Single-cell transcriptome atlas of testes from mice with high-fat diets.

Obesity is accompanied by multiple known health risks and increased morbidity, and obese men display reduced reproductive health. However, the impact of obesity on the testes at the molecular levels remain inadequately explored. This is partially attributed to the lack of monitoring tools for tracking alterations within cell clusters in testes associated with obesity. Here, we utilized single-cell RNA sequencing to analyze over 70,000 cells from testes of obese and lean mice, and to study changes related to obesity in non-spermatogenic cells and spermatogenesis. The Testicular Library encompasses all non-spermatogenic cells and spermatogenic cells spanning from spermatogonia to spermatozoa, which will significantly aid in characterizing alterations in cellular niches and the testicular microenvironment during high-fat diet (HFD)-induced obesity. This comprehensive dataset is indispensable for studying how HFD disrupts cell-cell communication networks within the testis and impacts alterations in the testicular microenvironment that regulate spermatogenesis. Being the inaugural dataset of single-cell RNA-seq in the testes of diet-induced obese (DIO) mice, this holds the potential to offer innovative insights and directions in the realm of single-cell transcriptomics concerning male reproductive injury associated with HFD.

Disulfidptosis-related signature elucidates the prognostic, immunologic, and therapeutic characteristics in ovarian cancer.

Introduction: Ovarian cancer (OC) is the deadliest malignancy in gynecology, but the mechanism of its initiation and progression is poorly elucidated. Disulfidptosis is a novel discovered type of regulatory cell death. This study aimed to develop a novel disulfidptosis-related prognostic signature (DRPS) for OC and explore the effects and potential treatment by disulfidptosis-related risk stratification. Methods: The disulfidptosis-related genes were first analyzed in bulk RNA-Seq and a prognostic nomogram was developed and validated by LASSO algorithm and multivariate cox regression. Then we systematically assessed the clinicopathological and mutational characteristics, pathway enrichment analysis, immune cell infiltration, single-cell-level expression, and drug sensitivity according to DRPS. Results: The DRPS was established with 6 genes (MYL6, PDLIM1, ACTN4, FLNB, SLC7A11, and CD2AP) and the corresponding prognostic nomogram was constructed based on the DRPS, FIGO stage, grade, and residual disease. Stratified by the risk score derived from DRPS, patients in high-risk group tended to have worse prognosis, lower level of disulfidptosis, activated oncogenic pathways, inhibitory tumor immune microenvironment, and higher sensitivity to specific drugs including epirubicin, stauroporine, navitoclax, and tamoxifen. Single-cell transcriptomic analysis revealed the expression level of genes in the DRPS significantly varied in different cell types between tumor and normal tissues. The protein-level expression of genes in the DRPS was validated by the immunohistochemical staining analysis. Conclusion: In this study, the DRPS and corresponding prognostic nomogram for OC were developed, which was important for OC prognostic assessment, tumor microenvironment modification, drug sensitivity prediction, and exploration of potential mechanisms in tumor development.

Stereoconvergent and Chemoenzymatic Synthesis of Tumor-Associated Glycolipid Disialosyl Globopentaosylceramide for Probing the Binding Affinity of Siglec-7.

Disialosyl globopentaosylceramide (DSGb5) is a tumor-associated complex glycosphingolipid. However, the accessibility of structurally well-defined DSGb5 for precise biological functional studies remains challenging. Herein, we describe the first total synthesis of DSGb5 glycolipid by an efficient chemoenzymatic approach. A Gb5 pentasaccharide-sphingosine was chemically synthesized by a convergent and stereocontrolled [2 + 3] method using an oxazoline disaccharide donor to exclusively form ß-anomeric linkage. After investigating the substrate specificity of different sialyltransferases, regio- and stereoselective installment of two sialic acids was achieved by two sequential enzyme-catalyzed reactions using α2,3-sialyltransferase Cst-I and α2,6-sialyltransferase ST6GalNAc5. A unique aspect of the approach is that methyl-ß-cyclodextrin-assisted enzymatic α2,6-sialylation of glycolipid substrate enables installment of the challenging internal α2,6-linked sialoside to synthesize DSGb5 glycosphingolipid. Surface plasmon resonance studies indicate that DSGb5 glycolipid exhibits better binding affinity for Siglec-7 than the oligosaccharide moiety of DSGb5. The binding results suggest that the ceramide moiety of DSGb5 facilitates its binding by presenting multivalent interactions of glycan epitope for the recognition of Siglec-7.

