CD87-targeted BiTE and CAR-T cells potently inhibit invasive nonfunctional pituitary adenomas.

Recently, bispecific T-cell engagers (BiTEs) and chimeric antigen receptor-modified T cells (CAR-Ts) have been shown to have high therapeutic efficacy in hematological tumors. CD87 is highly expressed in solid tumors with an oncogenic function. To assess their cytotoxic effects on invasive nonfunctioning pituitary adenomas (iNFPAs), we first examined CD87 expression and its effects on the metabolism of iNFPA cells. We generated CD87-specific BiTE and CAR/IL-12 T cells, and their cytotoxic effects on iNFPAs cells and in mouse models were determined. CD87 had high expression in iNFPA tissue and cell samples but was undetected in noncancerous brain samples. CD87×CD3 BiTE and CD87 CAR/IL-12 T-cells showed antigenic specificity and exerted satisfactory cytotoxic effects, decreasing tumor cell proliferation in vitro and reducing existing tumors in experimental mice. Overall, the above findings suggest that CD87 is a promising target for the immunotherapeutic management of iNFPAs using anti-CD87 BiTE and CD87-specific CAR/IL-12 T cells.

Occupational noise and genetic variants in stress hormone biosynthesis-based genes and rates of blood lipid changes in China: A five-year longitudinal study.

Lipid profiles are influenced by both noise and genetic variants. However, little is known about the associations of occupational noise and genetic variants with age-related changes in blood lipids, a crucial event in the initiation and evolution of atherosclerotic cardiovascular diseases. We aimed to evaluate the associations of blood lipid change rates with occupational noise and genetic variants in stress hormone biosynthesis-based genes. This cohort was established in 2012 and 2013 and was followed up until 2017. A total of 952 participants were included in the final analysis and all of them were categorized to two groups, the exposed group and control group, according to the exposed noise levels in their working area. Single nucleotide polymorphisms (SNPs) in stress hormone biosynthesis-based genes were genotyped. Five physical examinations were conducted from 2012 to 2017 and lipid measurements were repeated five times. The estimated annual changes (EACs) of blood lipid were calculated as the difference in blood lipid levels between any 2 adjacent examinations divided by their time interval (year). The generalized estimating equations for repeated measures analyses with exchangeable correlation structures were used to evaluate the influence of exposing to noise (versus being a control) and the SNPs mentioned above on the EACs of blood lipids. We found that the participants experienced accelerated age-related decline in high-density lipoprotein cholesterol (HDL-C) levels as they were exposed to noise (ß = -0.38, 95% confidence interval (CI), -0.66 to -0.10, P = 0.007), after adjusting for work duration, gender, smoking, alcohol consumption, and pack-years. This trend was only found in participants with COMT-rs165815 TT genotype (ß = -1.19, 95% CI, -1.80 to -0.58, P < 0.001), but not in those with the CC or CT genotypes. The interaction of noise exposure and rs165815 was marginally significant (Pinteraction = 0.010) after multiple adjustments. Compared with DDC-rs11978267 AA genotype carriers, participants carrying rs11978267 GG genotype had decreased EAC of triglycerides (TG) (ß = -5.06, 95% CI, -9.07 to -1.05, P = 0.013). Participants carrying DBH-rs4740203 CC genotype had increased EAC of total cholesterol (TC) (ß = 1.19, 95% CI, 0.06 to 2.33, P = 0.039). However, these findings were not statistically significant after multiple adjustments. These results indicated that Occupational noise exposure was associated with accelerated age-related decreases in HDL-C levels, and the COMT-rs165815 genotype appeared to modify the effect of noise exposure on HDL-C changes among the occupational population.

Observing astrocyte polarization in brains from mouse chronically infected with Toxoplasma gondii.

