A multi-channel electrochemical biosensor based on polyadenine tetrahedra for the detection of multiple drug resistance genes.

Antimicrobial resistance poses a serious threat to human health due to the high morbidity and mortality caused by drug-resistant microbial infections. Therefore, the development of rapid, sensitive and selective identification methods is key to improving the survival rate of patients. In this paper, a sandwich-type electrochemical DNA biosensor based on a polyadenine-DNA tetrahedron probe was constructed. The key experimental conditions were optimized, including the length of polyadenine, the concentration of the polyadenine DNA tetrahedron, the concentration of the signal probe and the hybridization time. At the same time, poly-avidin-HRP80 was used to enhance the electrochemical detection signal. Finally, excellent biosensor performance was achieved, and the detection limit for the synthetic DNA target was as low as 1 fM. In addition, we verified the practicability of the system by analyzing E. coli with the MCR-1 plasmid and realized multi-channel detection of the drug resistance genes MCR-1, blaNDM, blaKPC and blaOXA. With the ideal electrochemical interface, the polyA-based biosensor exhibits excellent stability, which provides powerful technical support for the rapid detection of antibiotic-resistant strains in the field.

The differential expression of AFF3 in cervical cancer and its correlation with clinicopathological features and prognosis.

BACKGROUND: Cervical cancer (CC) is the second most common malignancy in women, and identifying biomarkers of CC is crucial for prognosis prediction. Here, we investigated the expression of AF4/FMR2 Family Member 3 (AFF3) in CC and its association with clinicopathological features and prognosis. METHODS: Tumour and adjacent tissues, along with clinicopathological features and follow-up information, were collected from 78 patients. AFF3 expression was assessed using quantitative real-time polymerase chain reaction and Western blotting. The correlation between AFF3 expression and CC symptoms was using chi-square test. The 5-year overall survival (OS) was analysed using the Kaplan-Meier method. The Univariate analysis of prognostic risk factors was conducted using the COX proportional hazards model, followed by multivariate COX regression analysis including variables with p < 0.01. RESULTS: AFF3 expression was downregulated in CC, and its levels were correlated with lymph node metastasis (LNM) and International Federation of Gynaecology and Obstetrics (FIGO) stage. Patients with low AFF3 expression had a lower 5-year OS rate (52.78%, 19/36). Postoperative survival was reduced in patients with histological grade 3 (G3), myometrial invasion (depth ≥ 1/2), lymphovascular space invasion, LNM, and advanced FIGO stage. Low expression of AFF3 (HR: 2.848, 95% CI: 1.144-7.090) and histological grade G3 (HR: 4.393, 95% CI: 1.663-11.607) were identified as independent prognostic risk factors in CC patients. CONCLUSION: Low expression of AFF3 and histological G3 are independent predictors of poor prognosis in CC patients, suggesting that AFF3 could serve as a potential biomarker for prognostic assessment in CC.

Cervical cancer is a significant health concern worldwide, responsible for over 300,000 deaths annually and ranking as the fourth most common cancer in women. Existing screening methods have limitations, highlighting the need for innovative therapies. In our research, we identified a specific genetic material that varied significantly among cervical cancer patients with varying survival outcomes, detected in tissue samples obtained post-surgery. Our study demonstrates the considerable potential of this marker for accurately predicting outcomes in our study population. By analysing differences in the expression of this genetic marker, we can forecast the prognosis and progression of cervical cancer. These findings offer valuable insights for advancing cervical cancer treatment strategies, potentially improving outcomes for patients. Early detection and targeted treatment based on this genetic marker could extend patients' lives and prevent fatalities by enabling timely medical intervention and management.

Development of Optical Differential Sensing Based on Nanomaterials for Biological Analysis.