Non-sweep DC component estimation method for a virtual-carrier assisted Kramers-Kronig receiver.

The Kramers-Kronig (KK) receiver has attracted much attention in short-range optical interconnection because of its ability to recover the phase of the signal from the intensity information through KK algorithm. In high-speed KK systems, such as virtual-carrier (VC) assisted ones, an alternating current (AC) coupled photo-detector (PD) is preferred due to relaxing the requirements of analog-to-digital converter (ADC) and electronic amplifier by filtering direct current (DC) component. However, the loss of the DC component will cause the KK algorithm to break down, so it is necessary to accurately recover DC value in the digital domain with multiple-sweep. In this paper, we propose what we believe is a novel non-sweep DC component estimation scheme based on optimized digital carrier-to-signal power ratio (OD-CSPR) method, which can accurately estimate the DC component with only 3-4 iterations in the scenario of VC-assisted KK receiver optical transmission. The scheme utilizes the one-dimensional search optimization algorithm based on golden section search and parabolic interpolation without sweeping. The simulation and experimental results of the proposed non-sweep OD-CSPR method show that the DC component can be estimated accurately in a large CSPR range, and the system performance is close to that of the conventional DC-sweep method. Compared with the typical defined digital CSPR (DD-CSPR) based optimization method, the proposed one can realize optical signal-to-noise ratio (OSNR) gains of 0.9 dB in the back-to-back (B2B) and 0.7 dB under 80 km fiber transmission scenarios respectively with a total bit rate of 160Gb/s.

Methylprednisolone as Adjunct to Endovascular Thrombectomy for Large-Vessel Occlusion Stroke: The MARVEL Randomized Clinical Trial.

Importance: It is uncertain whether intravenous methylprednisolone improves outcomes for patients with acute ischemic stroke due to large-vessel occlusion (LVO) undergoing endovascular thrombectomy. Objective: To assess the efficacy and adverse events of adjunctive intravenous low-dose methylprednisolone to endovascular thrombectomy for acute ischemic stroke secondary to LVO. Design, Setting, and Participants: This investigator-initiated, randomized, double-blind, placebo-controlled trial was implemented at 82 hospitals in China, enrolling 1680 patients with stroke and proximal intracranial LVO presenting within 24 hours of time last known to be well. Recruitment took place between February 9, 2022, and June 30, 2023, with a final follow-up on September 30, 2023. Interventions: Eligible patients were randomly assigned to intravenous methylprednisolone (n = 839) at 2 mg/kg/d or placebo (n = 841) for 3 days adjunctive to endovascular thrombectomy. Main Outcomes and Measures: The primary efficacy outcome was disability level at 90 days as measured by the overall distribution of the modified Rankin Scale scores (range, 0 [no symptoms] to 6 [death]). The primary safety outcomes included mortality at 90 days and the incidence of symptomatic intracranial hemorrhage within 48 hours. Results: Among 1680 patients randomized (median age, 69 years; 727 female [43.3%]), 1673 (99.6%) completed the trial. The median 90-day modified Rankin Scale score was 3 (IQR, 1-5) in the methylprednisolone group vs 3 (IQR, 1-6) in the placebo group (adjusted generalized odds ratio for a lower level of disability, 1.10 [95% CI, 0.96-1.25]; P = .17). In the methylprednisolone group, there was a lower mortality rate (23.2% vs 28.5%; adjusted risk ratio, 0.84 [95% CI, 0.71-0.98]; P = .03) and a lower rate of symptomatic intracranial hemorrhage (8.6% vs 11.7%; adjusted risk ratio, 0.74 [95% CI, 0.55-0.99]; P = .04) compared with placebo. Conclusions and Relevance: Among patients with acute ischemic stroke due to LVO undergoing endovascular thrombectomy, adjunctive methylprednisolone added to endovascular thrombectomy did not significantly improve the degree of overall disability. Trial Registration: ChiCTR.org.cn Identifier: ChiCTR2100051729.

Electrochemical Direct Synthesis of N-Sulfenylimines from Amines in the Presence of Thiophenols.

