Biofortifying multiple micronutrients and decreasing arsenic accumulation in rice grain simultaneously by expressing a mutant allele of OAS-TL gene.

Rice grains typically contain relatively high levels of toxic arsenic (As) but low levels of essential micronutrients. Biofortification of essential micronutrients while decreasing As accumulation in rice would benefit human nutrition and health. We generated transgenic rice expressing a gain-of-function mutant allele astol1 driven by the OsGPX1 promoter. astol1 encodes a plastid-localized O-acetylserine (thiol) lyase (OAS-TL) with Ser189Asn substitution (OsASTOL1S189N), which enhances cysteine biosynthesis by forming an indissociable cysteine synthase complex with its partner serine acetyltransferase (SAT). The effects on growth, As tolerance, and nutrient and As accumulation in rice grain were evaluated in hydroponic, pot and field experiments. The expression of OsASTOL1S189N in pOsGPX1::astol1 transgenic lines enhanced SAT activity, sulphate uptake, biosynthesis of cysteine, glutathione, phytochelatins and nicotianamine, and enhanced tolerance to As. The expression of OsASTOL1S189N decreased As accumulation while increased the accumulation of multiple macronutrients (especially sulphur, nitrogen and potassium) and micronutrients (especially zinc and selenium) in rice grain in a pot experiment and two field experiments, and had little effect on plant growth and grain yield. Our study provides a new strategy to genetically engineer rice to biofortify multiple essential nutrients, reducing As accumulation in rice grain and enhancing As tolerance simultaneously.

Real-world effectiveness and safety of recombinant human endostatin plus PD-1 inhibitors and chemotherapy as first-line treatment for EGFR/ALK-negative, advanced or metastatic non-small cell lung cancer.

BACKGROUND: This study aimed to evaluate the effectiveness and safety of recombinant human endostatin (Rh-endostatin) plus programmed cell death 1 (PD-1) inhibitors and chemotherapy as first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) in a real-world setting. METHODS: This was a retrospective study on patients with EGFR/ALK-negative, advanced or metastatic NSCLC. Patients received Rh-endostatin plus PD-1 inhibitors and chemotherapy every three weeks for 4 to 6 cycles. The primary endpoint was progression-free survival (PFS), and the secondary endpoints were objective response rate (ORR), disease control rate (DCR), overall survival (OS), and safety. RESULTS: A total of 68 patients were included in this retrospective analysis. As of data cutoff (December 13, 2022), the median follow-up of 21.4 months (interquartile range [IQR], 8.3-44.4 months). The median PFS and OS was 22.0 (95% confidence interval [CI]: 16.6-27.4) and 31.0 months (95% CI: 23.4-not evaluable [NE]), respectively. The ORR was 72.06% (95% CI: 59.85-82.27%), and DCR was 95.59% (95% CI: 87.64-99.08%). Patients with stage IIIB/IIIC NSCLC had significantly longer median PFS (23.4 vs. 13.2 months), longer median OS (not reached vs. 18.0 months), and higher ORR (89.2% vs. 51.6%) than those with stage IV NSCLC (all p ≤ 0.001). The ORR was higher in patients with high PD-L1 expression (tumor proportion score [TPS] ≥ 50%) than in those with low PD-L1 expression or positive PD-L1 expression (75% vs. 50%, p = 0.025). All patients experienced treatment-related adverse events (TRAEs), and ≥ grade 3 TRAEs occurred in 16 (23.53%) patients. CONCLUSIONS: Rh-endostatin combined with PD-1 inhibitors plus chemotherapy as first-line treatment yielded favorable effectiveness with a manageable profile in patients with advanced or metastatic NSCLC, representing a promising treatment modality.

Connectomic insights into the impact of 1p/19q co-deletion in dominant hemisphere insular glioma patients.