The discrimination and recognition of biological targets, such as proteins, cells, and bacteria, are of utmost importance in various fields of biological research and production. These include areas like biological medicine, clinical diagnosis, and microbiology analysis. In order to efficiently and cost-effectively identify a specific target from a wide range of possibilities, researchers have developed a technique called differential sensing. Unlike traditional "lock-and-key" sensors that rely on specific interactions between receptors and analytes, differential sensing makes use of cross-reactive receptors. These sensors offer less specificity but can cross-react with a wide range of analytes to produce a large amount of data. Many pattern recognition strategies have been developed and have shown promising results in identifying complex analytes. To create advanced sensor arrays for higher analysis efficiency and larger recognizing range, various nanomaterials have been utilized as sensing probes. These nanomaterials possess distinct molecular affinities, optical/electrical properties, and biological compatibility, and are conveniently functionalized. In this review, our focus is on recently reported optical sensor arrays that utilize nanomaterials to discriminate bioanalytes, including proteins, cells, and bacteria.

Triblock PolyA-Mediated Protein Biosensor Based on a Size-Matching Proximity Hybridization Analysis.

The antibodies in the natural biological world utilize bivalency/multivalency to achieve a higher affinity for antigen capture. However, mimicking this mechanism on the electrochemical sensing interface and enhancing biological affinity through precise spatial arrangement of bivalent aptamer probes still pose a challenge. In this study, we have developed a novel self-assembly layer (SAM) incorporating triblock polyA DNA to enable accurate organization of the aptamer probes on the interface, constructing a "lock-and-key-like" proximity hybridization assay (PHA) biosensor. The polyA fragment acts as an anchoring block with a strong affinity for the gold surface. Importantly, it connects the two DNA probes, facilitating one-to-one spatial proximity and enabling a controllable surface arrangement. By precisely adjusting the length of the polyA fragment, we can tailor the distance between the probes to match the molecular dimensions of the target protein. This design effectively enhances the affinity of the aptamers. Notably, our biosensor demonstrates exceptional specificity and sensitivity in detecting PDGF-BB, as confirmed through successful validation using human serum samples. Overall, our biosensor presents a novel and versatile interface for proximity assays, offering a significantly improved surface arrangement and detection performance.

Construction of an Enzyme Cascade Based on the Accurate Adjacent Arrangement of Coupled Enzymes Using a Triblock PolyA DNA Probe.

Intracellular enzyme cascades are essential for various biological processes, and mimicking their functions in artificial systems has attracted significant research attention. However, achieving convenient and efficient spatial organization of enzymes on interfaces remains a critical challenge. In this work, we designed a simple single-DNA scaffold using triblock polyA single-stranded DNA for the arrangement of coupled enzymes. The scaffold was assembled onto a gold electrode through the affinity of polyA-Au, and two enzymes (glucose oxidase and horseradish peroxidase) were captured through hybridization. The molecular distance between the enzymes was regulated by changing the length of the polyA fragment. As a proof of concept, a glucose biosensor was constructed based on the enzyme cascade amplification. The biosensor exhibited excellent detection capability for glucose in human serum samples with a limit of detection of 1.6 µM. Additionally, a trienzyme cascade reaction was successfully activated, demonstrating the potential scalability of our approach for multienzyme reactions. This study provides a promising platform for the development of easy-to-operate, highly efficient, and versatile enzyme cascade systems using DNA scaffolds.

Acute pancreatitis associated with diabetic ketoacidosis in a child with COVID-19 infection.

BACKGROUND: There is a mutual influence between COVID-19, diabetes ketoacidosis, and acute pancreatitis, with clinical manifestations overlapping each other, which can lead to misdiagnosis and delayed treatment that could aggravate the condition and affect the prognosis. COVID-19-induced diabetes ketoacidosis and acute pancreatitis are extremely rare, with only four case reports in adults and no cases yet reported in children. CASE PRESENTATION: We reported a case of acute pancreatitis associated with diabetic ketoacidosis in a 12-year-old female child post novel coronavirus infection. The patient presented with vomiting, abdominal pain, shortness of breath, and confusion. Laboratory findings showed elevated levels of inflammatory markers, hypertriglyceridemia, and high blood glucose. The patient was treated with fluid resuscitation, insulin, anti-infection treatments, somatostatin, omeprazole, low-molecular-weight heparin, and nutritional support. Blood purification was administered to remove inflammatory mediators. The patient's symptoms improved, and blood glucose levels stabilized after 20 days of admission. CONCLUSION: The case highlights the need for greater awareness and understanding of the interrelated and mutually promoting conditions of COVID-19, diabetes ketoacidosis, and acute pancreatitis among clinicians, to reduce misdiagnosis and missed diagnoses.

