2019. We combined ultrasound and vaginal tactile imaging (VTI) to assess the anatomy and biomechanical functions of the anterior and posterior vaginal walls. Both examinations included relaxation and muscle tension tests. RESULTS: Of the 42 VTI parameters, 13 were associated with the degree of cystocele, six with an increase in the urethral rotation angle (pointing to the mobility of the urethra), and six with a decrease in the retrovesical angle (pointing to hypsokinesis and decrease in bladder position). According to these data, the strength of tissues, especially the muscles in both the anterior and posterior compartments, contributes to the stability of the pelvic floor structure. The strength of the levator ani muscle (LAM) is important for the degree of cystocele, mobility of the urethra, hypsokinesis, and decrease in bladder position. CONCLUSIONS: In general, the biomechanical status of the pelvic floor in patients with cystocele is complex and involves various muscles, ligaments, tendons, and fascia. Of these, repair and exercise of the LAM have not received much attention in the treatment of patients with cystoceles, which may be an important risk factor for the high recurrence rate.

Pneumonia, lymphocytes and C-reactive protein are valuable tests for predicting surgical intervention in necrotizing enterocolitis.

Background: Necrotizing enterocolitis (NEC) is one of the important causes of neonatal death, and proper timing of operation is of critical significance. This study aimed to explore the high-risk factors for NEC requiring surgical intervention and to provide a reference for its clinical diagnosis and treatment. Methods: Clinical and radiological evidence of NEC neonates admitted to Zhujiang Hospital of Southern Medical University and Zhongshan Boai Hospital from January 2010 to October 2022 were retrospectively analyzed. Patients were divided into surgical group and conservative group according to whether they underwent surgery or not. Univariate analysis of the clinical data of the two groups was conducted, and multivariate logistic regression analysis was then performed for statistically significant results in the univariate analysis. Results: 267 infants were included in this study, of which 90 patients underwent surgical intervention for NEC and 177 conservation treatment. The univariate analysis showed that the gestational age, pneumonia, leukocytes, lymphocytes, erythrocytes, platelets, C-reactive protein, and blood glucose were statistically significant in the surgical group compared to the conservative group (All P < 0.05). Furthermore, the results of multivariate logistic regression analysis showed that compared to the conservative group, patients in the surgical group had a higher proportion of pneumonia (OR = 2.098; 95% CI: 1.030-4.272; P = 0.041), lower lymphocyte values (OR = 0.749; 95% CI: 0.588-0.954; P = 0.019), and higher C-reactive protein values (OR = 1.009; 95% CI: 1.003-1.016; P = 0.004). Conclusions: Pneumonia, decreased lymphocytes, and elevated C-reactive protein are potential high-risk factors for neonates with NEC requiring surgical intervention and may have potential clinical implications for predicting surgical risk.

Degradation of Sulfamethoxazole by Manganese(IV) Oxide in the Presence of Humic Acid: Role of Stabilized Semiquinone Radicals.

In this work, we demonstrate for the first time the abatement of sulfamethoxazole (SMX) induced by stabilized ortho-semiquinone radicals (o-SQ•-) in the MnO2-mediated system in the presence of humic acid. To evaluate the performance of different MnO2/mediator systems, 16 mediators are examined for their effects on MnO2 reactions with SMX. The key role of the bidentate Mn(II)-o-SQ• complex and MnO2 surface in stabilizing SQ•- is revealed. To illustrate the formation of the Mn(II)-o-SQ• complex, electron spin resonance, cyclic voltammetry, and mass spectra were used. To demonstrate the presence of o-SQ• on the MnO2 surface, EDTA was used to quench Mn(II)-o-SQ•. The high stability of o-SQ•- on the MnO2 surface is attributed to the higher potential of o-SQ•- (0.9643 V) than the MnO2 surface (0.8598 V) at pH 7.0. The SMX removal rate constant by different stabilized o-SQ• at pH 7.0 ranges from 0.0098 to 0.2252 min-1. The favorable model is the rate constant ln (kobs, 7.0) = 6.002EHOMO(o-Qred) + 33.744(ELUMO(o-Q) - EHOMO(o-Qred)) - 32.800, whose parameters represent the generation and reactivity of o-SQ•, respectively. Moreover, aniline and cystine are competitive substrates for SMX in coupling o-SQ•-. Due to the abundance of humic constituents in aquatic environments, this finding sheds light on the low-oxidant-demand, low-carbon, and highly selective removal of sulfonamide antibiotics.

Thymidine kinase 1 drives hepatocellular carcinoma in enzyme-dependent and -independent manners.

