Hepatocyte-intrinsic SMN deficiency drives metabolic dysfunction and liver steatosis in spinal muscular atrophy.

Spinal Muscular Atrophy (SMA) is typically characterized as a motor neuron disease, but extra-neuronal phenotypes are present in almost every organ in severely affected patients and animal models. Extra-neuronal phenotypes were previously underappreciated as patients with severe SMA phenotypes usually died in infancy; however, with current treatments for motor neurons increasing patient lifespan, impaired function of peripheral organs may develop into significant future comorbidities and lead to new treatment-modified phenotypes. Fatty liver is seen in SMA animal models , but generalizability to patients and whether this is due to hepatocyte-intrinsic Survival Motor Neuron (SMN) protein deficiency and/or subsequent to skeletal muscle denervation is unknown. If liver pathology in SMA is SMN-dependent and hepatocyte-intrinsic, this suggests SMN repleting therapies must target extra-neuronal tissues and motor neurons for optimal patient outcome. Here we showed that fatty liver is present in SMA and that SMA patient-specific iHeps were susceptible to steatosis. Using proteomics, functional studies and CRISPR/Cas9 gene editing, we confirmed that fatty liver in SMA is a primary SMN-dependent hepatocyte-intrinsic liver defect associated with mitochondrial and other hepatic metabolism implications. These pathologies require monitoring and indicate need for systematic clinical surveillance and additional and/or combinatorial therapies to ensure continued SMA patient health.

C-176 reduces inflammation-induced pain by blocking the cGAS-STING pathway in microglia.

OBJECTIVE: Inflammatory pain, is caused by lesions or diseases of the somatosensory tissue, is a prevalent chronic condition that profoundly impacts the quality of life. However, clinical treatment for this type of pain remains limited. Traditionally, the stimulation of microglia and subsequent inflammatory reactions are considered crucial elements to promote the worsening of inflammatory pain. Recent research has shown the crucial importance of the cGAS-STING pathway in promoting inflammation. It is still uncertain if the cGAS-STING pathway plays the role in the fundamental cause of inflammatory pain. We aim to explore the treatment of inflammatory pain by interfering with cGAS-STING signaling pathway. METHODS: In this study, we established an inflammatory pain model by CFA into the plantar of mice. Activation of microglia, various inflammatory factors and cGAS-STING protein in the spinal dorsal horn were evaluated. Immunofluorescence staining was used to observe the cellular localization of cGAS and STING. The cGAS-STING pathway proteins expression and mRNA expression of indicated microglial M1/M2 phenotypic markers in the BV2 microglia were detected. STING inhibitor C-176 was intrathecal injected into mice with inflammatory pain, and the pain behavior and microglia were observed. RESULTS: This research showed that injecting CFA into the left hind paw of mice caused mechanical allodynia and increased inflammation in the spine. Our research results suggested that the cGAS-STING pathway had a function in the inflammation mediated by microglia in the spinal cord dorsal horn. Blocking the cGAS-STING pathway using STING antagonists (C-176) led to reduced release of inflammatory factors and prevented M1 polarization of BV2 microglia in a laboratory setting. Additionally, intrathecal administration of C-176 reduced the allodynia in CFA treated mice. CONCLUSION: Our results suggest that inhibiting microglial polarization through the cGAS-STING pathway represents a potential novel therapeutic strategy for inflammatory pain.

Development of 1 Month Sustained-Release Microspheres Containing Liraglutide for Type 2 Diabetes Treatment.