Development of a Single-Molecule Nanobalance Ratiometric Electrochemical DNA Biosensor Using a Triblock Poly-Adenine Probe.

The development of electrochemical DNA biosensors has been limited by their reliability and reproducibility due to many interfering factors such as electrode properties, DNA surface densities, and complex biological samples. In this work, we developed a nanobalance polyA hairpin probe (polyA-HP), which was effectively assembled onto the gold electrode surface through the affinity between the central polyA fragment and the Au surface. One flanking probe of the polyA-HP captured the target sequence together with a MB-labeled signal probe, and the other flanking probe captured a reference probe simultaneously. The MB signal related to the amount of target was normalized by the reference Fc signal; thus, the signal-to-noise (S/N) was as high as 2000, and the reproducibility was remarkably improved to 2.77%, even facing deliberately changed experiment conditions. By designing a hairpin structure at the terminal of the polyA-HP, the selectivity and specificity were dramatically improved for the analysis of mismatched sequences. The analysis performance of biological samples was dramatically improved after normalization, which is critical for its practicability. Our novel biosensor is a universal single-molecule platform for ratiometric biosensors with excellent performance in real samples, indicating great potential for next-generation high-precision electrochemical sensors.

Protective Effect of l-Theanine on Cyclophosphamide-Induced Testicular Toxicity in Mice.

l-Theanine is the most abundant free amino acid present in tea. Several tea components have been studied for their impact on male fertility, but little is known about the effects of l-theanine. Cyclophosphamide (CP) is an antineoplastic and immunosuppressive agent that reduces fertility in males. In the present study, we evaluated the effect of l-theanine on CP-induced testicular toxicity in male mice. A single dosage of 50 mg/kg saline or CP was administered intraperitoneally over the course of 5 days. Mice were administered l-theanine (80 mg/kg) or saline by gavage for 30 days. Animals were euthanized 24 h after the last l-theanine administration, and the testes were removed for histopathological and transmission electron microscopy analysis. Histological evaluation and transmission electron microscopy showed that administration of l-theanine alleviated CP-induced damage to the testicles, including spermatogonial cells, epithelial cells, seminiferous tubules, and basement membrane. An integrated proteomics and metabolomics investigation of testes revealed that l-theanine therapy substantially affected the quantity of 719 proteins (395 upregulated and 324 downregulated) and 196 metabolites (75 upregulated and 111 downregulated). The top three enriched Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways for these proteins and metabolites were purine metabolism, choline metabolism in cancer, and arachidonic acid metabolism. This is the first study to reveal the protective effect of l-theanine on CP-induced testicular toxicity. l-Theanine could be a potential natural active substance for resistance to the testis toxicity induced by CP.

Fabricating strong and tough aramid fibers by small addition of carbon nanotubes.

Synthetic high-performance fibers present excellent mechanical properties and promising applications in the impact protection field. However, fabricating fibers with high strength and high toughness is challenging due to their intrinsic conflicts. Herein, we report a simultaneous improvement in strength, toughness, and modulus of heterocyclic aramid fibers by 26%, 66%, and 13%, respectively, via polymerizing a small amount (0.05 wt%) of short aminated single-walled carbon nanotubes (SWNTs), achieving a tensile strength of 6.44 ± 0.11 GPa, a toughness of 184.0 ± 11.4 MJ m-3, and a Young's modulus of 141.7 ± 4.0 GPa. Mechanism analyses reveal that short aminated SWNTs improve the crystallinity and orientation degree by affecting the structures of heterocyclic aramid chains around SWNTs, and in situ polymerization increases the interfacial interaction therein to promote stress transfer and suppress strain localization. These two effects account for the simultaneous improvement in strength and toughness.