N-Sulfenylimines are important molecules owing to their value in organic synthesis. Herein, we developed an electrochemical oxidative cross-coupling reaction between amines and thiols to synthesize N-sulfenylimines without a transition-metal catalyst and external oxidant. Various amines and thiols were compatible, generating the desired products in up to 86% yield.

Quantitative Measurement on Contrast-Enhanced CT Distinguishes Small Clear Cell Renal Cell Carcinoma From Benign Renal Tumors: A Multicenter Study.

RATIONALE AND OBJECTIVES: To evaluate the potential of quantitative measurements on contrast-enhanced CT (CECT) in differentiating small (≤4 cm) clear cell renal cell carcinoma (ccRCC) from benign renal tumors, including fat-poor angiomyolipoma (fpAML) and renal oncocytoma (RO). MATERIALS AND METHODS: 244 patients with pathologically confirmed ccRCC (n = 184) and benign renal tumors (fpAML, n = 50; RO, n = 10) were randomly assigned into training cohort (n = 193) and test cohort 1 (n = 51), while external test cohort 2 (n = 50) was from another hospital. Quantitative parameters were obtained from CECT (unenhanced phase, UP; corticomedullary phase, CMP; nephrographic phase, NP; excretory phase, EP) by measuring attenuation of renal mass and cortex and subsequently calculated. Univariable and multivariable logistic regression analyses were performed to evaluate the association between these parameters and ccRCC. Finally, the constructed models were compared with radiologists' diagnoses. RESULTS: In univariable analysis, UP-related parameters, particularly UPC-T (cortex minus tumor attenuation on UP), demonstrated AUC of 0.766 in training cohort, 0.901 in test cohort 1, 0.805 in test cohort 2. The heterogeneity-related parameter SD (standard deviation) showed AUC of 0.781, 0.834, and 0.875 respectively. In multivariable analysis, model 1 incorporating UPC-T, NPC-T (cortex minus tumor attenuation on NP), CMPT-UPT (tumor attenuation on CMP minus UP), and SD yielded AUC of 0.866, 0.923, and 0.949 respectively. When compared with radiologists, multivariate models demonstrated higher accuracy (0.800-0.860) and sensitivity (0.794-0.971) than radiologists' assessments (accuracy: 0.700-0.720, sensitivity: 0.588-0.706). CONCLUSION: Quantitative measurements on CECT, particularly UP- and heterogeneity-related parameters, have potential to discriminate ccRCC and benign renal tumors (fpAML, RO).

Paternal high-fat diet altered H3K36me3 pattern of pre-implantation embryos.

The global transition towards diets high in calories has contributed to 2.1 billion people becoming overweight, or obese, which damages male reproduction and harms offspring. Recently, more and more studies have shown that paternal exposure to stress closely affects the health of offspring in an intergenerational and transgenerational way. SET Domain Containing 2 (SETD2), a key epigenetic gene, is highly conserved among species, is a crucial methyltransferase for converting histone 3 lysine 36 dimethylation (H3K36me2) into histone 3 lysine 36 trimethylation (H3K36me3), and plays an important regulator in the response to stress. In this study, we compared patterns of SETD2 expression and the H3K36me3 pattern in pre-implantation embryos derived from normal or obese mice induced by high diet. The results showed that SETD2 mRNA was significantly higher in the high-fat diet (HFD) group than the control diet (CD) group at the 2-cell, 4-cell, 8-cell, and 16-cell stages, and at the morula and blastocyst stages. The relative levels of H3K36me3 in the HFD group at the 2-cell, 4-cell, 8-cell, 16-cell, morula stage, and blastocyst stage were significantly higher than in the CD group. These results indicated that dietary changes in parental generation (F0) male mice fed a HFD were traceable in SETD2/H3K36me3 in embryos, and that a paternal high-fat diet brings about adverse effects for offspring that might be related to SETD2/H3K36me3, which throws new light on the effect of paternal obesity on offspring from an epigenetic perspective.

Significant alteration of protein profiles in a mouse model of polycystic ovary syndrome.