Objectives: This study aimed to elucidate the influences of 1p/19q co-deletion on structural connectivity alterations in patients with dominant hemisphere insular diffuse gliomas. Methods: We incorporated 32 cases of left insular gliomas and 20 healthy controls for this study. Using diffusion MRI, we applied correlational tractography, differential tractography, and graph theoretical analysis to explore the potential connectivity associated with 1p/19q co-deletion. Results: The study revealed that the quantitative anisotropy (QA) of key deep medial fiber tracts, including the anterior thalamic radiation, superior thalamic radiation, fornix, and cingulum, had significant negative associations with 1p/19q co-deletion (FDR = 4.72 × 10-5). These tracts are crucial in maintaining the integrity of brain networks. Differential analysis further supported these findings (FWER-corrected p < 0.05). The 1p/19q non-co-deletion group exhibited significantly higher clustering coefficients (FDR-corrected p < 0.05) and reduced betweenness centrality (FDR-corrected p < 0.05) in regions around the tumor compared to HC group. Graph theoretical analysis indicated that non-co-deletion patients had increased local clustering and decreased betweenness centrality in peritumoral brain regions compared to co-deletion patients and healthy controls (FDR-corrected p < 0.05). Additionally, despite not being significant through correction, patients with 1p/19q co-deletion exhibited lower trends in weighted average clustering coefficient, transitivity, small worldness, and global efficiency, while showing higher tendencies in weighted path length compared to patients without the co-deletion. Conclusion: The findings of this study underline the significant role of 1p/19q co-deletion in altering structural connectivity in insular glioma patients. These alterations in brain networks could have profound implications for the neural functionality in patients with dominant hemisphere insular gliomas.

Biochar alleviates inhibition effects of humic acid on anaerobic digestion: Insights to performances and mechanisms.

To recover methane from waste activated sludge through anaerobic digestion (AD) is one promising alternative to achieve carbon neutrality for wastewater treatment plants. However, humic acids (HAs) are one of the major compositions in waste activated sludge, and their accumulation performs inhibition effects on AD. This study investigated the potentials of biochar (BC) in alleviating inhibition effects of HAs on AD. Results showed that although the accumulated HAs reduced methane yield by 9.37% compared to control, the highest methane yield, 132.6 mL CH4/g VSS, was obtained after adding BC, which was 45.9% higher than that in HA group. Mechanism analysis showed that BC promoted the activities of hydrolase such as protease and α-glucosidase, which were 69.7% and 29.7% higher than those in HA group, respectively. The conversion of short-chain fatty acids was accelerated. In addition, the evolutions of electroactive microorganisms like Clostridium_sensu_stricto_13 and Methanosaeta were consistent with the activitiies of electron transfer and the contents of cytochrome c. Furthermore, parts of HAs rather than all of them were adsorbed by BC, and the remaining free HAs and BC formed synergistic effects on methanogenesis, then both CO2 reduction and acetoclastic methanogenesis pathways were improved. The findings may provide some solutions to alleviate inhibition effects of HAs on AD.

Single-cell analyses reveal evolution mimicry during the specification of breast cancer subtype.

Background: The stem or progenitor antecedents confer developmental plasticity and unique cell identities to cancer cells via genetic and epigenetic programs. A comprehensive characterization and mapping of the cell-of-origin of breast cancer using novel technologies to unveil novel subtype-specific therapeutic targets is still absent. Methods: We integrated 195,144 high-quality cells from normal breast tissues and 406,501 high-quality cells from primary breast cancer samples to create a large-scale single-cell atlas of human normal and cancerous breasts. Potential heterogeneous origin of malignant cells was explored by contrasting cancer cells against reference normal epithelial cells. Multi-omics analyses and both in vitro and in vivo experiments were performed to screen and validate potential subtype-specific treatment targets. Novel biomarkers of identified immune and stromal cell subpopulations were validated by immunohistochemistry in our cohort. Results: Tumor stratification based on cancer cell-of-origin patterns correlated with clinical outcomes, genomic aberrations and diverse microenvironment constitutions. We found that the luminal progenitor (LP) subtype was robustly associated with poor prognosis, genomic instability and dysfunctional immune microenvironment. However, the LP subtype patients were sensitive to neoadjuvant chemotherapy (NAC), PARP inhibitors (PARPi) and immunotherapy. The LP subtype-specific target PLK1 was investigated by both in vitro and in vivo experiments. Besides, large-scale single-cell profiling of breast cancer inspired us to identify a range of clinically relevant immune and stromal cell subpopulations, including subsets of innate lymphoid cells (ILCs), macrophages and endothelial cells. Conclusion: The present single-cell study revealed the cellular repertoire and cell-of-origin patterns of breast cancer. Combining single-cell and bulk transcriptome data, we elucidated the evolution mimicry from normal to malignant subtypes and expounded the LP subtype with vital clinical implications. Novel immune and stromal cell subpopulations of breast cancer identified in our study could be potential therapeutic targets. Taken together, Our findings lay the foundation for the precise prognostic and therapeutic stratification of breast cancer.

Antibody-Drug Conjugate Sacituzumab Govitecan Enables a Sequential TOP1/PARP Inhibitor Therapy Strategy in Patients with Breast Cancer.