Salt-induced phosphoproteomic changes in the subfornical organ in rats with chronic kidney disease.

OBJECTIVES: Subfornical organ (SFO) is vital in chronic kidney disease (CKD) progression caused by high salt levels. The current study investigated the effects of high salt on phosphoproteomic changes in SFO in CKD rats. METHODS: 5/6 nephrectomized rats were fed a normal-salt diet (0.4%) (NC group) or a high-salt diet (4%) (HC group) for three weeks, while sham-operated rats were fed a normal-salt diet (0.4%) (NS group). For phosphoproteomic analysis of SFO in different groups, TiO2 enrichment, isobaric tags for relative and absolute quantification (iTRAQ) labeling, and liquid chromatography-tandem mass spectrometry (LC-MS/MS) were used. RESULTS: There were 6808 distinct phosphopeptides found, which corresponded to 2661 phosphoproteins. NC group had 168 upregulated and 250 downregulated phosphopeptides compared to NS group. Comparison to NC group, HC group had 154 upregulated and 124 downregulated phosphopeptides. Growth associated protein 43 (GAP43) and heat shock protein 27 (Hsp27) were significantly upregulated phosphoproteins and may protect against high-salt damage. Differential phosphoproteins with tight functional connection were synapse proteins and microtubule-associated proteins, implying that high-salt diet disrupted brain's structure and function. Furthermore, differential phosphoproteins in HC/NC comparison group were annotated to participate in GABAergic synapse signaling pathway and aldosterone synthesis and secretion, which attenuated inhibitory neurotransmitter effects and increased sympathetic nerve activity (SNA). DISCUSSION: This large scale phosphoproteomic profiling of SFO sheds light on how salt aggravates CKD via the central nervous system.

Efficacy and safety of 177Lu-DOTATATE targeted therapy in advanced/metastatic pulmonary neuroendocrine tumors: A systematic review and meta-analysis.

Objective: To perform a meta-analysis of the efficacy and safety about 177Lu-DOTATATE therapy for advanced/metastatic pNETs based on the current clinical evidence. Methods: This systematic review follows the PRISMA guideline. Search PubMed, Medline, EMBASE and CNKI, VIP, Wanfang databases, from establishment to June 2022, on the study of 177Lu-DOTATATE for advanced/metastatic pNETs, the primary endpoint was to evaluate the treatment effect through DRRs and DCRs. Secondary endpoint included assessment of OS, PFS, and treatment-related adverse events across all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Meta-analysis was performed using stata16.0 software, and the data were merged and displayed using forest graphs. Results: A total of 5 studies, 174 patients, on 177Lu-DOTATATE for advanced/metastatic pNETs were included. The pools of DRRs and DCRs were 24% (95% CI: 15%~32%) and 77% (95% CI: 62%~92%), respectively. The pool of OS was 48.78 months (95% CI: 41~56.57 months) and the pool of PFS was 21.59 months (95% CI: 17.65~25.53 months). In all studies, the most common side effect of treatment was hematological toxicity. In 174 patients, hematological toxicity of grade III accounted for 4.0% (7/174), and only 4.0% (7/174) and 1.0% (2/174) of patients had mild nephrotoxicity and hepatotoxicity. Gastrointestinal adverse reactions in 3% (6/174), nausea in 2% (3/174), superior vena cava occlusion in 0.5% (1/174). Conclusion: 177Lu-DOTATATE is effective and safe for advanced/metastatic pNETs, which can delay the progression of the disease, may improve patients' survival, and has low treatment-related toxicity and high safety. However, its efficacy and safety need to be further evaluated in high-quality, multicenter randomized controlled trials in the future. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022344436.