Polycystic ovary syndrome (PCOS) is an endocrine disorder, affecting women of child-bearing age, and the incidence rate is growing and assuming epidemic proportions. The etiology of PCOS remains unknown and there is no cure. Some animal models for PCOS have been established which have enhanced our understanding of the underlying mechanisms, but omics data for revealing PCOS pathogenesis and for drug discovery are still lacking. In the present study, proteomics analysis was used to construct a protein profile of the ovaries in a PCOS mouse model. The result showed a clear difference in protein profile between the PCOS and control group, with 495 upregulated proteins and 404 downregulated proteins in the PCOS group. The GO term and KEGG pathway analyses of differentially expressed proteins mainly showed involvement in lipid metabolism, oxidative stress, and immune response, which are consistent with pathological characteristics of PCOS in terms of abnormal metabolism, endocrine disorders, chronic inflammation and imbalance between oxidant and antioxidant levels. Also, we found that inflammatory responses were activated in the PCOS ovarium, while lipid biosynthetic process peroxisome, and bile secretion were inhibited. In addition, we found some alteration in unexpected pathways, such as glyoxylate and dicarboxylate metabolism, which should be investigated. The present study makes an important contribution to the current lack of PCOS ovarian proteomic data and provides an important reference for research and development of effective drugs and treatments for PCOS.

Paternal high-fat diet altered SETD2 gene methylation in sperm of F0 and F1 mice.

Paternal high-fat diet (HFD) can alter the epigenetics of sperm DNA, resulting in the transmission of obesity-related traits to the offspring. Previous studies have mainly focused on the HFD-induced changes in DNA methylation of imprinted genes, overlooking the potential involvement of non-imprinted genes in this process. SETD2, an important epigenetically-regulated gene known for its response to environmental stress, remains poorly understood in the context of high-fat diet-induced epigenetic changes. Here we examined the effect of obesity from a HFD on paternal SETD2 expression and methylation in sperm, and embryos at the blastocyst stage and during subsequent development, to determine the alteration of SETD2 in paternal intergenerational and transgenerational inheritance. The result showed that mice fed with HFD for two months had significantly increased SETD2 expression in testis and sperm. The paternal HFD significantly altered the DNA methylation level with 20 of the 26 CpG sites being changed in sperm from F0 mice. Paternal high-fat diet increased apoptotic index and decreased total cell number of blastocysts, which were closely correlated with DNA methylation level of sperm. Out of the 26 CpG sites, we also found three CpG sites that were significantly changed in the sperm from F1 mice, which meant that the methylation changes at these three CpG sites were maintained.In conclusion, we found that paternal exposure to an HFD disrupted the methylation pattern of SETD2 in the sperm of F0 mice and resulted in perturbed SETD2 expression. Furthermore, the paternal high-fat diet influenced embryo apoptosis and development, possibly through the SETD2 pathway. The altered methylation of SETD2 in sperm induced by paternal HFD partially persisted in the sperm of the F1 generation, highlighting the role of SETD2 as an epigenetic carrier for paternal intergenerational and transgenerational inheritance.

Clinical efficacy and imaging analysis for the surgical treatment of thoracolumbar infections in elderly patients: a retrospective study.

Few reports have been conducted to comparing surgical results and safety evaluations between the different types of infections in geriatric patients with thoracolumbar infections. The aim of this study is to investigate the safety and efficacy of surgical treatment for thoracolumbar infections in elderly patients. 21 patients with pyogenic spondylodiscitis (PS) and 26 patients with tuberculous spondylodiscitis (TS) were enrolled in the study. All patients were treated using one-stage posterior debridement, decompression, and pedicle screw fixation. Comparison of operative safety parameters between the two groups. Clinical efficacy was evaluated using visual analogue scale (VAS) score, the American Spinal Injury Association (ASIA) grade, the short form (SF)-36 survey and Oswestry disability index (ODI) to determine patient quality of life pre- and post-operatively. Hospitalisation and intensive care unit duration in the PS group were significantly shorter than in the TS group (P < 0.05). The total incidence of post-operative complications for both groups was 44.7%. More complications occurred in the TS group, but the difference was not significant. The scores of VAS, ODI and SF-36 of all 47 patients were significantly improved compared with those before operation.The VAS and SF-36 scores (physical component) were significantly better in the PS group 6 months post-operatively, and the SF-36 (mental component) scores were significantly better in the PS group at the 1-year follow-up. Neurological status in both groups improved post-operatively, and 83% of patients reported satisfactory results based on the modified MacNab standard. Imaging results showed that bone graft fusion improved in both groups at 6 months, 1 year and at the final follow-up. One-stage posterior debridement, decompression, interbody fusion, and internal fixation can be considered a safe and effective method of treating spinal infections in the elderly. This method can improve nerve function, reconstruct spinal stability, and enhance the quality of life of elderly patients. Both PS and TS who underwent surgery achieve similar clinical and radiological results.