PURPOSE: The antibody-drug conjugate (ADC) sacituzumab govitecan (SG) comprises the topoisomerase 1 (TOP1) inhibitor (TOP1i) SN-38, coupled to a monoclonal antibody targeting trophoblast cell surface antigen 2 (TROP-2). Poly(ADP-ribose) polymerase (PARP) inhibition may synergize with TOP1i and SG, but previous studies combining systemic PARP and TOP1 inhibitors failed due to dose-limiting myelosuppression. Here, we assess the proof-of-mechanism and clinical feasibility for SG and talazoparib (TZP) employing an innovative sequential dosing schedule. PATIENTS AND METHODS: In vitro models tested pharmacodynamic endpoints, and in a phase 1b clinical trial (NCT04039230), 30 patients with metastatic triple-negative breast cancer (mTNBC) received SG and TZP in a concurrent (N = 7) or sequential (N = 23) schedule. Outcome measures included safety, tolerability, preliminary efficacy, and establishment of a recommended phase 2 dose. RESULTS: We hypothesized that tumor-selective delivery of TOP1i via SG would reduce nontumor toxicity and create a temporal window, enabling sequential dosing of SG and PARP inhibition. In vitro, sequential SG followed by TZP delayed TOP1 cleavage complex clearance, increased DNA damage, and promoted apoptosis. In the clinical trial, sequential SG/TZP successfully met primary objectives and demonstrated median progression-free survival (PFS) of 7.6 months without dose-limiting toxicities (DLT), while concurrent dosing yielded 2.3 months PFS and multiple DLTs including severe myelosuppression. CONCLUSIONS: While SG dosed concurrently with TZP is not tolerated clinically due to an insufficient therapeutic window, sequential dosing of SG followed by TZP proved a viable strategy. These findings support further clinical development of the combination and suggest that ADC-based therapy may facilitate novel, mechanism-based dosing strategies.

MR-linac MLC positioning QA by digitally stitching dual double-exposed films.

PURPOSE: The picket fence (PF) test is highly recommended for multi-leaf collimator (MLC) quality assurance. However, since the electronic portal imaging device (EPID) on the Elekta Unity only covers a small area, it is not feasible to perform the PF test for the entire MLC. Here, we propose a technique for the PF test by stitching two double-exposed films. METHODS: Two EBT3 films were used to encompass the entire MLC, with each one covering one half of the area. Two fields were employed to apply double exposure: a PF pattern consisting of 11 2 mm wide pickets and a 2.84 cm x 22 cm open field. The edges of the open field defined by the diaphragms were used to correct film rotation as well as align them horizontally. The PF pattern was also measured with the EPID where the pickets were used to align the films vertically. Individual leaf positions were detected on the merged film for quantitative analysis. Various MLC positioning errors were introduced to evaluate the technique's sensitivity. RESULTS: The merged films covered 72 leaf pairs properly (four leaf pairs on both sides were outside the treatment couch). With the EPID, the leaf positioning accuracy was -0.02 ± 0.07 mm (maximum: 0.29 mm) and the picket width variation was 0.00 ± 0.03 mm (maximum: 0.11 mm); with the films, the position accuracy and width variation were -0.03 ± 0.13 mm (maximum: 0.80 mm) and 0.00 ± 0.13 mm (maximum: 0.74 mm), respectively. The EPID was able to detect errors of 0.5 mm or above with submillimeter accuracy; the films were only able to detect errors > 1.0 mm. CONCLUSION: We developed a quantitative technique for the PF test on the Elekta Unity. The merged films covered nearly the entire MLC leaf banks. The technique exhibited clinically acceptable accuracy and sensitivity to MLC positioning errors.

Association of thyroid autoimmunity with extra-thyroid diseases and the risk of mortality among adults: evidence from the NHANES.

Background: Thyroid autoimmunity is one of the most prevalent autoimmune diseases. However, its association with extra-thyroid diseases and mortality risk in the general population remains uncertain. Our study aims to evaluate the association of thyroid autoimmunity with extra-thyroid disease and the risk of mortality. Methods: A prospective cohort study was conducted using data from the National Health and Nutrition Examination Survey (NHANES) with participants from 2007-2008, 2009-2010, and 2011-2012, tracking their mortality until 2019. Associations between thyroid autoimmunity, which was defined as having positive thyroid peroxidase antibody (TPOAb) and/or thyroglobulin antibody (TgAb), and extra-thyroid disease including diabetes, hypertension, cardiovascular disease, chronic lung disease, arthritis, cancer and chronic renal disease and the risk of mortality were investigated. Results: A total of 7431 participants were included in this study. Positive The prevalence of positive TgAb was 7.54%, and positive TPOAb prevalence was 11.48%. TgAb was significantly associated with diabetes (Model 1: OR=1.64, 95% CI:1.08-2.50; Model 2: OR=1.93, 95% CI: 1.21-3.08) and hypertension (Model 1: OR=0.67, 95% CI: 0.49-0.91; Model 2: OR=0.62, 95% CI: 0.44-0.88). TPOAb was associated with a lower prevalence of chronic lung disease (model 1: OR=0.71, 95% CI: 0.54-0.95; model 2: OR=0.71, 95% CI: 0.53-0.95). No associations were observed between TgAb, TPOAb and other extra-thyroid diseases. Neither TgAb nor TPOAb were associated with all-cause mortality or heart disease mortality. Conclusion: TgAb was linked to a higher prevalence of diabetes and a lower prevalence of hypertension, while TPOAb was associated with a decreased prevalence of chronic lung disease. However, neither TgAb nor TPOAb posed a risk for all-cause mortality or heart disease mortality.