A systematic review of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG PET/CT in the diagnostic value of malignant tumor bone metastasis.

Objective: This study aims to perform a systemic analysis of [68Ga]Ga-DOTA-FAPI-04 positron emission tomography (PET)/computerized tomography (CT) and [18F]FDG PET/CT for the diagnosis of malignant tumor bone metastasis based on existing clinical evidence. Methods: This systematic review followed the guidelines of the Preferred Reporting Project (PRISMA) for systematic reviews and meta-analysis. This is a retrospective study of articles published in PubMed. Embase was searched online from the start of May 2022. The main endpoints were the maximum standardized uptake value and the tumor-to-background ratio to determine the examination performance of [68Ga]Ga-DOTA-FAPI-04 and [18F]FDG for bone transfer stoves. Based on the entry and discharge standards, two researchers extracted documents and data and then performed the quality evaluation. Results: A total of eight studies on the metastasis of malignant tumors on bone were included, which involved 358 patients in the final analysis. Conclusion: [68Ga]Ga-DOTA-FAPI-04 showed better detection performance for bone metastasis. The sensitivity of [68Ga]Ga-DOTA-FAPI-04 for the diagnosis of the primary tumor was higher than that of [18F]FDG, whereas the specificity of [18F]FDG was higher than that of [68Ga]Ga-DOTA-FAPI-04. However, further randomized controlled trials and prospective clinical trials are warranted to compare the diagnostic performance of [68Ga]Ga-DOTA-FAPI-04 PET/CT and [18F]FDG PET/CT. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier (CRD42022313019).

An immune-related gene prognostic risk index for pancreatic adenocarcinoma.

Objective: Our goal is to construct an immune-related gene prognostic risk index (IRGPRI) for pancreatic adenocarcinoma (PAAD), and to clarify the immune and molecular features in IRGPRI-defined PAAD subgroups and the benefit of immune checkpoint inhibitors (ICIs) therapy. Method: Through differential gene expression analysis, weighted gene co-expression network analysis (WGCNA), and univariate Cox regression analysis, 16 immune-related hub genes were identified using the Cancer Genome Atlas (TCGA) PAAD dataset (n = 182) and immune gene set. From these genes, we constructed an IRGPRI with the Cox regression method and the IRGPRI was verified based on the Gene Expression Omnibus (GEO) dataset (n = 45). Then, we analyzed the immune and molecular features and the benefit of ICI therapy in IRGPRI-defined subgroups. Results: Five genes, including S100A16, CD40, VCAM1, TNFRSF4 and TRAF1 were used to construct IRGPRI. As with the results of the GEO cohort, the overall survival (OS) was more favorable in low IRGPRI patients versus high IRGPRI patients. The composite results pointed out that low IRGPRI was associated with immune response-related pathways, high level of CTLA4, low KRAS and TP53 mutation rate, more infiltration of activated memory CD4+ T cells, CD8+ T cells, and more benefits from ICIs therapy. In comparison, high IRGPRI was associated with cancer-related pathways, low expression of CTLA4, high KRAS and TP53 mutation rate, more infiltration of M2 macrophages, and less benefit from ICIs therapies. Conclusion: This IRGPRI is an encouraging biomarker to define the prognosis, immune and molecular features, and benefits from ICIs treatments in PAAD.

Elevated 68 Ga-FAPI Uptake by Primary Benign Intraosseous Meningioma.

ABSTRACT: Intraosseous meningioma is an extremely rare benign tumor. We present the 68 Ga-fibroblast activation protein inhibitor (FAPI) PET/CT findings of primary intraosseous meningioma in a 71-year-old woman. 68 Ga-FAPI PET/CT revealed an intraosseous mass in the right parietal bone with increased FAPI activity. Primary skull malignancy was suspected. However, pathological examination after resection of the mass in the right parietal bone confirmed the diagnosis of benign meningioma (WHO I). A final diagnosis of benign intraosseous meningioma was made.