Toxoplasma gondii (T. gondii) is a protozoan parasite that infects approximately one-third of the global human population, often leading to chronic infection. While acute T. gondii infection can cause neural damage in the central nervous system and result in toxoplasmic encephalitis, the consequences of T. gondii chronic infection (TCI) are generally asymptomatic. However, emerging evidence suggests that TCI may be linked to behavioral changes or mental disorders in hosts. Astrocyte polarization, particularly the A1 subtype associated with neuronal apoptosis, has been identified in various neurodegenerative diseases. Nevertheless, the role of astrocyte polarization in TCI still needs to be better understood. This study aimed to establish a mouse model of chronic TCI and examine the transcription and expression levels of glial fibrillary acidic protein (GFAP), C3, C1q, IL-1α, and TNF-α in the brain tissues of the mice. Quantitative real-time PCR (qRT-PCR), enzyme-linked immunosorbent assay, and Western blotting were employed to assess these levels. Additionally, the expression level of the A1 astrocyte-specific marker C3 was evaluated using indirect fluorescent assay (IFA). In mice with TCI, the transcriptional and expression levels of the inflammatory factors C1q, IL-1α, and TNF-α followed an up-down-up pattern, although they remained elevated compared to the control group. These findings suggest a potential association between astrocyte polarization towards the A1 subtype and synchronized changes in these three inflammatory mediators. Furthermore, immunofluorescence assay (IFA) revealed a significant increase in the A1 astrocytes (GFAP+C3+) proportion in TCI mice. This study provides evidence that TCI can induce astrocyte polarization, a biological process that may be influenced by changes in the levels of three inflammatory factors: C1q, IL-1α, and TNF-α. Additionally, the release of neurotoxic substances by A1 astrocytes may be associated with the development of TCI.

H2O2-triggered CO release based on porphyrinic covalent organic polymers for photodynamic/gas synergistic therapy.

A novel H2O2-responsive carbon monoxide nanogenerator was designed by effectively encapsulating a manganese carbonyl prodrug into porphyrinic covalent organic polymers for realizing the combined CO gas and photodynamic therapy under near infrared light irradiation.

Artificial neural network identified a 20-gene panel in predicting immunotherapy response and survival benefits after anti-PD1/PD-L1 treatment in glioblastoma patients.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are a promising immunotherapy approach, but glioblastoma clinical trials have not yielded satisfactory results. OBJECTIVE: To screen glioblastoma patients who may benefit from immunotherapy. METHODS: Eighty-one patients receiving anti-PD1/PD-L1 treatment from a large-scale clinical trial and 364 patients without immunotherapy from The Cancer Genome Atlas (TCGA) were included. Patients in the ICI-treated cohort were divided into responders and nonresponders according to overall survival (OS), and the most critical responder-relevant features were screened using random forest (RF). We constructed an artificial neural network (ANN) model and verified its predictive value with immunotherapy response and OS. RESULTS: We defined two groups of ICI-treated glioblastoma patients with large differences in survival benefits as nonresponders (OS ≤6 months, n = 18) and responders (OS ≥17 months, n = 8). No differentially mutated genes were observed between responders and nonresponders. We performed RF analysis to select the most critical responder-relevant features and developed an ANN with 20 input variables, five hidden neurons and one output neuron. Receiver operating characteristic analysis and the DeLong test demonstrated that the ANN had the best performance in predicting responders, with an AUC of 0.97. Survival analysis indicated that ANN-predicted responders had significantly better OS rates than nonresponders. CONCLUSION: The 20-gene panel developed by the ANN could be a promising biomarker for predicting immunotherapy response and prognostic benefits in ICI-treated GBM patients and may guide oncologists to accurately select potential responders for the preferential use of ICIs.

A long-term prognosis study of human USP8-mutated ACTH-secreting pituitary neuroendocrine tumours.