Assessing Postoperative Motor Risk in Insular Low-Grade Gliomas Patients: The Potential Role of Presurgery MRI Corticospinal Tract Shape Measures.

BACKGROUND: Insular low-grade gliomas (LGGs) are surgically challenging due to their proximity to critical structures like the corticospinal tract (CST). PURPOSE: This study aims to determine if preoperative CST shape metrics correlate with postoperative motor complications in insular LGG patients. STUDY TYPE: Retrospective. POPULATION: 42 patients (mean age 40.26 ± 10.21 years, 25 male) with insular LGGs. FIELD STRENGTH/SEQUENCE: Imaging was performed using 3.0 Tesla MRI, incorporating T1-weighted magnetization-prepared rapid gradient-echo, T2-weighted space dark-fluid with spin echo (SE), and diffusional kurtosis imaging (DKI) with gradient echo sequences, all integrated with echo planar imaging. ASSESSMENT: Shape metrics of the CST, including span, irregularity, radius, and irregularity of end regions (RER and IER, respectively), were compared between the affected and healthy hemispheres. Total end region radius (TRER) was determined as the sum of RER 1 and RER 2. The relationships between shape metrics and postoperative short-term (4 weeks) and long-term (>8 weeks) motor disturbances assessing by British Medical Research Council grading system, was analyzed using multivariable regression models. STATISTICAL TESTING: Paired t-tests compared CST metrics between hemispheres. Logistic regression identified associations between these metrics and motor disturbances. The models were developed using all available data and there was no independent validation dataset. Significance was set at P < 0.05. RESULTS: Short-term motor disturbance risk was significantly related to TRER (OR = 199.57). Long-term risk significantly correlated with IER 1 (OR = 59.84), confirmed as a significant marker with an AUC of 0.78. Furthermore, the CST on the affected side significantly had the greater irregularity, larger TRER and RER 1, and smaller span compared to the healthy side. DATA CONCLUSION: Preoperative evaluation of TRER and IER 1 metrics in the CST may serve as a tool for assessing the risk of postoperative motor complications in insular LGG patients. LEVEL OF EVIDENCE: 2 TECHNICAL EFFICACY: Stage 2.

Duhuo Jisheng Decoction regulates intracellular zinc homeostasis by enhancing autophagy via PTEN/Akt/mTOR pathway to improve knee cartilage degeneration.

BACKGROUND: Articular cartilage and cartilage matrix degradation are key pathological changes occurring in the early stage of knee osteoarthritis (KOA). However, currently, there are limited strategies for early prevention and treatment of KOA. Duhuo Jisheng Decoction (DHJSD) is a formula quoted in Bei Ji Qian jin Yao Fang, which was compiled by Sun Simiao in the Tang Dynasty of China. As a complementary therapy, it is widely used to treat early-stage KOA in China; however, its mechanism has not been completely elucidated. OBJECTIVE: This study investigated the potential role of DHJSD in preventing cartilage degradation and the underlying mechanism. METHODS: A rat model of KOA model was established via the Hulth method. Subsequently, 25 rats were randomized into sham (saline), model control (saline), high-DHJSD (1.9g/mL of DHJSD), medium-DHJSD (1.2g/mL of DHJSD), and low-DHJSD groups (0.6g/mL of DHJSD). After 4 weeks of treatment, all rats were sacrificed and the severity of the cartilage degeneration was evaluated by a series of histological methods. The autophagosome was observed using transmission electron microscopy, and the related functional proteins were detected by the western blotting and real-time polymerase chain reaction. Next, the mechanism by which DHJSD improves knee cartilage degeneration was further clarified the in vitro by gene silencing technology combined with a series of functional experiments. The proteins levels of PTEN, Akt, p-Akt, mTOR, and p-mTOR, as well as the marker proteins of autophagy and apoptosis were determined. Zinc levels in chondrocytes were determined using inductively coupled plasma mass spectrometry. RESULTS: Histopathological staining revealed that DHJSD had a protective effect on the cartilage. DHJSD increased autophagosome synthesis and the expression of autophagy proteins LC3 and Beclin-1 in chondrocytes. Moreover, it reduced the phosphorylation levels of Akt and mTOR and the levels of zinc, MMP-13, Bax, and Bcl-2. Following PTEN silencing, this DHJSD-mediated reduction in Akt and mTOR phosphorylation and Bax, Bcl-2, and zinc levels were further decreased; in addition, DHJSD-mediated increase in LC3 and Beclin-1 levels was decreased. CONCLUSION: DHJSD inhibits the Akt/mTOR signaling pathway by targeting PTEN to promote autophagy in chondrocytes, which may help reduce MMP-13 production by regulating zinc levels in chondrocytes.