Triblock probe-polyA-probe electrochemical interfacial engineering for the sensitive analysis of RNAi plants.

RNA interference (RNAi) is currently under fast development, which brings improved crop quality and new activity against pests in agriculture, by producing RNAs to specifically inhibit gene expression. This technology, in turn, creates a pressing need for sensitive and specific analytical methods of exogenous RNA molecules in genetically modified (GM) crops for safety assessment and regulation of RNAi plants and their products. In this work, we developed a novel RNA electrochemical biosensor for the analysis of GM maize samples based on a polyA-DNA capturing probe containing three DNA segments: the central polyA segment combined onto a gold electrode surface with adjustable configuration and density, and two flanking DNA probes simultaneously captured the RNA targets through hybridization. Both the assembling and hybridization capability of our probe were demonstrated, and we systematically optimized the analytical conditions. Finally, the ultrasensitive detection of 10 fM RNA was realized without any amplification processes, and the specificity was verified by analyzing non-target maize samples. Our electrochemical biosensor provided a reliable and convenient measurement strategy for RNAi safety and quality assessment, and more importantly, our PAP (probe-polyA-probe) capturing probe exhibited an innovative design for the detection of large RNA molecules with complex secondary structures.

Family with sequence similarity 46 member a confers chemo-resistance to ovarian carcinoma via TGF-ß/Smad2 signaling.

Ovarian cancer is the most lethal malignancy with depressive 5-year survival rate, mainly due to patients with advanced stages experience tumor recurrence and resistance to the current chemotherapeutic agents. Thus, exploring the underlying molecular mechanisms involved in chemo-resistance is crucial for management of treatment to improve therapeutic outcomes. In the current study, we found overexpression of FAM46A in ovarian cancer patients demonstrated an aggressive phenotype and poor outcome. Furthermore, FAM46A overexpression in ovarian cancer cells induces higher CDDP resistance. However, inhibition of FAM46A sensitized ovarian cancer cell lines to CDDP cytotoxicity both in vitro and in vivo. Mechanically, upregulation of FAM46A activated transforming growth factor-ß (TGF-ß)/Smad signaling and upregulated the levels of nuclear Smad2. Taken together, our results highlight the important oncogenic role of FAM46A in ovarian cancer progression and might provide a potential clinical target for patients with chemo resistant ovarian cancer.

CF1 reduces grain-cadmium levels in rice (Oryza sativa).

Rice (Oryza sativa) is a leading source of dietary cadmium (Cd), a non-essential heavy metal that poses a serious threat to human health. There are significant variations in grain-Cd levels in natural rice populations, which make the breeding of low-Cd rice a cost-effective way to mitigate grain-Cd accumulation. However, the genetic factors that regulate grain-Cd accumulation have yet to be fully established, thereby hindering the development of low-Cd varieties. Here, we reported a low-Cd quantitative trait locus, CF1, that has the potential to reduce Cd accumulation in rice grains. CF1 is allelic to the metal transporter OsYSL2, which transports Fe from the roots to the shoots. However, it is incapable of binding Cd, and thus, reduces grain-Cd levels indirectly rather than directly in the form of upward delivery. Further analysis showed that high expression levels of CF1 improve Fe nutrition in the shoots, subsequently inhibiting Cd uptake by systemically inhibiting expression of the main Cd uptake gene OsNramp5 in the roots. Compared with the CF1 allele from '02428' (CF102428 ), higher expression levels of CF1 from 'TQ' (CF1TQ ) increased the Fe contents and decreased Cd levels in rice grains. In natural rice populations, CF1TQ was found to be a minor allele, while CF102428 is present in most japonica rice, suggesting that CF1TQ could be widely integrated into the japonica rice genome to generate low-Cd varieties. Overall, these results broaden our mechanistic understanding of the natural variation in grain-Cd accumulation, supporting marker-assisted selection of low-Cd rice.