OBJECTIVE: Somatic variants in the ubiquitin-specific protease 8 (USP8) gene are the most common genetic cause of Cushing disease. We aimed to explore the relationship between clinical outcomes and USP8 status in a single centre. DESIGN, PATIENTS AND MEASUREMENTS: We investigated the USP8 status in 48 patients with pituitary corticotroph tumours. A median of 62 months of follow-up was conducted after surgery from November 2013 to January 2015. The clinical, biochemical and imaging features were collected and analysed. RESULTS: Seven USP8 variants (p.Ser718Pro, p.Ser719del, p.Pro720Arg, p.Pro720Gln, p.Ser718del, p.Ser718Phe, p.Lys713Arg) were identified in 24 patients (50%). USP8 variants showed a female predominance (100% vs. 75% in wild type [WT], p = .022). Patients with p.Ser719del showed an older age at surgery compared to patients with the p.Pro720Arg variant (47- vs. 24-year-olds, p = .033). Patients with p.Pro720Arg showed a higher rate of macroadenoma compared to patients harbouring the p.Ser718Pro variant (60% vs. 0%, p = .037). No significant differences were observed in serum and urinary cortisol and adrenocorticotropin hormone (ACTH) levels. Immediate surgical remission (79% vs. 75%) and long-term hormone remission (79% vs. 67%) were not significantly different between the two groups. The recurrence rate was 21% (4/19) in patients harbouring USP8 variants and 13% (2/16) in WT patients. Recurrence-free survival presented a tendency to be shorter in USP8-mutated individuals (76.7 vs. 109.2 months, p = .068). CONCLUSIONS: Somatic USP8 variants accounted for 50% of the genetic causes in this cohort with a significant female frequency. A long-term follow-up revealed a tendency toward shorter recurrence-free survival in USP8-mutant patients.

Fiber-optic immunosensor based on a Fabry-Perot interferometer for single-molecule detection of biomarkers.

Immunosensors capable of ultralow-concentration and single-molecule detection of biomarkers are garnering attention for the early diagnosis of cancer. Herein, a fiber-optic Fabry-Perot interferometer (FPI)-based immunosensor was used for the first time for single-molecule detection of progastrin-releasing peptide (ProGRP). The cascaded FPI structure of the immunosensor introduces a high-order harmonic Vernier effect (HVE). A piece of a side-polished D-shaped hollow-core photonic crystal fiber (HCPCF) was used as a sensing FPI, on which the biomarker was deposited to detect ProGRP. Compared with traditional FPIs with open-cavity structures, this structure provided a larger contact area and improved the sensitivity of the immunosensor. The polished side surface of the D-shaped HCPCF was modified using a gold nanoparticle-graphene oxide (AuNP@GO) nanointerface to enhance refractive index (RI) modulation via antigen-antibody binding and achieve selective energy enhancement of the binding site. The antigen binding changes the RI of the D-shaped HCPCF and the effective RI of the transmitted light in the sensing FPI, thereby changing the spectrum of the immunosensor. Experimental results showed that the high-order HVE and AuNP@GO nanointerface considerably improved the immunosensor sensitivity, exhibiting a liquid RI sensitivity of 583,000 nm/RIU. After functionalization with an anti-ProGRP antibody, the limit of detection of the immunosensor for ProGRP reached 17.1 ag/mL; moreover, the immunosensor could perform detection at the single-molecule level. The proposed novel immunosensor overcomes the sensitivity limitations of optical devices and achieves single-molecule detection of a protein.

Double pituitary adenomas: report of two cases and systematic review of the literature.

Objective: Double pituitary adenomas (DPA) are a rare clinical condition, and our knowledge of them is limited. Missing the second lesion leading to incomplete biochemical remission after surgery is an important challenge in DPA management. This study aims to analyze independent prognostic factors in DPA patients and summarize clinical experiences to prevent surgical failure. Methods: Two cases of DPA patients with Cushing's disease diagnosed and surgically treated at Peking Union Medical College Hospital are reported. A literature review was performed on the online database Pubmed, and 57 DPA patients from 22 retrieved articles were included. Demographic characteristics, endocrine manifestations, diagnostic methods, tumor size, and immunohistochemical features of 59 patients were analyzed. Binary logistic regression models were used to identify independent prognostic factors affecting postoperative biochemical remission. Results: Among 59 DPA patients, the mean ± SD age was 43.64 ± 14.42 years, with 61.02% being female (n = 36). The most common endocrine manifestations were Cushing's syndrome (23/59, 38.98%) and acromegaly (20/59, 33.90%). The most prevalent immunohistochemical types were ACTH-immunopositive (31/118, 26.27%) and GH-immunopositive (31/118, 26.27%) tumors. Microadenomas (<1cm) were the most frequent in terms of tumor size (62/92, 67.39%). The detection rate for double lesions on 3.0T MRI was 50.00% (14/28), which significantly higher than 1.5T MRI (P = 0.034). Univariate analysis revealed that female, Cushing's syndrome and only single lesion detected by surgical exploration were associated with significantly worse prognosis (P<0.05). Multivariate analysis identified double lesion detected by surgical exploration (OR = 0.08, P = 0.003) and contiguous type tumor (OR = 0.06, P = 0.017) as independent protective factors for DPA patients. Conclusions: The double lesion detected by surgical exploration is independently associated with a better prognosis for DPA patients. Comprehensive intraoperative exploration are crucial measures to avoid missing causative lesions.