Liraglutide has been extensively applied in the treatment of type 2 diabetes mellitus (T2DM), but its 11-15 h half-life resulted in daily administration, which led to poor patient compliance. This study aimed to solve this problem by developing liraglutide-loaded microspheres with a 1 month sustained release prepared by the W1/O/W2 method combined with the premix membrane emulsification technique to improve therapeutic efficacy. Remarkably, we found that the amphiphilic properties of liraglutide successfully reduced the oil-water interfacial tension, resulting in a stable primary emulsion and decreasing the level of drug leakage into the external water phase. As a result, exceptional drug loading (>8%) and encapsulation efficiency (>85%) of microspheres were achieved. Furthermore, the uniformity in microsphere size facilitated an in-depth exploration of the structural characteristics of liraglutide-loaded microspheres. The results indicated that the dimensions of the internal cavities of the microspheres were significantly influenced by the size of the inner water droplets in the primary emulsion. A denser and more uniform cavity structure decreased the initial burst release, improving the release process of liraglutide from the microspheres. To evaluate the release behavior of liraglutide from microspheres, a set of in vitro release assays and in vivo pharmacodynamics were performed. The liraglutide-loaded microspheres effectively decreased fasting blood glucose (FBG) levels and hemoglobin A1c (HbA1c) levels while enhancing the pancreatic and hepatic functions in db/db mice. In conclusion, liraglutide sustained-release microspheres showed the potential for future clinical applications in the management of T2DM and provided an effective therapeutic approach to overcoming patient compliance issues.

Seagrass repression by green turtles (Chelonia mydas) around Taiping Island in the south China sea: Experimental evidence and management insights.

Seagrass meadows serve as critical marine habitats, offering numerous benefits to both humans and wildlife. Taiping Island, situated in the South China Sea, has been historically known for its abundant seagrass meadows. However, satellite imagery suggested there was a low density of seagrasses around Taiping Island. On the other hand, many green turtles (Chelonia mydas) were observed from the shore. To investigate this phenomenon, we conducted drone surveys of the shallow reefs and discovered a density of 902 ± 601 (mean ± SD) individual turtles per square kilometer during high tides. In addition, we conducted a cage experiment to test the hypothesis that large herbivores are impacting seagrass abundance negatively. The results indicated that the blade lengths of seagrasses in cages were significantly longer than those outside. It is likely that large herbivores such as green sea turtles are the key consumers of seagrass on the shallow reef flats of Taiping Island. Accordingly, further research and management should take into account that the increasing number of sea turtles may deplete the seagrasses and have an impact on the seagrass ecosystems.

Manipulating Chiroptical Activities in 0D Chiral Hybrid Manganese Bromides by Solvent Molecular Engineering.

0D hybrid metal halides (0D HMHs) with fully isolated inorganic units provide an ideal platform for studying the correlations between chiroptical activities and crystal structures at atomic levels. Here, through the incorporation of different solvent molecules, a series of 0D chiral manganese bromides (RR/SS-C20H28N2)3MnBr8·2X (X = C2H5OH, CH3OH, or H2O) are synthesized to elucidate their chiroptical properties. They show negligible circular dichroism signals of Mn absorptions due to C2v-symmetric [MnBr4]2- tetrahedra. However, they display distinct circularly polarized luminescence (CPL) signals with continuously increased luminescence asymmetry factors (glum) from 10-4 (X = C2H5OH) to 10-3 (X = H2O). The increased glum value is structurally revealed to originate from the enhancement of [MnBr4]2- tetrahedral bond-angle distortions, due to the presence of different solvent molecules. Furthermore, (RR/SS-C20H28N2)MnBr4·H2O enantiomers with larger bond-angle distortions of [MnBr4]2- tetrahedra are synthesized based on hydrobromic acid-induced structural transformation of (RR/SS-C20H28N2)3MnBr8·2H2O enantiomers. Therefore, such (RR/SS-C20H28N2)MnBr4·H2O enantiomers exhibit enhanced CPL signals with |glum| up to 1.23 × 10-2. This work provides unique insight into enhancing chiroptical activities in 0D HMH systems.