Chemoenzymatic Total Synthesis of Haemophilus ducreyi Lipooligosaccharide Core Octasaccharides Containing Natural and Unnatural Sialic Acids.

The first total synthesis of Haemophilus ducreyi lipooligosaccharide core octasaccharides containing natural and unnatural sialic acids has been achieved by an efficient chemoenzymatic approach. A highly convergent [3 + 3] coupling strategy was developed to chemically assemble a unique hexasaccharide bearing multiple rare higher-carbon sugars d-glycero-d-manno-heptose (d,d-Hep), l-glycero-d-manno-heptose (l,d-Hep), and 3-deoxy-α-d-manno-oct-2-ulosonic acid (Kdo). Key features include sequential one-pot glycosylations for oligosaccharide assembly and the construction of the challenging α-(1 → 5)-linked Hep-Kdo glycosidic bond by gold-catalyzed glycosylation with a glycosyl ortho-alkynylbenzoate donor. Furthermore, the sequential enzyme-catalyzed regio- and stereoselective introduction of a galactose residue using ß-1,4-galactosyltransferase and different sialic acids using a one-pot multienzyme sialylation system was efficiently accomplished to provide the target octasaccharides.

Association between intravenous tirofiban and intracranial hemorrhage in acute large vessel occlusion stroke: insight from the RESCUE BT randomized placebo-controlled trial.

BACKGROUND: The aim of this study is to investigate the association between intravenous tirofiban and symptomatic intracranial hemorrhage (SICH) in patients with acute ischemic stroke (AIS) secondary to large vessel occlusion (LVO) receiving endovascular thrombectomy (EVT) within 24 h of time last known well (LKW). METHODS: Patients with AIS-LVO who were randomly assigned to receive intravenous tirofiban or placebo before EVT within 24 h of time LKW and had follow-up brain non-contrast computed tomography within 24 h after stopping tirofiban treatment were derived from "RESCUE BT": a multicenter, randomized, placebo-controlled, double-blind trial. All eligible patients were divided into SICH and NO-SICH groups. Subgroup analyses were performed to explore for heterogeneity. RESULTS: Of 945 patients included in this cohort, there were 76 (8.0%) in the SICH group and 869 (92.0%) in the NO-SICH group. The incidence of SICH was not higher in patients receiving intravenous tirofiban compared with placebo (adjusted risk ratio (RR), 1.51; 95% confidence interval (CI), 0.97-2.36; P = 0.07). Subgroup analyses showed that age greater than 67-year-old (adjusted RR, 2.18; 95% CI 1.18-4.00), NIHSS greater than 16 (adjusted RR, 1.88; 95% CI 1.06-3.34), and cardioembolism (adjusted RR, 3.73; 95% CI 1.66-8.35) were associated with increased SICH risk. CONCLUSIONS: In patients with acute large vessel occlusion stroke, intravenous tirofiban before EVT within 24 h of time from last known well is not associated with increased risk of SICH. Patients who are older, have more severe neurological deficits, or with cardioembolism are at higher risk of SICH with intravenous tirofiban. TRIAL REGISTRATION NUMBER: URL: http://www.chictr.org.cn ; Unique identifier: ChiCTR-INR-17014167.

Construction of a competing endogenous RNA network in head and neck squamous cell carcinoma by pan-cancer analysis.