The crosstalk between mitochondrial quality control and metal-dependent cell death.

Mitochondria are the centers of energy and material metabolism, and they also serve as the storage and dispatch hubs of metal ions. Damage to mitochondrial structure and function can cause abnormal levels and distribution of metal ions, leading to cell dysfunction and even death. For a long time, mitochondrial quality control pathways such as mitochondrial dynamics and mitophagy have been considered to inhibit metal-induced cell death. However, with the discovery of new metal-dependent cell death including ferroptosis and cuproptosis, increasing evidence shows that there is a complex relationship between mitochondrial quality control and metal-dependent cell death. This article reviews the latest research results and mechanisms of crosstalk between mitochondrial quality control and metal-dependent cell death in recent years, as well as their involvement in neurodegenerative diseases, tumors and other diseases, in order to provide new ideas for the research and treatment of related diseases.

Interferon-α stimulates DExH-box helicase 58 to prevent hepatocyte ferroptosis.

BACKGROUND: Liver ischemia/reperfusion (I/R) injury is usually caused by hepatic inflow occlusion during liver surgery, and is frequently observed during war wounds and trauma. Hepatocyte ferroptosis plays a critical role in liver I/R injury, however, it remains unclear whether this process is controlled or regulated by members of the DEAD/DExH-box helicase (DDX/DHX) family. METHODS: The expression of DDX/DHX family members during liver I/R injury was screened using transcriptome analysis. Hepatocyte-specific Dhx58 knockout mice were constructed, and a partial liver I/R operation was performed. Single-cell RNA sequencing (scRNA-seq) in the liver post I/R suggested enhanced ferroptosis by Dhx58hep-/-. The mRNAs and proteins associated with DExH-box helicase 58 (DHX58) were screened using RNA immunoprecipitation-sequencing (RIP-seq) and IP-mass spectrometry (IP-MS). RESULTS: Excessive production of reactive oxygen species (ROS) decreased the expression of the IFN-stimulated gene Dhx58 in hepatocytes and promoted hepatic ferroptosis, while treatment using IFN-α increased DHX58 expression and prevented ferroptosis during liver I/R injury. Mechanistically, DHX58 with RNA-binding activity constitutively associates with the mRNA of glutathione peroxidase 4 (GPX4), a central ferroptosis suppressor, and recruits the m6A reader YT521-B homology domain containing 2 (YTHDC2) to promote the translation of Gpx4 mRNA in an m6A-dependent manner, thus enhancing GPX4 protein levels and preventing hepatic ferroptosis. CONCLUSIONS: This study provides mechanistic evidence that IFN-α stimulates DHX58 to promote the translation of m6A-modified Gpx4 mRNA, suggesting the potential clinical application of IFN-α in the prevention of hepatic ferroptosis during liver I/R injury.

GSNOR negatively regulates the NLRP3 inflammasome via S-nitrosation of MAPK14.