Novel molecular classification and prognosis of papillary renal cell carcinoma based on a large-scale CRISPR-Cas9 screening and machine learning.

Papillary renal cell carcinoma (PRCC) is a highly heterogeneous cancer, and PRCC patients with advanced/metastatic subgroup showed obviously shorter survival compared to other kinds of renal cell carcinomas. However, the molecular mechanism and prognostic predictors of PRCC remain unclear and are worth deep studying. The aim of this study is to identify novel molecular classification and construct a reliable prognostic model for PRCC. The expression data were retrieved from TCGA, GEO, GTEx and TARGET databases. CRISPR data was obtained from Depmap database. The key genes were selected by the intersection of CRISPR-Cas9 screening genes, differentially expressed genes, and genes with prognostic capacity in PRCC. The molecular classification was identified based on the key genes. Drug sensitivity, tumor microenvironment, somatic mutation, and survival were compared among the novel classification. A prognostic model utilizing multiple machine learning algorithms based on the key genes was developed and tested by independent external validation set. Our study identified three clusters (C1, C2 and C3) in PRCC based on 41 key genes. C2 had obviously higher expression of the key genes and lower survival than C1 and C3. Significant differences in drug sensitivity, tumor microenvironment, and mutation landscape have been observed among the three clusters. By utilizing 21 combinations of 9 machine learning algorithms, 9 out of 41 genes were chosen to construct a robust prognostic signature, which exhibited good prognostic ability. SERPINH1 was identified as a critical gene for its strong prognostic ability in PRCC by univariate and multiple Cox regression analyses. Quantitative real-time PCR and Western blot demonstrated that SERPINH1 mRNA and protein were highly expressed in PRCC cells compared with normal human renal cells. This study exhibited a new molecular classification and prognostic signature for PRCC, which may provide a potential biomarker and therapy target for PRCC patients.

Exploring MGMT methylation-driven structural connectivity changes in insular gliomas: a tractography and graph theoretical analysis.

OBJECTIVES: This study aims to explore the relationship between the methylation levels of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter and the structural connectivity in insular gliomas across hemispheres. METHODS: We analyzed 32 left and 29 right insular glioma cases and 50 healthy controls, using differential tractography, correlational tractography, and graph theoretical analysis to investigate the correlation between structural connectivity and the methylation level. RESULTS: The differential tractography results revealed that in left insular glioma, the volume of affected inferior fronto-occipital fasciculus (IFOF, p = 0.019) significantly correlated with methylation levels. Correlational tractography results showed that the quantitative anisotropy (QA) value of peritumoral fiber tracts also exhibited a significant correlation with methylation levels (FDR < 0.05). On the other hand, in right insular glioma, anterior internal part of the reticular tract, IFOF, and thalamic radiation showed a significant correlation with methylation levels but at a different correlation direction from the left side (FDR < 0.05). The graph theoretical analysis showed that in the left insular gliomas, only the radius of graph was significantly lower in methylated MGMT group than unmethylated group (p = 0.047). No significant correlations between global properties and methylation levels were observed in insular gliomas on both sides. CONCLUSION: Our findings highlight a significant, hemisphere-specific correlation between MGMT promoter methylation and structural connectivity in insular gliomas. This study provides new insights into the genetic influence on glioma pathology, which could inform targeted therapeutic strategies.

A preliminary study on corticospinal tract morphology in incidental and symptomatic insular low-grade glioma: implications for post-surgical motor outcomes.