ABO and Rhesus blood groups and multiple health outcomes: an umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Numerous studies have been conducted to investigate the relationship between ABO and Rhesus (Rh) blood groups and various health outcomes. However, a comprehensive evaluation of the robustness of these associations is still lacking. METHODS: We searched PubMed, Web of Science, Embase, Scopus, Cochrane, and several regional databases from their inception until Feb 16, 2024, with the aim of identifying systematic reviews with meta-analyses of observational studies exploring associations between ABO and Rh blood groups and diverse health outcomes. For each association, we calculated the summary effect sizes, corresponding 95% confidence intervals, 95% prediction interval, heterogeneity, small-study effect, and evaluation of excess significance bias. The evidence was evaluated on a grading scale that ranged from convincing (Class I) to weak (Class IV). We assessed the certainty of evidence according to the Grading of Recommendations Assessment, Development, and Evaluation criteria (GRADE). We also evaluated the methodological quality of included studies using the A Measurement Tool to Assess Systematic Reviews (AMSTAR). AMSTAR contains 11 items, which were scored as high (8-11), moderate (4-7), and low (0-3) quality. We have gotten the registration for protocol on the PROSPERO database (CRD42023409547). RESULTS: The current umbrella review included 51 systematic reviews with meta-analysis articles with 270 associations. We re-calculated each association and found only one convincing evidence (Class I) for an association between blood group B and type 2 diabetes mellitus risk compared with the non-B blood group. It had a summary odds ratio of 1.28 (95% confidence interval: 1.17, 1.40), was supported by 6870 cases with small heterogeneity (I2 = 13%) and 95% prediction intervals excluding the null value, and without hints of small-study effects (P for Egger's test > 0.10, but the largest study effect was not more conservative than the summary effect size) or excess of significance (P < 0.10, but the value of observed less than expected). And the article was demonstrated with high methodological quality using AMSTAR (score = 9). According to AMSTAR, 18, 32, and 11 studies were categorized as high, moderate, and low quality, respectively. Nine statistically significant associations reached moderate quality based on GRADE. CONCLUSIONS: Our findings suggest a potential relationship between ABO and Rh blood groups and adverse health outcomes. Particularly the association between blood group B and type 2 diabetes mellitus risk.

Elevated CO2 concentration enhance carbon and nitrogen metabolism and biomass accumulation of Ormosiahosiei.

Elevated CO2 concentrations may inhibit photosynthesis due to nitrogen deficiency, but legumes may be able to overcome this limitation and continue to grow. Our study confirms this conjecture well. First, we placed the two-year-old potted saplings of Ormosia hosiei (O. hosiei) (a leguminous tree species) in the open-top chamber (OTC) with three CO2 concentrations of 400 (CK), 600 (E1), and 800 µmol·mol-1 (E2) to simulate the elevated CO2 concentration environment. After 146 days, the light saturation point (LSP), light compensation point (LCP), apparent quantum efficiency (AQE), and dark respiration rate (Rd) of O. hosiei were increased under increasing CO2 concentration and obtain the maximum ribulose diphosphate (RuBP) carboxylation rate (Vc max) and RuBP regenerated photosynthetic electron transfer rate (Jmax) were also significantly increased under E2 treatment (P < 0.05). This results in a significant increase of the maximum assimilation rate (Amax) under elevated CO2 concentrations. Sucrose phosphate synthase (SPS) activity in sucrose metabolism increased in the leaves, more soluble sugars, starches, and sucrose was produced, but sucrose content only in leaves increased at E2, and more carbon flows to the roots. The activity of the NH4+ assimilating enzymes glutamine synthetase (GS), glutamate synthetase (GOGAT), and glutamate dehydrogenase (GDH) in the leaves of O. hosiei increases under elevated CO2 concentrations to promote nitrogen synthesis that reduces the content of ammonium nitrogen and increases the content of nitrate nitrogen. In addition, under E1 conditions, sucrose synthase (SS), direction of synthesis activity was highest and sucrose invertase (INV) activity was lowest, this means that the balance of C and N metabolism is maintained. While under E2 conditions SS activity decreased and INV activity increased, this increased C/N and nitrogen use efficiency. So, the elevated CO2 concentration promotes the accumulation of O. hosiei biomass, especially in the aboveground part, but did not have a significant effect on the accumulation of root biomass. This means that O. hosiei is able to cope under the elevated CO2 concentration without showing photosynthetic adaptation during the experimental period.