Hyperactivation of the NLRP3 inflammasome has been implicated in the pathogenesis of numerous diseases. However, the precise molecular mechanisms that modulate the transcriptional regulation of NLRP3 remain largely unknown. In this study, we demonstrated that S-nitrosoglutathione reductase (GSNOR) deficiency in macrophages leads to significant increases in the Nlrp3 and Il-1ß expression levels and interleukin-1ß (IL-1ß) secretion in response to NLRP3 inflammasome stimulation. Furthermore, in vivo experiments utilizing Gsnor-/- mice revealed increased disease severity in both lipopolysaccharide (LPS)-induced septic shock and dextran sodium sulfate (DSS)-induced colitis models. Additionally, we showed that both LPS-induced septic shock and DSS-induced colitis were ameliorated in Gsnor-/- Nlrp3-/- double-knockout (DKO) mice. Mechanistically, GSNOR deficiency increases the S-nitrosation of mitogen-activated protein kinase 14 (MAPK14) at the Cys211 residue and augments MAPK14 kinase activity, thereby promoting Nlrp3 and Il-1ß transcription and stimulating NLRP3 inflammasome activity. Our findings suggested that GSNOR is a regulator of the NLRP3 inflammasome and that reducing the level of S-nitrosylated MAPK14 may constitute an effective strategy for alleviating diseases associated with NLRP3-mediated inflammation.

A prognostic model for Schistosoma japonicum infection-associated liver hepatocellular carcinoma: strengthening the connection through initial biological experiments.

BACKGROUND: Numerous studies have shown that Schistosoma japonicum infection correlates with an increased risk of liver hepatocellular carcinoma (LIHC). However, data regarding the role of this infection in LIHC oncogenesis are scarce. This study aimed to investigate the potential mechanisms of hepatocarcinogenesis associated with Schistosoma japonicum infection. METHODS: By examining chronic liver disease as a mediator, we identified the genes contributing to Schistosoma japonicum infection and LIHC. We selected 15 key differentially expressed genes (DEGs) using weighted gene co-expression network analysis (WGCNA) and random survival forest models. Consensus clustering revealed two subgroups with distinct prognoses. Least Absolute Shrinkage and Selection Operator (LASSO) and Cox regression identified six prognostic DEGs, forming an Schistosoma japonicum infection-associated signature for strong prognosis prediction. This signature, which is an independent LIHC risk factor, was significantly correlated with clinical variables. Four DEGs, including BMI1, were selected based on their protein expression levels in cancerous and normal tissues. We confirmed BMI1's role in LIHC using Schistosoma japonicum-infected mouse models and molecular experiments. RESULTS: We identified a series of DEGs that mediate schistosomiasis, the parasitic disease caused by Schistosoma japonicum infection, and hepatocarcinogenesis, and constructed a suitable prognostic model. We analyzed the mechanisms by which these DEGs regulate disease and present the differences in prognosis between the different genotypes. Finally, we verified our findings using molecular biology experiments. CONCLUSION: Bioinformatics and molecular biology analyses confirmed a relationship between schistosomiasis and liver hepatocellular cancer. Furthermore, we validated the role of a potential oncoprotein factor that may be associated with infection and carcinogenesis. These findings enhance our understanding of Schistosoma japonicum infection's role in LIHC carcinogenesis.

Tumor-associated macrophages promoting PD-L1 expression in infiltrating B cells through the CXCL12/CXCR4 axis in human hepatocellular carcinoma.

The inflammation-related tumor microenvironment (TME) is one of the major driving forces of hepatocarcinogenesis. We aimed to investigate cell-to-cell communication among Hepatocellular Carcinoma (HCC) through re-analyzing HCC single-cell RNA-seq data, and to confirm such cellular interaction through in vitro and in vivo study. We found a subset of Regulatory B cells with PD-L1 expression (PD-L1+ Bregs), mainly located in adjacent HCC tissues. In co-localization with PD-L1+ Bregs, a subset of Tumor Associated Macrophages with high expression of CXCL12 (CXCL12+ TAMs) was also mainly located in adjacent HCC tissues. Moreover, CXCL12+ TAMs can be stimulated in vitro using an HCC conditional medium. Using CellChat analysis and Multiplex Immunohistochemistry staining (mIHC), CXCL12+ TAMs were found to be first recruited by Cancer-Associated Fibroblasts (CAFs) through a CD74/macrophage migration inhibitory factor (MIF) pattern, and further differentiated into TGF-ß-enriched tissues. Furthermore, CXCL12+ TAMs recruited PD-L1+ Bregs via the CXCL12/CXCR4 axis, and CXCR4 expression was significantly positively correlated to PD-L1 expression in PD-L1+ Bregs. At last, we confirmed the communications among CAFs, Macrophages and B cells and their tumor-promoting effects by using an orthotopic mouse model of HCC. Immunosuppressive HCC TME involving cell-to-cell communications comprised MIF-secreting CAFs, CXCL12-secreting TAMs, and PD-L1-producing Bregs, and their regulation could be promising therapeutic targets in future immunotherapy for human HCC.