Metabolic reprogramming plays a crucial role in the development of hepatocellular carcinoma (HCC). However, the key drivers of metabolic reprogramming underlying HCC progression remain unclear. Using a large-scale transcriptomic database and survival correlation screening, we identify thymidine kinase 1 (TK1) as a key driver. The progression of HCC is robustly mitigated by TK1 knockdown and significantly aggravated by its overexpression. Furthermore, TK1 promotes the oncogenic phenotypes of HCC not only through its enzymatic activity and production of deoxythymidine monophosphate (dTMP) but also by promoting glycolysis via binding with protein arginine methyltransferase 1 (PRMT1). Mechanistically, TK1 directly binds PRMT1 and stabilizes it by interrupting its interactions with tripartite-motif-containing 48 (TRIM48), which inhibits its ubiquitination-mediated degradation. Subsequently, we validate the therapeutic capacity of hepatic TK1 knockdown in a chemically induced HCC mouse model. Therefore, targeting both the enzyme-dependent and -independent activity of TK1 may be therapeutically promising for HCC treatment.

Vitamin D Receptor Regulates Autophagy to Inhibit Apoptosis and Promote Proliferation in Hepatocyte Injury.

BACKGROUND: Oxidative stress is an important mechanism in liver ischemia/reperfusion (I/R) injury. Hepatocyte apoptosis and proliferation occur in parallel with liver I/R injury, and the degree of apoptosis and proliferation determines the effects on hepatocytes. Vitamin D receptor (VDR) can lessen liver I/R injury, but previous studies focused mostly on inflammation and immunity. METHODS: H2O2 was used to induce hepatocyte injury. Before treatment with H2O2, Hep-3B cells were pretreated with paricalcitol (PC) and siRNA-VDR. Rapamycin and chloroquine were also applied in the study. RESULTS: The number of apoptotic cells was measured with an annexin V (AV) -fluorescein isothiocyanate apoptosis detection kit. Expression of proteins was measured by western blotting. As compared with the H2O2+Hep-3B group, levels of AV/PI, cleaved caspase-3, and p62 were lower, and expression levels of Bcl-2, proliferating cell nuclear antigen, and VDR were higher, in the PC+H2O2+Hep-3B group. When the VDR gene was silenced by siRNA-VDR in the siRNA-VDR+H2O2+Hep-3B group, expressions of AV/PI, cleaved caspase-3, and p62 were upregulated, and expressions of Bcl-2, proliferating cell nuclear antigen, and VDR were downregulated, as compared with values for the siRNA-NC+H2O2+Hep-3B group. Treatment with rapamycin or chloroquine partially reversed the effect of PC and siRNA-VDR on apoptosis and proliferation. CONCLUSIONS: VDR mediates hepatocyte apoptosis and proliferation through autophagy.

Liver metabolomic characteristics in three different rat models of deficiency based on ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry.

OBJECTIVE: To investigate the mechanism of deficiency syndrome (YDS) by analyzing the liver metabolomic characteristics of three different deficiency rat models METHODS: Following the TCM etiology, for clinical features and pathological manifestations of modern medicine, three kinds of animal models of deficiency were induced and replicated. Totally 48 Sprague-Dawley (SD) male rats were randomly divided into blank group, irritation induced model group, Fuzi-Ganjiang induced model group, and thyroxine-reserpine induced model group. After successful development of model, the ultra-performance liquid chromatography coupled to quadrupole time-of-flight mass spectrometry was carried out to detect metabolites in each group. The metabolites of rat liver were analyzed for the characteristics of their biomarkers. The pathway enrichment analysis and metabolic network construction were performed through various online databases including Metabolite Biology Role, Human Metabolome Database, MetaboAnalyst, and Kyoto Encyclopedia of Genes and Genomes. RESULTS: The SD rats in the experimental group showed symptoms like less weight gain, reduced diet and water intake, high body temperature, increased liver and kidney indexes, and abnormal liver and kidney tissue morphology. Moreover, the rats showed high increased levels of serum cyclic adenosine monophosphate, estradiol, alanine transaminase, and aspartate aminotransferase and decreased levels of cyclic guanosinc monophosphate and testosterone. We found four key interrelated metabolic pathways in the liver tissue metabolomics, including the biosynthesis of pantothenic acid and coenzyme A, and metabolism of alpha-linolenic acid metabolism, glycerophospholipid metabolism, and sphingolipid. CONCLUSION: The liver and kidney YDS is closely related to the biosynthesis of pantothenic acid and CoA and abnormal metabolism of α-linolenic acid, glycerophospholipid, and sphingolipid in SD rats.