Per- and polyfluoroalkyl substances and human health outcomes: An umbrella review of systematic reviews with meta-analyses of observational studies.

BACKGROUND: Although evidence on the association between per- and polyfluoroalkyl substances (PFASs) and human health outcomes has grown exponentially, specific health outcomes and their potential associations with PFASs have not been conclusively evaluated. METHODS: We conducted a comprehensive search through the databases of PubMed, Embase, and Web of Science from inception to February 29, 2024, to identify systematic reviews with meta-analyses of observational studies examining the associations between the PFASs and multiple health outcomes. The quality of included studies was evaluated using the A Measurement Tool to Assess Systematic Reviews (AMSTAR) tool, and credibility of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) criteria. The protocol of this umbrella review (UR) had been registered in PROSPERO (CRD 42023480817). RESULTS: The UR identified 157 meta-analyses from 29 articles. Using the AMSTAR measurement tool, all articles were categorized as of moderate-to-high quality. Based on the GRADE assessment, significant associations between specific types of PFASs and low birth weight, tetanus vaccine response, and triglyceride levels showed high certainty of evidence. Moreover, moderate certainty of evidence with statistical significance was observed between PFASs and health outcomes including lower BMI z-score in infancy, poor sperm progressive motility, and decreased risk of preterm birth as well as preeclampsia. Fifty-two (33%) associations (e.g., PFASs and gestational hypertension, cardiovascular disease, etc) presented low certainty evidence. Additionally, eighty-five (55%) associations (e.g., PFASs with infertility, lipid metabolism, etc) presented very low certainty evidence. CONCLUSION: High certainty of evidence supported that certain PFASs were associated with the incidence of low birth weight, low efficiency of the tetanus vaccine, and low triglyceride levels.

Developing preclinical dog models for reconstructive severed spinal cord continuity via spinal cord fusion technique.

Background: Spinal cord injury (SCI) is a severe impairment of the central nervous system, leading to motor, sensory, and autonomic dysfunction. The present study investigates the efficacy of the polyethylene glycol (PEG)-mediated spinal cord fusion (SCF) techniques, demonstrating efficacious in various animal models with complete spinal cord transection at the T10 level. This research focuses on a comparative analysis of three SCF treatment models in beagles: spinal cord transection (SCT), vascular pedicle hemisected spinal cord transplantation (vSCT), and vascularized allograft spinal cord transplantation (vASCT) surgical model. Methods: Seven female beagles were included in the SCT surgical model, while four female dogs were enrolled in the vSCT surgical model. Additionally, twelve female dogs underwent vASCT in a paired donor-recipient setup. Three surgical model were evaluated and compared through electrophysiology, imaging and behavioral recovery. Results: The results showed a progressive recovery in the SCT, vSCT and vASCT surgical models, with no statistically significant differences observed in cBBB scores at both 2-month and 6-month post-operation (both P>0.05). Neuroimaging analysis across the SCT, vSCT and vASCT surgical models revealed spinal cord graft survival and fiber regrowth across transection sites at 6 months postoperatively. Also, positive MEP waveforms were recorded in all three surgical models at 6-month post-surgery. Conclusion: The study underscores the clinical relevance of PEG-mediated SCF techniques in promoting nerve fusion, repair, and motor functional recovery in SCI. SCT, vSCT, and vASCT, tailored to specific clinical characteristics, demonstrated similar effective therapeutic outcomes.

Complement system is overactivated in patients with IgA nephropathy after COVID-19.