OBJECTIVE: Our study aimed to investigate the shape and diffusion properties of the corticospinal tract (CST) in patients with insular incidental and symptomatic low-grade gliomas (LGGs), especially those in the incidental group, and evaluate their association with post-surgical motor function. METHODS: We performed automatic fiber tracking on 41 LGG patients, comparing macroscopic shape and microscopic diffusion properties of CST between ipsilateral and contralateral tracts in both incidental and symptomatic groups. A correlation analysis was conducted between properties of CST and post-operative motor strength grades. RESULTS: In the incidental group, no significant differences in mean diffusion properties were found between bilateral CST. While decreased anisotropy of the CST around the superior limiting sulcus and increased axial diffusivity of the CST near the midbrain level were noted, there was no significant correlation between pre-operative diffusion metrics and post-operative motor strength. In comparison, we found significant correlations between the elongation of the affected CST in the preoperative scans and post-operative motor strength in short-term and long-term follow ups (p = 1.810 × 10-4 and p = 9.560 × 10-4, respectively). CONCLUSIONS: We found a significant correlation between CST shape measures and post-operative motor function outcomes in patients with incidental insular LGGs. CST morphology shows promise as a potential prognostic factor for identifying functional deficits in this patient population.

TC2N Promotes Cell Proliferation and Metastasis in Hepatocellular Carcinoma by Targeting the Wnt/ß-Catenin Signaling Pathway.

Hepatocellular carcinoma (HCC), one of the most prevalent types of cancer worldwide, has an exceedingly poor prognosis. Tandem C2 domain nuclear protein (TC2N) has been implicated in tumorigenesis and serves as an oncogene or tumor suppressor in different types of cancer. Here, we explore the possible regulatory activities and molecular mechanisms of TC2N in HCC progression. However, TC2N expression was significantly upregulated in HCC tissues and hepatoma cell lines, and this upregulation was positively correlated with tumor progression in HCC patients. The ectopic overexpression of TC2N accelerated the proliferation, migration, and invasion of HCC cells, whereas its knockdown showed the opposite effects. Bioinformatics analysis showed that TC2N participates in the regulation of the Wnt/ß-catenin signaling pathway. Mechanistically, TC2N activated the Wnt/ß-catenin signaling pathway by regulating the expression levels of ß-catenin and its downstream targets CyclinD1, MMP7, c-Myc, c-Jun, AXIN2, and glutamine synthase. Furthermore, the deletion of ß-catenin effectively neutralized the regulation of TC2N in HCC proliferation and metastasis. Overall, this study showed that TC2N promotes HCC proliferation and metastasis by activating the Wnt/ß-catenin signaling pathway, indicating that TC2N might be a potential molecular target for the treatment of HCC.

Current perspectives and trends in nanoparticle drug delivery systems in breast cancer: bibliometric analysis and review.

The treatment of breast cancer (BC) is a serious challenge due to its heterogeneous nature, multidrug resistance (MDR), and limited therapeutic options. Nanoparticle-based drug delivery systems (NDDSs) represent a promising tool for overcoming toxicity and chemotherapy drug resistance in BC treatment. No bibliometric studies have yet been published on the research landscape of NDDS-based treatment of BC. In this review, we extracted data from 1,752 articles on NDDS-based treatment of BC published between 2012 and 2022 from the Web of Science Core Collection (WOSCC) database. VOSviewer, CiteSpace, and some online platforms were used for bibliometric analysis and visualization. Publication trends were initially observed: in terms of geographical distribution, China and the United States had the most papers on this subject. The highest contributing institution was Sichuan University. In terms of authorship and co-cited authorship, the most prolific author was Yu Zhang. Furthermore, Qiang Zhang and co-workers have made tremendous achievements in the field of NDDS-based BC treatment. The article titled "Nanomedicine in cancer therapy: challenges, opportunities, and clinical applications" had the most citations. The Journal of Controlled Release was one of the most active publishers in the field. "Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries" was the most cited reference. We also analysed "hot" and cutting-edge research for NDDSs in BC treatment. There were nine topic clusters: "tumour microenvironment," "nanoparticles (drug delivery)," "breast cancer/triple-negative breast cancer," "combination therapy," "drug release (pathway)," "multidrug resistance," "recent advance," "targeted drug delivery", and "cancer nanomedicine." We also reviewed the core themes of research. In summary, this article reviewed the application of NDDSs in the treatment of BC.

Green tea polyphenols alleviate di-(2-ethylhexyl) phthalate-induced liver injury in mice.