Background: Head and neck squamous cell carcinoma (HNSC) is the sixth most common cancer worldwide, and new cases are anticipated to reach 1.08 million in 2030. Our study aimed to identify the competing endogenous RNAs (ceRNAs) involved in HNSC tumorigenesis. Methods: First, a pan-cancer correlation analysis was conducted on the expression and survival conditions of sideroflexin (SFXN3) based on data downloaded from the Xena database. Second, the upstream regulatory microRNAs (miRNAs) and long non-coding RNAs (lncRNAs) of SFXN3 were predicted using the Encyclopedia of RNA Interactomes (ENCORI) database. Expression and survival analyses were subsequently used to construct lncRNA-miRNA-mRNA ceRNA network that correlated with HNSC. Third, the proportion of various types of immune cells in HNSC was calculated using the CIBERSORT algorithm. Finally, a correlation analysis was performed on SFXN3, including immune cell infiltration (ICI), clinical stage, and immune checkpoints. Results: The pan-cancer analysis suggested that SFXN3 was up-regulated in HNSC, and it correlated with poor prognosis. The ceRNA regulatory network MIR193BHG-miR-29c-3p-SFXN3 was identified as one of the potential biological regulatory pathways of HNSC. The upstream lncRNA MIR193BHG was associated with a poor prognosis in HNSC, and its target gene SFXN3 was correlated with tumor ICI, immune cell biomarkers, and immune checkpoints. Conclusions: By performing ceRNA analysis, our study demonstrated that MIR193HG-miR-29c-3p-SFXN3 is significantly involved in HNSC, and this action axis markedly affect the therapeutic effect and prognosis.

Nitric oxide nano-prodrug platform with synchronous glutathione depletion and hypoxia relief for enhanced photodynamic cancer therapy.

Photodynamic therapy (PDT) is a promising non-invasive and selective cancer treatment. However, its efficacy is curtailed by tumor hypoxia and high levels of glutathione (GSH) in the tumor and addressing both limitations simultaneously remain challenging. Here, an all-in-one nanoplatform was designed using a GSH-responsive nitric oxide (NO) nano-prodrug that synchronously depletes GSH and relieves hypoxia in tumors, enhancing PDT efficacy. The nano-prodrug PEG-PAMAM-PA/SNO was prepared by integrating the GSH-sensitive NO and pheophorbide A (PA) prodrugs N-acetyl-d-penicillamine thiolactone and PAMAM-PA into polyethylene glycol (PEG), and the NPPA/NO and NPPA were then obtained through nanoprecipitation method. This nanoplatform depletes the intracellular antioxidant, GSH, by integrating GSH-responsive NO prodrug and generating NO that relaxes blood vessels, thereby relieving tumor hypoxia and defeating antioxidant defense system in tumor, while PEGylated PAMAM dendrimers have abundant surface functional groups and can greatly prolong their circulation lifetime in the bloodstream. These effects make this GSH-activatable NO nano-prodrug platform an appealing strategy for enhancing PDT's antitumor effects.

Radiomics can differentiate high-grade glioma from brain metastasis: a systematic review and meta-analysis.

OBJECTIVE: (1) To evaluate the diagnostic performance of radiomics in differentiating high-grade glioma from brain metastasis and how to improve the model. (2) To assess the methodological quality of radiomics studies and explore ways of embracing the clinical application of radiomics. METHODS: Studies using radiomics to differentiate high-grade glioma from brain metastasis published by 26 July 2021 were systematically reviewed. Methodological quality and risk of bias were assessed using the Radiomics Quality Score (RQS) system and Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) tool, respectively. Pooled sensitivity and specificity of the radiomics model were also calculated. RESULTS: Seventeen studies combining 1,717 patients were included in the systematic review, of which 10 studies without data leakage suspicion were employed for the quantitative statistical analysis. The average RQS was 5.13 (14.25% of total), with substantial or almost perfect inter-rater agreements. The inclusion of clinical features in the radiomics model was only reported in one study, as was the case for publicly available algorithm code. The pooled sensitivity and specificity were 84% (95% CI, 80-88%) and 84% (95% CI, 81-87%), respectively. The performances of feature extraction from the volume of interest (VOI) or (semi) automatic segmentation in the radiomics models were superior to those of protocols employing region of interest (ROI) or manual segmentation. CONCLUSION: Radiomics can accurately differentiate high-grade glioma from brain metastasis. The adoption of standardized workflow to avoid potential data leakage as well as the integration of clinical features and radiomics are advised to consider in future studies. KEY POINTS: • The pooled sensitivity and specificity of radiomics for differentiating high-grade gliomas from brain metastasis were 84% and 84%, respectively. • Avoiding potential data leakage by adopting an intensive and standardized workflow is essential to improve the quality and generalizability of the radiomics model. • The application of radiomics in combination with clinical features in differentiating high-grade gliomas from brain metastasis needs further validation.