The minimum weight and age of kidney donors: en bloc kidney transplantation from preterm neonatal donors weighing less than 1.2 kg to adult recipients.

En bloc kidney transplantation (EBKT) to adults from preterm neonates following donation after circulatory death has not been described in the literature. We report 2 successful cases of EBKT from preterm neonatal donation after circulatory death donors weighing <1.2 kg to adult recipients. The first case was a preterm female infant born at 29 weeks' gestational age, weighing 1.07 kg. The recipient was a 34-year-old woman weighing 75 kg. At the 9-month follow-up, the patient demonstrated excellent graft function with a creatinine concentration of 1.48 mg/dL. The second donor was a preterm female infant born at 29 weeks and 5 days' gestation, weighing 1.17 kg. The recipient was a 25-year-old woman weighing 46 kg. By 5 months post surgery, the serum creatinine level had gradually decreased to 1.47 mg/dL. In our experience, EBKT from preterm neonates <30 weeks' gestation and weighing <1.2 kg has demonstrated acceptable short- to medium-term results.

The Intratumoral Bacterial Metataxonomic Signature of Hepatocellular Carcinoma.

Microbiota is implicated in hepatocellular carcinoma (HCC). The spectrum of intratumoral microbiota associated with HCC progression remains elusive. Fluorescence in situ hybridization revealed that microbial DNAs were distributed in the cytosol of liver hepatocytes and erythrocytes. Viable anaerobic or aerobic bacteria were recovered in HCC tissues by fresh tissue culture. We performed a comprehensive DNA sequencing of bacterial 16S rRNA genes in 156 samples from 28 normal liver, 64 peritumoral, and 64 HCC tissues, and the DNA sequencing yielded 4.2 million high-quality reads. Both alpha and beta diversity in peritumor and HCC microbiota were increased compared to normal controls. The most predominant phyla in HCC were Patescibacteria, Proteobacteria, Bacteroidota, Firmicutes, and Actinobacteriota. phyla of Proteobacteria, Firmicutes, and Actinobacteriota, and classes of Bacilli and Actinobacteria, were consistently enriched in peritumor and HCC tissues, while Gammaproteobacteria was especially abundant in HCC tissues compared to normal controls. Streptococcaceae and Lactococcus were the marker taxa of HCC cirrhosis. The Staphylococcus branch and Caulobacter branch were selectively enriched in HBV-negative HCCs. The abundance of Proteobacteria, Gammaproteobacteria, Firmicutes, Actinobacteriota, and Saccharimonadia were associated with the clinicopathological features of HCC patients. The inferred functions of different taxa were changed between the microbiota of normal liver and peritumor/HCC. Random forest machine learning achieved great discriminative performance in HCC prediction (area under the curve [AUC] = 1.00 in the training cohort, AUC = 0.950 for top five class signature, and AUC = 0.943 for the top 50 operational taxonomy units [OTUs] in the validation cohort). Our analysis highlights the complexity and diversity of the liver and HCC microbiota and established a specific intratumoral microbial signature for the potential prediction of HCC. IMPORTANCE Gut microbiome is an important regulator of hepatic inflammation, detoxification, and immunity, and contributes to the carcinogenesis of liver cancer. Intratumoral bacteria are supposed to be closer to the tumor cells, forming a microenvironment that may be relevant to the pathological process of hepatocellular carcinoma (HCC). However, the presence of viable intratumoral bacteria remains unclear. It is worth exploring whether the metataxonomic characteristics of intratumoral bacteria can be used as a potential marker for HCC prediction. Here, we present the first evidence of the existence of viable intratumoral bacteria in HCC using the tissue culture method. We revealed that microbial DNAs were distributed in the cytosol of liver hepatocytes and erythrocytes. We analyzed the diversity, structure, and abundance of normal liver and HCC microbiota. We built a machine learning model for HCC prediction using intratumoral bacterial features. We show that specific taxa represent potential targets for both therapeutic and diagnostic interventions.

Matricellular protein tenascin C: Implications in glioma progression, gliomagenesis, and treatment.

Matricellular proteins are nonstructural extracellular matrix components that are expressed at low levels in normal adult tissues and are upregulated during development or under pathological conditions. Tenascin C (TNC), a matricellular protein, is a hexameric and multimodular glycoprotein with different molecular forms that is produced by alternative splicing and post-translational modifications. Malignant gliomas are the most common and aggressive primary brain cancer of the central nervous system. Despite continued advances in multimodal therapy, the prognosis of gliomas remains poor. The main reasons for such poor outcomes are the heterogeneity and adaptability caused by the tumor microenvironment and glioma stem cells. It has been shown that TNC is present in the glioma microenvironment and glioma stem cell niches, and that it promotes malignant properties, such as neovascularization, proliferation, invasiveness, and immunomodulation. TNC is abundantly expressed in neural stem cell niches and plays a role in neurogenesis. Notably, there is increasing evidence showing that neural stem cells in the subventricular zone may be the cells of origin of gliomas. Here, we review the evidence regarding the role of TNC in glioma progression, propose a potential association between TNC and gliomagenesis, and summarize its clinical applications. Collectively, TNC is an appealing focus for advancing our understanding of gliomas.