BACKGROUND: Di (2-ethylhexyl) phthalate (DEHP) is a common plasticizer known to cause liver injury. Green tea is reported to exert therapeutic effects on heavy metal exposure-induced organ damage. However, limited studies have examined the therapeutic effects of green tea polyphenols (GTPs) on DEHP-induced liver damage. AIM: To evaluate the molecular mechanism underlying the therapeutic effects of GTPs on DEHP-induced liver damage. METHODS: C57BL/6J mice were divided into the following five groups: Control, model [DEHP (1500 mg/kg bodyweight)], treatment [DEHP (1500 mg/kg bodyweight) + GTP (70 mg/kg bodyweight), oil, and GTP (70 mg/kg bodyweight)] groups. After 8 wk, the liver function, blood lipid profile, and liver histopathology were examined. Differentially expressed micro RNAs (miRNAs) and mRNAs in the liver tissues were examined using high-throughput sequencing. Additionally, functional enrichment analysis and immune infiltration prediction were performed. The miRNA-mRNA regulatory axis was elucidated using the starBase database. Protein expression was evaluated using immunohistochemistry. RESULTS: GTPs alleviated DHEP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, liver fibrosis, and mitochondrial and endoplasmic reticulum lesions in mice. The infiltration of macrophages, mast cells, and natural killer cells varied between the model and treatment groups. mmu-miR-141-3p (a differentially expressed miRNA), Zcchc24 (a differentially expressed mRNA), and Zcchc24 (a differentially expressed protein) constituted the miRNA-mRNA-protein regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage in mice. CONCLUSION: This study demonstrated that GTPs mitigate DEHP-induced liver dysfunction, blood lipid dysregulation, fatty liver disease, and partial liver fibrosis, and regulate immune cell infiltration. Additionally, an important miRNA-mRNA-protein molecular regulatory axis involved in mediating the therapeutic effects of GTPs on DEHP-induced liver damage was elucidated.

Integrative multi-omics analyses unravel the immunological implication and prognostic significance of CXCL12 in breast cancer.

Background: CXCL12 is a vital factor in physiological and pathological processes, by inducing migration of multiple cells. We aimed to comprehensively detect the role of CXCL12 in breast cancer, and explore novel CXCL12-related biomarkers through integrative multi-omics analyses to build a powerful prognostic model for breast cancer patients. Methods: Immunohistochemistry analysis of the tissue microarray was performed to evaluate the correlation between CXCL12 expression levels and breast cancer patient outcomes. Combined single-nucleus and spatial transcriptomics data was used to uncover the expression distribution of CXCL12 in breast cancer microenvironment. CXCL12-related genes were identified by WGCNA analysis. Univariate Cox and LASSO regression analyses were then conducted to screen prognostic genes from above CXCL12-related genes, followed by the construction of the CXCL12-related prognostic signature, identification of risk groups, and external validation of the prognostic signature. Analyses of biological function, mutation landscape, immune checkpoint genes and immune cells, were performed to further reveal the differences between high/low-risk groups. Paired single-cell RNA-seq and bulk RNA-seq were analyzed to further disclose the association between the risk score and the complex tumor immune microenvironment. To screen potential therapeutic agents for breast cancer patients, analyses of gene-drug correlation and sensitivity to immunotherapy were conducted. Results: High expression of CXCL12 was linked with a prolonged survival in breast cancer. A total of 402 genes were identified by WGCNA analysis and 11 genes, covering VAT1L, TMEM92, SDC1, RORB, PCSK9, NRN1, NACAD, JPH3, GJA1, BMP8B and ADAMTS2, were screened as the candidate prognostic genes. Next, the prognostic signature was built and validated using these genes to predict the outcomes of breast cancers. The high-risk group patients exhibited significantly inferior prognoses. The combination of the risk score and tumor mutational burden (TMB) had remarkably improved performance in predicting patient outcomes. Besides, high-risk group patients showed higher infiltration of M2-like macrophages. Finally, several potential anticancer drugs were identified. The high-risk group patients were more sensitive to immunotherapy but resistant to docetaxel. Conclusions: CXCL12 has important immunological implication and prognostic significance in breast cancer. The CXCL12-related prognostic model could well predict the prognosis and treatment response of breast cancers.

Combination immunotherapy of glioblastoma with dendritic cell cancer vaccines, anti-PD-1 and poly I:C.