Investigation of the Proteasome 26S Subunit, ATPase Family Genes as Potential Prognostic Biomarkers and Therapeutic Targets for Hepatocellular Carcinoma.

Background: Several studies suggest that Proteasome 26S Subunit, ATPase (PSMC) family genes are of great importance in tumor progression and spreading, but the study for systematic evaluation of the function of PSMC genes in hepatocellular carcinoma (HCC) is currently lacking. Methods: The functions of PSMC genes in HCC were analyzed using multiple online databases, including the TCGA database, GEO database, HPA database, cBioPortal database, DAVID, and KEGG pathway. Experiments were later conducted to verify PSMC expression. Results: High levels of PSMC gene expression were detected in HCC tissues and PSMCs exhibited potentially powerful abilities in diagnosing HCC patients. All PSMC proteins are expressed to varying degrees in HCC tissues and high expression of the PSMC genes lead to poor prognosis in patients with HCC. Moreover, DNA methylation involves the regulation of the expression of PSMC2 and PSMC5 in HCC, and the levels of methylation of PSMC2 or PSMC5 correlate positively with patient overall survival in HCC patients. The copy number alteration and mutation of PSMC genes were observed and related to the expression of PSMCs in HCC. Functional enrichment analysis showed that many highly co-expressed genes of PSMCs had a potential role in tumor progression and metastasis, which merited further in-depth study. Functional network analysis also suggests that the primary biological function of PSMC genes is the regulation of protein homeostasis and energy metabolism in HCC. Moreover, the expression levels of PSMCs are related to immune cell infiltrates and immunomodulatory factors in HCC. Conclusion: Our study indicates that PSMC genes are the potential target for precision immunotherapy and novel prognostic biomarkers for HCC.

Pharmacologically significant constituents collectively responsible for anti-sepsis action of XueBiJing, a Chinese herb-based intravenous formulation.

Sepsis, a life-threatening health issue, lacks effective medicine targeting the septic response. In China, treatment combining the intravenous herbal medicine XueBiJing with conventional procedures reduces the 28-day mortality of critically ill patients by modulating septic response. In this study, we identified the combined active constituents that are responsible for the XueBiJing's anti-sepsis action. Sepsis was induced in rats by cecal ligation and puncture (CLP). The compounds were identified based on their systemic exposure levels and anti-sepsis activities in CLP rats that were given an intravenous bolus dose of XueBiJing. Furthermore, the identified compounds in combination were assessed, by comparing with XueBiJing, for levels of primary therapeutic outcome, pharmacokinetic equivalence, and pharmacokinetic compatibility. We showed that a total of 12 XueBiJing compounds, unchanged or metabolized, circulated with significant systemic exposure in CLP rats that received XueBiJing. Among these compounds, hydroxysafflor yellow A, paeoniflorin, oxypaeoniflorin, albiflorin, senkyunolide I, and tanshinol displayed significant anti-sepsis activities, which involved regulating immune responses, inhibiting excessive inflammation, modulating hemostasis, and improving organ function. A combination of the six compounds, with the same respective doses as in XueBiJing, displayed percentage survival and systemic exposure in CLP rats similar to those by XueBiJing. Both the combination and XueBiJing showed high degrees of pharmacokinetic compatibility regarding interactions among the six active compounds and influences of other circulating XueBiJing compounds. The identification of XueBiJing's pharmacologically significant constituents supports the medicine's anti-sepsis use and provides insights into a polypharmacology-based approach to develop medicines for effective sepsis management.

Polydopamine modified by pillar[5]arene in situ for targeted chemo-photothermal cancer therapy.

A pillar[5]arene-modified polydopamine (PDA-P[5]OH) displaying pH/NIR dual-responsive properties was constructed successfully in situ for targeted chemo-photothermal cancer therapy.