Multidomain Narrowband Interference Intelligent Suppression Method Based on Cognitive Radio and MIMO in UAV Data Link.

In this paper, a kind of antinarrowband interference intelligent method based on cognitive MIMO (multiple-input multiple-output) airspace, time domain, frequency domain, and code domain is proposed. This method combines perceptual technology, spread spectrum code, MIMO space-time coding, and so on. Through coordinating space, time, frequency, and code element diversity, the narrowband interference in the UAV (unmanned aerial vehicle) monitoring and control link is effectively countered. The input and output model of MIMO monitoring and control link of UAV with natural interference are described. Then, the realization principle of the multidomain antinarrowband interference method based on CR-MIMO is presented, and the corresponding models of receiving and transmitting are also given. Finally, the anti-interference performance of the proposed method is analyzed theoretically and validated through simulation experiments, and the effectiveness of the proposed method is verified.

Treatment of experimental autoimmune encephalomyelitis using AAV gene therapy by blocking T cell costimulatory pathways.

Multiple sclerosis (MS) is a chronic autoimmune disease of the central nervous system (CNS), characterized by inflammation and demyelination. Presently, repeated relapses of MS necessitate long-term immune-regulatory therapy. Blocking the CD28-B7 and CD40-CD40L costimulatory pathways is an effective and synergistic method for the prevention and amelioration of clinical symptoms of experimental autoimmune encephalomyelitis (EAE), a mouse model of MS. In this study, to explore the efficacy and safety of MS gene therapy, we used adeno-associated virus (AAV) as a vector to deliver CTLA4-immunoglobulin (Ig) or CD40-Ig on the EAE induced by myelin oligodendrocyte glycoprotein (MOG). Our results showed that a single administration of AAV8-CTLA4-Ig, either alone or with AAV8-CD40-Ig, protected mice from EAE and reversed disease progression. Decreased CD4+ and CD8+ T cell infiltration, inhibition of MOG antibody response, and downregulation of neuroinflammation were observed in mice receiving AAV, suggesting that autoimmunity was suppressed in EAE pathology. Moreover, no hematological or hepatic toxicity was observed in AAV-treated mice. Thus, compared with treatment with recombinant CTLA4-Ig (belatacept), AAV gene therapy could effectively control clinical symptoms and suppress autoimmunity in the long term. In summary, our study provides a potential therapeutic method for blocking T cell costimulation for the treatment of MS via gene therapy.

Safety and activity of an engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX administered with prophylactic glucocorticoids in patients with haemophilia B: a single-centre, single-arm, phase 1, pilot trial.

BACKGROUND: A novel, engineered, liver-tropic adeno-associated virus vector expressing a hyperactive Padua factor IX (FIX) protein (BBM-H901) has been developed and is promising for haemophilia B gene therapy. We aimed to explore its safety and activity in increasing FIX concentrations and reducing bleeding frequency. METHODS: We did a single-centre, single-arm, phase 1, pilot trial evaluating the safety and activity of a single intravenous infusion of BBM-H901 at the Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College (Tianjin, China). We enrolled adult patients with haemophilia B (aged >18 years) with baseline FIX coagulation activity (FIX:C) of less than 2 IU/dL, no FIX inhibitor, and low titre of neutralising antibodies (≤1:4) against vector capsid. Eligible participants were intravenously infused with a single dose of 5 × 1012 vector genomes (vg)/kg of BBM-H901 after 1 week of prophylactic prednisone treatment (1 mg/kg per day). Primary endpoints were the incidence of treatment-related adverse events, change in alanine aminotransferase (ALT) and aspartate amino transferase (AST), and development of antibodies against vector capsid within 1 year of infusion. We report the results of the prespecified 1-year analysis following complete enrolment. The trial is registered with ClinicalTrials.gov, NCT04135300, and is complete. FINDINGS: Between Oct 16, 2019, and Jan 13, 2021, 12 male participants were assessed, and ten Chinese participants were enrolled and infused with BBM-H901. After a median follow-up of 58 weeks (IQR 51·5-99·5), mean FIX:C reached mean 36·9 IU/dL (SD 20·5). No serious adverse events, no grade 3-4 adverse events were observed. Grade 1-2 adverse events related to BBM-H901 include pyrexia (1 [10%]) and elevation of aminotransferase(1 [10%]). No FIX inhibitors were observed. All participants developed antibodies against vector capsid after infusion. Eight (80%) participants had ALT and AST concentrations below the upper limit of normal throughout the follow-up period. Two (20%) participants had elevation of ALT and AST accompanied with decrease of FIX:C, which remained at 7 IU/dL and 11.8 IU/dL, respectively. INTERPRETATION: This pilot study suggests that liver-tropic BBM-H901 is safe 1 year after infusion. Vector derived FIX:C concentration is sufficiently high to prevent bleeding events and minimise the need for replacement therapy in small populations with haemophilia B. These findings support further study. FUNDING: Non-profit Central Research Institute Fund of Chinese Academy of Medical Sciences, National Key Research and Development Program of China, National Natural Science Foundation of China, Tianjin Municipal Science and Technology Commission Grant, and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences.