Glioblastoma (GBM) is a lethal cancer with limited therapeutic options. Dendritic cell (DC)-based cancer vaccines provide a promising approach for GBM treatment. Clinical studies suggest that other immunotherapeutic agents may be combined with DC vaccines to further enhance antitumor activity. Here, we report a GBM case with combination immunotherapy consisting of DC vaccines, anti-programmed death-1 (anti-PD-1) and poly I:C as well as the chemotherapeutic agent cyclophosphamide that was integrated with standard chemoradiation therapy, and the patient remained disease-free for 69 months. The patient received DC vaccines loaded with multiple forms of tumor antigens, including mRNA-tumor associated antigens (TAA), mRNA-neoantigens, and hypochlorous acid (HOCl)-oxidized tumor lysates. Furthermore, mRNA-TAAs were modified with a novel TriVac technology that fuses TAAs with a destabilization domain and inserts TAAs into full-length lysosomal associated membrane protein-1 to enhance major histocompatibility complex (MHC) class I and II antigen presentation. The treatment consisted of 42 DC cancer vaccine infusions, 26 anti-PD-1 antibody nivolumab administrations and 126 poly I:C injections for DC infusions. The patient also received 28 doses of cyclophosphamide for depletion of regulatory T cells. No immunotherapy-related adverse events were observed during the treatment. Robust antitumor CD4+ and CD8+ T-cell responses were detected. The patient remains free of disease progression. This is the first case report on the combination of the above three agents to treat glioblastoma patients. Our results suggest that integrated combination immunotherapy is safe and feasible for long-term treatment in this patient. A large-scale trial to validate these findings is warranted.

Single-cell analysis of white adipose tissue reveals the tumor-promoting adipocyte subtypes.

BACKGROUND: The tumor-adipose microenvironment (TAME) is characterized by the enrichment of adipocytes, and is considered a special ecosystem that supports cancer progression. However, the heterogeneity and diversity of adipocytes in TAME remains poorly understood. METHODS: We conducted a single-cell RNA sequencing analysis of adipocytes in mouse and human white adipose tissue (WAT). We analyzed several adipocyte subtypes to evaluate their relationship and potential as prognostic factors for overall survival (OS). The potential drugs are screened by using bioinformatics methods. The tumor-promoting effects of a typical adipocyte subtype in breast cancer are validated by performing in vitro functional assays and immunohistochemistry (IHC) in clinical samples. RESULTS: We profiled a comprehensive single-cell atlas of adipocyte in mouse and human WAT and described their characteristics, origins, development, functions and interactions with immune cells. Several cancer-associated adipocyte subtypes, namely DPP4+ adipocytes in visceral adipose and ADIPOQ+ adipocytes in subcutaneous adipose, are identified. We found that high levels of these subtypes are associated with unfavorable outcomes in four typical adipose-associated cancers. Some potential drugs including Trametinib, Selumetinib and Ulixertinib are discovered. Emphatically, knockdown of adiponectin receptor 1 (AdipoR1) and AdipoR2 impaired the proliferation and invasion of breast cancer cells. Patients with AdipoR2-high breast cancer display significantly shorter relapse-free survival (RFS) than those with AdipoR2-low breast cancer. CONCLUSION: Our results provide a novel understanding of TAME at the single-cell level. Based on our findings, several adipocyte subtypes have negative impact on prognosis. These cancer-associated adipocytes may serve as key prognostic predictor and potential targets for treatment in the future.

Mitochondrial Dysfunction in Cardiotoxicity Induced by BCR-ABL1 Tyrosine Kinase Inhibitors -Underlying Mechanisms, Detection, Potential Therapies.

The advent of BCR-ABL tyrosine kinase inhibitors (TKIs) targeted therapy revolutionized the treatment of chronic myeloid leukemia (CML) patients. Mitochondria are the key organelles for the maintenance of myocardial tissue homeostasis. However, cardiotoxicity associated with BCR-ABL1 TKIs can directly or indirectly cause mitochondrial damage and dysfunction, playing a pivotal role in cardiomyocytes homeostatic system and putting the cancer survivors at higher risk. In this review, we summarize the cardiotoxicity caused by BCR-ABL1 TKIs and the underlying mechanisms, which contribute dominantly to the damage of mitochondrial structure and dysfunction: endoplasmic reticulum (ER) stress, mitochondrial stress, damage of myocardial cell mitochondrial respiratory chain, increased production of mitochondrial reactive oxygen species (ROS), and other kinases and other potential mechanisms of cardiotoxicity induced by BCR-ABL1 TKIs. Furthermore, detection and management of BCR-ABL1 TKIs will promote our rational use, and cardioprotection strategies based on mitochondria will improve our understanding of the cardiotoxicity from a mitochondrial perspective. Ultimately, we hope shed light on clinical decision-making. By integrate and learn from both research and practice, we will endeavor to minimize the mitochondria-mediated cardiotoxicity and reduce the adverse sequelae associated with BCR-ABL1 TKIs.