IgA nephropathy (IgAN), which has been confirmed as a complement mediated autoimmune disease, is also one form of glomerulonephritis associated with COVID-19. Here, we aim to investigate the clinical and immunological characteristics of patients with IgAN after COVID-19. The level of plasma level of C5a (p < 0.001), soluble C5b-9 (p = 0.018), FHR5 (p < 0.001) were all significantly higher in Group CoV (33 patients with renal biopsy-proven IgAN experienced COVID-19) compared with Group non-CoV (44 patients with IgAN without COVID-19), respectively. Compared with Group non-CoV, the intensity of glomerular C4d (p = 0.017) and MAC deposition (p < 0.001) and Gd-IgA1 deposition (p = 0.005) were much stronger in Group CoV. Our finding revealed that for IgAN after COVID-19, mucosal immune responses to SARS-CoV-2 infection may result in the overactivation of systemic and renal local complement system, and increased glomerular deposition of Gd-IgA1, which may lead to renal dysfunction and promote renal progression in IgAN patients.

Association between coffee and caffeine intake and risk of COPD: Findings based on NHANES 2007-2012.

BACKGROUND: The association between coffee and caffeine intake and the risk of COPD and lung function has not been thoroughly discussed in Americans, with subgroup and threshold effects remaining unclear. OBJECTIVES: This study investigated the association between coffee and caffeine consumption and the risk of chronic obstructive pulmonary disease (COPD) as well as lung function utilizing data from the NHANES 2007-2012. METHODS: We assessed the associations of coffee and caffeine consumption with the risk of COPD and lung function parameters, including FEV1 and FVC, adjusting for common demographic and disease characteristics in a cross-sectional analysis of NHANES data. RESULTS: A total of 9763 participants were included in the study, and 592 were diagnosed with COPD. Multivariate regression models revealed positive associations between coffee and caffeine consumption and the risk of COPD and lung function. Subgroup analyses stratified by sex, DM, hypertension status, and smoking habits identified potential effect modifiers as well as inflection points from threshold effect examinations. CONCLUSIONS: The results of this cross-sectional study indicated significant positive correlations between coffee and caffeine consumption and the risk of COPD. Additionally, positive correlations between exposure variables and FEV1 and FVC were detected. Among the stratification factors, smoking status exhibited the most potential for modifying effects. Future practices and research are needed to validate the results and explore the underlying mechanisms.

Paracrinal regulation of neutrophil functions by coronaviral infection in iPSC-derived alveolar type II epithelial cells.

Coronaviruses (CoVs) are enveloped single-stranded RNA viruses that predominantly attack the human respiratory system. In recent decades, several deadly human CoVs, including SARS-CoV, SARS-CoV-2, and MERS-CoV, have brought great impact on public health and economics. However, their high infectivity and the demand for high biosafety level facilities restrict the pathogenesis research of CoV infection. Exacerbated inflammatory cell infiltration is associated with poor prognosis in CoV-associated diseases. In this study, we used human CoV 229E (HCoV-229E), a CoV associated with relatively fewer biohazards, to investigate the pathogenesis of CoV infection and the regulation of neutrophil functions by CoV-infected lung cells. Induced pluripotent stem cell (iPSC)-derived alveolar epithelial type II cells (iAECIIs) exhibiting specific biomarkers and phenotypes were employed as an experimental model for CoV infection. After infection, the detection of dsRNA, S, and N proteins validated the infection of iAECIIs with HCoV-229E. The culture medium conditioned by the infected iAECIIs promoted the migration of neutrophils as well as their adhesion to the infected iAECIIs. Cytokine array revealed the elevated secretion of cytokines associated with chemotaxis and adhesion into the conditioned media from the infected iAECIIs. The importance of IL-8 secretion and ICAM-1 expression for neutrophil migration and adhesion, respectively, was demonstrated by using neutralizing antibodies. Moreover, next-generation sequencing analysis of the transcriptome revealed the upregulation of genes associated with cytokine signaling. To summarize, we established an in vitro model of CoV infection that can be applied for the study of the immune system perturbations during severe coronaviral disease.

Ethylene-responsive VviERF003 modulates glycosylated monoterpenoid synthesis by upregulating VviGT14 in grapes.