A tumor microenvironment responsive nanoplatform with oxidative stress amplification for effective MRI-based visual tumor ferroptosis.

As a promising new form of non-apoptotic regulated cell death, ferroptosis has potential as an effective supplement to apoptosis-based cancer treatments. However, high intracellular glutathione (GSH) levels and insufficient hydrogen peroxide (H2O2) in the tumor limit the efficacy of ferroptosis. Here, we designed a theranostic nanoplatform, named FCS/GCS, by incorporating amphiphilic polymer skeletal (P-SS-D), cinnamaldehyde prodrug (CA-OH) and iron ions (Fe3+)/gadolinium ions (Gd3+) via chelation reactions between Fe3+/Gd3+ and polyphenols. When delivered in the tumor microenvironment with high GSH level, the nanoparticles are depolymerized by the poly(disulfide) backbone of P-SS-D. The activated CA consumes the GSH and elevates intracellular H2O2, followed by a high level of Fenton reaction to generate abundant •OH levels. The generation of reactive oxygen species (ROS) further accelerates CA activation. The GSH consumption by disulfide, CA and Fe3+, downregulates GPX4 and generates •OH, which accelerate lipid peroxides (LPO) accumulation and consequently enhances ferroptosis. Additionally, the released Gd3+ may serve as a contrast agent for tumor-specific T1-weighted magnetic resonance imaging (MRI). Thus, the rationally designed FCS/GCS system is a promising strategy for effective MRI-based visual ferroptosis therapy. STATEMENT OF SIGNIFICANCE: Ferroptosis is a new form of non-apoptotic regulated cell death and has potential as an effective supplement to apoptosis-based cancer treatment. However, the efficiency of ferroptosis is limited by excessive glutathione level and insufficient hydrogen peroxide level in tumor site. In this study, we fabricate a theranostic nanoplatform (FCS/GCS) to amplify oxidation stress in tumor site for effective ferroptosis-based cancer treatment, and tumor specific magnetic resonance imaging is introduced for supervision. Our nanoplatform may provide a promising strategy for MRI-based visual ferroptosis therapy with high specificity and efficiency.

Fuhrman nuclear grade prediction of clear cell renal cell carcinoma: influence of volume of interest delineation strategies on machine learning-based dynamic enhanced CT radiomics analysis.

OBJECTIVE: To investigate the influence of different volume of interest (VOI) delineation strategies on machine learning-based predictive models for discrimination between low and high nuclear grade clear cell renal cell carcinoma (ccRCC) on dynamic contrast-enhanced CT. METHODS: This study retrospectively collected 177 patients with pathologically proven ccRCC (124 low-grade; 53 high-grade). Tumor VOI was manually segmented, followed by artificially introducing uncertainties as: (i) contour-focused VOI, (ii) margin erosion of 2 or 4 mm, and (iii) margin dilation (2, 4, or 6 mm) inclusive of perirenal fat, peritumoral renal parenchyma, or both. Radiomics features were extracted from four-phase CT images (unenhanced phase (UP), corticomedullary phase (CMP), nephrographic phase (NP), excretory phase (EP)). Different combinations of four-phasic features for each VOI delineation strategy were used to build 176 classification models. The best VOI delineation strategy and superior CT phase were identified and the top-ranked features were analyzed. RESULTS: Features extracted from UP and EP outperformed features from other single/combined phase(s). Shape features and first-order statistics features exhibited superior discrimination. The best performance (ACC 81%, SEN 67%, SPE 87%, AUC 0.87) was achieved with radiomics features extracted from UP and EP based on contour-focused VOI. CONCLUSION: Shape and first-order features extracted from UP + EP images are better feature representations. Contour-focused VOI erosion by 2 mm or dilation by 4 mm within peritumor renal parenchyma exerts limited impact on discriminative performance. It provides a reference for segmentation tolerance in radiomics-based modeling for ccRCC nuclear grading. KEY POINTS: • Lesion delineation uncertainties are tolerated within a VOI erosion range of 2 mm or dilation range of 4 mm within peritumor renal parenchyma for radiomics-based ccRCC nuclear grading. • Radiomics features extracted from unenhanced phase and excretory phase are superior to other single/combined phase(s) at differentiating high vs low nuclear grade ccRCC. • Shape features and first-order statistics features showed superior discriminative capability compared to texture features.