Effects of levosimendan on the outcome of veno-arterial extracorporeal membrane oxygenation: a systematic review and meta-analysis.

OBJECTIVES: For patients with severe cardiopulmonary failure, such as cardiogenic shock, veno-arterial extracorporeal membrane oxygenation (VA-ECMO) is primarily utilized to preserve their life by providing continuous extracorporeal respiration and circulation. However, because of the complexity of patients' underlying diseases and serious complications, successful weaning from ECMO is often difficult. At present, there have been limited studies on ECMO weaning strategies, so the principal purpose of this meta-analysis is to examine how levosimendan contributes to the weaning of extracorporeal membrane oxygenation. METHODS: The Cochrane Library, Embase, Web of Science, and PubMed were browsed for all potentially related research about clinical benefits of levosimendan in weaning patients receiving VA-ECMO and included 15 of them. The main outcome is success of weaning from extracorporeal membrane oxygenation, with the secondary outcomes of 1-month mortality (28 or 30 days), ECMO duration, hospital or intensive care unit (ICU) length of stay, and use of vasoactive drugs. RESULTS: 1772 patients altogether from 15 publications were incorporated in our meta-analysis. We used fixed and random-effect models to combine odds ratio (OR) and 95% confidence interval (CI) for dichotomous outcomes and standardized mean difference (SMD) for continuous outcomes. The weaning success rate in the levosimendan group was considerably higher in contrast to the comparison (OR = 2.78, 95% CI 1.80-4.30; P < 0.00001; I2 = 65%), and subgroup analysis showed that there was less heterogeneity in patients after cardiac surgery (OR = 2.06, 95% CI, 1.35-3.12; P = 0.0007; I2 = 17%). In addition, the effect of levosimendan on improving weaning success rate was statistically significant only at 0.2 mcg/kg/min (OR = 2.45, 95% CI, 1.11-5.40; P = 0.03; I2 = 38%). At the same time, the 28-day or 30-day proportion of deaths in the sample receiving levosimendan also decreased (OR = 0.47, 95% CI, 0.28-0.79; P = 0.004; I2 = 73%), and the difference was statistically significant. In terms of secondary outcomes, we found that individuals undergoing levosimendan treatment had a longer duration of VA-ECMO support. CONCLUSIONS: In patients receiving VA-ECMO, levosimendan treatment considerably raised the weaning success rate and helped lower mortality. Since most of the evidence comes from retrospective studies, more randomized multicenter trials are required to verify the conclusion.

Hypoxia-Responsive Tetrameric Supramolecular Polypeptide Nanoprodrugs for Combination Therapy.

Despite the intense progress of photodynamic and chemotherapy, however, they cannot prevent solid tumor invasion, metastasis, and relapse, along with inferior efficacy and severe side effects. The hypoxia-responsive nanoprodrugs integrating photodynamic functions are highly sought to address the above-mentioned problems and overcome the tumor hypoxia-reduced efficacy. Herein, a hypoxia-responsive tetrameric supramolecular polypeptide nanoprodrug (SPN-TAPP-PCB4) is constructed from the self-assembly of tetrameric porphyrin-central poly(l-lysine-azobenzene-chlorambucil) (TAPP-(PLL-Azo-CB)4) and an anionic water-soluble [2]biphenyl-extended-pillar[6]arene (AWBpP6) via the synergy of hydrophobic, π-π stacking, and host-guest interactions. Upon laser irradiation, the central TAPP can convert oxygen to generate single oxygen (1 O2 ) to kill tumor cells. Furthermore, under the acidic and PDT-aggravated hypoxia tumor cell microenvironment, SPN-TAPP-PCB4 is rapidly disassembled, and then efficiently releases activated CB through the hypoxic-responsive cleavage of azobenzene linkages. Both in vitro and in vivo biological studies showcase synergistic cancer-killing actions between photodynamic therapy (PDT) and chemotherapy (CT) with negligible toxicity. Consequently, this supramolecular polypeptide nanoprodrug offers an effective strategy to design a hypoxia-responsive nanoprodrug for a potential combo PDT-CT transition.