Terpenoids are important contributors to the aroma of grapes and wines. Grapes contain terpenoids in both volatile free form and non-volatile glycosidic form, with the latter being more abundant. Glycosylated terpenoids are deemed as latent aromatic potentials for their essential role in adding to the flowery and fruity bouquet of wines. However, the transcriptional regulatory mechanism underlying glycosylated terpenoid biosynthesis remains poorly understood. Our prior study identified an AP2/ERF transcription factor, VviERF003, through DNA pull-down screening using the promoter of terpenoid glycosyltransferase VviGT14 gene. This study demonstrated that both genes were co-expressed and synchronized with the accumulation of glycosylated monoterpenoids during grape maturation. VviERF003 can bind to the VviGT14 promoter and promote its activity according to yeast one-hybrid and dual-luciferase assays. VviERF003 upregulated VviGT14 expression in vivo, leading to increased production of glycosylated monoterpenoids based on the evidence from overexpression or RNA interference in leaves, berry skins, and calli of grapes, as well as tomato fruits. Additionally, VviERF003 and VviGT14 expressions and glycosylated monoterpenoid levels were induced by ethylene in grapes. The findings suggest that VviERF003 is ethylene-responsive and stimulates glycosylated monoterpenoid biosynthesis through upregulating VviGT14 expression.

TAF2, within the TFIID complex, regulates the expression of a subset of protein-coding genes.

TFIID, one of the general transcription factor (GTF), regulates transcriptional initiation of protein-coding genes through direct binding to promoter elements and subsequent recruitment of other GTFs and RNA polymerase II. Although generally required for most protein-coding genes, accumulated studies have also demonstrated promoter-specific functions for several TFIID subunits in gene activation. Here, we report that TBP-associated factor 2 (TAF2) specifically regulates TFIID binding to a small subset of protein-coding genes and is essential for cell growth of multiple cancer lines. Co-immunoprecipitation assays revealed that TAF2 may be sub-stoichiometrically associated with the TFIID complex, thus indicating a minor fraction of TAF2-containing TFIID in cells. Consistently, integrated genome-wide profiles show that TAF2 binds to and regulates only a small subset of protein-coding genes. Furthermore, through the use of an inducible TAF2 degradation system, our results reveal a reduction of TBP/TFIID binding to several ribosomal genes upon selective ablation of TAF2. In addition, depletion of TAF2, as well as the TAF2-regulated ribosomal protein genes RPL30 and RPL39, decreases ribosome assembly and global protein translation. Collectively, this study suggests that TAF2 within the TFIID complex is of functional importance for TBP/TFIID binding to and expression of a small subset of protein-coding genes, thus establishing a previously unappreciated promoter-selective function for TAF2.

Electrochemical Cross-Coupling between N-(4-Hydroxyphenyl)-sulfonamides and 2-Naphthols: Synthesis of 2,2'-Bis(arenol)s.

We herein present an electrochemical method for the dehydrogenative cross-coupling of N-(4-hydroxyphenyl)-sulfonamides and 2-naphthols. This transformation provides a direct and scalable approach to a wide range of C1-symmetric 2,2'-bis(arenol)s with moderate to high yields under mild conditions. Preliminary attempts with the asymmetric variant of this reaction were also performed with ≤55% ee for the synthesis of 2,2'-bis(arenol)s. Control experiments were conducted to propose a plausible mechanism for the reaction.

Analysis of the causes of primary revision after unicompartmental knee arthroplasty: A case series.

BACKGROUND: Unicompartmental knee arthroplasty (UKA) has great advantages in the treatment of unicompartmental knee osteoarthritis, but its revision rate is higher than that of total knee arthroplasty. AIM: To summarize and analyse the causes of revision after UKA. METHODS: This is a retrospective case series study in which the reasons for the first revision after UKA are summarized. We analysed the clinical symptoms, medical histories, laboratory test results, imaging examination results and treatment processes of the patients who underwent revision and summarized the reasons for primary revision after UKA. RESULTS: A total of 13 patients, including 3 males and 10 females, underwent revision surgery after UKA. The average age of the included patients was 67.62 years. The prosthesis was used for 3 d to 72 months. The main reasons for revision after UKA were improper suturing of the surgical opening (1 patient), osteophytes (2 patients), intra-articular loose bodies (2 patients), tibial prosthesis loosening (2 patients), rheumatoid arthritis (1 patient), gasket dislocation (3 patients), anterior cruciate ligament injury (1 patient), and medial collateral ligament injury with residual bone cement (1 patient). CONCLUSION: The causes of primary revision after UKA were gasket dislocation, osteophytes, intra-articular loose bodies and tibial prosthesis loosening. Avoidance of these factors may greatly reduce the rate of revision after UKA, improve patient satisfaction and reduce medical burden.