Efficacy and Safety of 225Ac-PSMA-617-Targeted Alpha Therapy in Metastatic Castration-Resistant Prostate Cancer: A Systematic Review and Meta-Analysis.

OBJECTIVE: To conduct a meta-analysis of the efficacy and safety of 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer based on existing clinical evidence. METHODS: Search for retrospective studies about 225Ac-PSMA-617 in the treatment of metastatic castration-resistant prostate cancer from establishment to July 2021 in PubMed and EMBASE. The primary endpoint was 225Ac-PSMA-617 biochemical response evaluation criteria after treatment [any prostate specific antigen (PSA) decrease and PSA decrease >50% from baseline] to evaluate the treatment effect. Secondary endpoints included assessment of overall survival (OS), progression-free survival (PFS), molecular response, and toxicity for all studies. Two researchers conducted literature screening, data extraction and quality evaluation according to the inclusion and exclusion criteria. Use stata16.0 software for analysis, fixed-effects model for data merging and forest plots for display. RESULTS: A total of 6 retrospective studies, namely, 201 patients, were included in the final analysis. The pooled proportions of patients with decreased PSA and PSA decreased by more than 50% were 87.0% (95% confidence interval, 0.820 to 0.920) and 66.1% (95% confidence interval, 0.596 to 0.726), respectively. The pooled proportions of OS and PFS were 12.5 months (95%CI: 6.2-18.8 months) and 9.1 months (95%CI: 2.6-15.7 months). The patients showing molecular responses were 54% (95% confidence interval: 25-84%). In all studies, the most common side effect of 225Ac-PSMA-617 TAT was xerostomia, with any degree of xerostomia occurring in 77.1% (155 out of 201), and grade III only accounted for 3.0%. The second was 30.3% (61 out of 201) anemia of any degree, and grade III accounts for 7.5% (15 out of 201). Grade III leukopenia and thrombocytopenia were 4.5% (9 out of 201) and 5.5% (11 out of 201), respectively. Only 6 (3.0%) of 201 patients had Grade III nephrotoxicity. CONCLUSION: 225Ac-PSMA-617 is an effective and safe treatment option for mCRPC patients, and the toxicity caused by it is relatively low. However, future randomized controlled trials and prospective trials are required in the future to judge the therapeutic effects and survival benefits compared with existing clinical treatments. SYSTEMATIC REVIEW REGISTRATION: PROSPERO: CRD42021281967.

Serpinc1 Acts as a Tumor Suppressor in Hepatocellular Carcinoma Through Inducing Apoptosis and Blocking Macrophage Polarization in an Ubiquitin-Proteasome Manner.

Serpinc1 is a serine protease inhibitor in the coagulation cascade, but its role in tumor biology remains obscure. Here, we report an unexpected role of serpinc1 in suppression of hepatocellular carcinoma (HCC). In HCC patients, the mRNA and protein expression of serpinc1 is upregulated, which is negatively correlated with tumor grade, and has a better prognosis than patients with low serpinc1. In addition, patients with high expression of serpinc1 generally have a better tumor immune microenvironment, accompanied by changes in multiple immune cells and mediators. In particular, tumor-promoting M2 macrophages are negatively correlated with serpinc1 expression and the prognosis of HCC patients. In vitro experiments further show that overexpression of serpinc1 inhibits the growth of HCC cells (HepG2 and SMMC7721) by inducing apoptosis. Accordingly, cell co-culture experiments reveal the direct role of serpinc1-overexpressed HCC cells in inhibiting the formation of M2 macrophages. Subsequent unbiased quantitative proteomic and ubiquitinome analyses identify that multiple poly-ubiquitination of proteins involved in signal pathways (such as autophagy, apoptosis, lactate metabolism, and VEGF signaling) are regulated by serpinc1. Overall, these findings establish a serpinc1-dependent ubiquitin-proteasome system to control apoptosis and antitumor immunity.