A histidine cluster determines YY1-compartmentalized coactivators and chromatin elements in phase-separated enhancer clusters.

As an oncogenic transcription factor, Yin Yang 1 (YY1) regulates enhancer and promoter connection. However, gaps still exist in understanding how YY1 coordinates coactivators and chromatin enhancer elements to assemble enhancers and super-enhancers. Here, we demonstrate that a histidine cluster in YY1's transactivation domain is essential for its formation of phase separation condensates, which can be extended to additional proteins. The histidine cluster is also required for YY1-promoted cell proliferation, migration, clonogenicity and tumor growth. YY1-rich nuclear puncta contain coactivators EP300, BRD4, MED1 and active RNA polymerase II, and colocalize with histone markers of gene activation, but not that of repression. Furthermore, YY1 binds to the consensus motifs in the FOXM1 promoter to activate its expression. Wild-type YY1, but not its phase separation defective mutant, connects multiple enhancer elements and the FOXM1 promoter to form an enhancer cluster. Consistently, fluorescent in situ hybridization (FISH) assays reveal the colocalization of YY1 puncta with both the FOXM1 gene locus and its nascent RNA transcript. Overall, this study demonstrates that YY1 activates target gene expression through forming liquid-liquid phase separation condensates to compartmentalize both coactivators and enhancer elements, and the histidine cluster of YY1 plays a determinant role in this regulatory mechanism.

Loss of SIRT5 promotes bile acid-induced immunosuppressive microenvironment and hepatocarcinogenesis.

BACKGROUND & AIMS: The liver is a metabolically active organ and is also 'tolerogenic', exhibiting sophisticated mechanisms of immune regulation that prevent pathogen attacks and tumorigenesis. How metabolism impacts the tumor microenvironment (TME) in hepatocellular carcinoma (HCC) remains understudied. METHODS: We investigated the role of the metabolic regulator SIRT5 in HCC development by conducting metabolomic analysis, gene expression profiling, flow cytometry and immunohistochemistry analyses in oncogene-induced HCC mouse models and human HCC samples. RESULTS: We show that SIRT5 is downregulated in human primary HCC samples and that Sirt5 deficiency in mice synergizes with oncogenes to increase bile acid (BA) production, via hypersuccinylation and increased BA biosynthesis in the peroxisomes of hepatocytes. BAs act as a signaling mediator to stimulate their nuclear receptor and promote M2-like macrophage polarization, creating an immunosuppressive TME that favors tumor-initiating cells (TICs). Accordingly, high serum levels of taurocholic acid correlate with low SIRT5 expression and increased M2-like tumor-associated macrophages (TAMs) in HCC patient samples. Finally, administration of cholestyramine, a BA sequestrant and FDA-approved medication for hyperlipemia, reverses the effect of Sirt5 deficiency in promoting M2-like polarized TAMs and liver tumor growth. CONCLUSIONS: This study uncovers a novel function of SIRT5 in orchestrating BA metabolism to prevent tumor immune evasion and suppress HCC development. Our results also suggest a potential strategy of using clinically proven BA sequestrants for the treatment of patients with HCC, especially those with decreased SIRT5 and abnormally high BAs. LAY SUMMARY: Hepatocellular caricinoma (HCC) development is closely linked to metabolic dysregulation and an altered tumor microenvironment. Herein, we show that loss of the metabolic regulator Sirt5 promotes hepatocarcinogenesis, which is associated with abnormally elevated bile acids and subsequently an immunosuppressive microenvironment that favors HCC development. Targeting this mechanism could be a promising clinical strategy for HCC.