Delta-sigma modulation supporting the 4194304QAM dual polarization signal at the W-band transmission over a 4.6†km wireless distance.

In this Letter, we propose a dual-polarized coherent millimeter-wave system based on differential delta-sigma modulation (D-DSM) intended for long-distance wireless transmission in the W-band. The proposed system can transmit polarization-division-multiplexed (PDM) D-DSM signals with modulation orders up to 4194304QAM over a wireless channel for 4.6 km at a signal baud rate of 20 G. After 4.6 km of wireless transmission, we successfully achieve a bit error rate (BER) lower than the hard-decision forward error correction (HD-FEC) of 3.8 × 10-3 for 34.51 Gbit/s PDM-524288QAM and a BER lower than the soft-decision forward error correction (SD-FEC) of 4.2 × 10-2 for 32.23 Gbit/s PDM-4194304QAM.

Comprehensive analysis of fibroblast activation protein expression across 23 tumor indications: insights for biomarker development in cancer immunotherapies.

Introduction: Fibroblast activation protein (FAP) is predominantly upregulated in various tumor microenvironments and scarcely expressed in normal tissues. Methods: We analyzed FAP across 1216 tissue samples covering 23 tumor types and 70 subtypes. Results: Elevated FAP levels were notable in breast, pancreatic, esophageal, and lung cancers. Using immunohistochemistry and RNAseq, a correlation between FAP gene and protein expression was found. Evaluating FAP's clinical significance, we assessed 29 cohorts from 12 clinical trials, including both mono and combination therapies with the PD-L1 inhibitor atezolizumab and chemotherapy. A trend links higher FAP expression to poorer prognosis, particularly in RCC, across both treatment arms. However, four cohorts showed improved survival with high FAP, while in four others, FAP had no apparent survival impact. Conclusions: Our results emphasize FAP's multifaceted role in therapy response, suggesting its potential as a cancer immunotherapy biomarker.

Engineering Nanozymes for Tumor Therapy via Ferroptosis Self-Amplification.

Ferroptosis induction is an emerging strategy for tumor therapy. Reactive oxygen species (ROS) can induce ferroptosis but are easily consumed by overexpressed glutathione (GSH) in tumor cells. Therefore, achieving a large amount of ROS production in tumor cells without being consumed is key to efficiently inducing ferroptosis. In this study, a self-amplifying ferroptosis-inducing therapeutic agent, Pd@CeO2-Fe-Co-WZB117-DSPE-PEG-FA (PCDWD), is designed for tumor therapy. PCDWD exhibits excellent multi-enzyme activities due to the loading of Fe-Co dual atoms with abundant active sites, including peroxidase-like enzymes, catalase-like enzymes, and glutathione oxidases (GSHOx), which undergo catalytic reactions in the tumor microenvironment to produce ROS, thereby inducing ferroptosis. Furthermore, PCDWD can also deplete GSH in tumor cells, thus reducing the consumption of ROS by GSH and inhibiting the expression of GSH peroxidase 4. Moreover, the photothermal effect of PCDWD can not only directly kill tumor cells but also further enhance its own enzyme activities, consequently promoting ferroptosis in tumor cells. In addition, WZB117 can reduce the expression of heat shock protein 90 by inhibiting glucose transport, thereby reducing the thermal resistance of tumor cells and further improving the therapeutic effect. Finally, X-ray computed tomography imaging of PCDWD guides it to achieve efficient tumor therapy.