Pretreatment Sarcopenia and MRI-Based Radiomics to Predict the Response of Neoadjuvant Chemotherapy in Triple-Negative Breast Cancer.

The association between sarcopenia and the effectiveness of neoadjuvant chemotherapy (NAC) in triple-negative breast cancer (TNBC) remains uncertain. This study aims to examine the potential of sarcopenia as a predictive factor for the response to NAC in TNBC, and to assess whether its combination with MRI radiomic signatures can improve the predictive accuracy. We collected clinical and pathological information, as well as pretreatment breast MRI and abdominal CT images, of 121 patients with TNBC who underwent NAC at our hospital between January 2012 and September 2021. The presence of pretreatment sarcopenia was assessed using the L3 skeletal muscle index. Clinical models were constructed based on independent risk factors identified by univariate regression analysis. Radiomics data were extracted on breast MRI images and the radiomics prediction models were constructed. We integrated independent risk factors and radiomic features to build the combined models. The results of this study demonstrated that sarcopenia is an independent predictive factor for NAC efficacy in TNBC. The combination of sarcopenia and MRI radiomic signatures can further improve predictive performance.

8-Cl-Ado and 8-NH2-Ado synergize with venetoclax to target the methionine-MAT2A-SAM axis in acute myeloid leukemia.

Targeting the metabolic dependencies of acute myeloid leukemia (AML) cells is a promising therapeutical strategy. In particular, the cysteine and methionine metabolism pathway (C/M) is significantly altered in AML cells compared to healthy blood cells. Moreover, methionine has been identified as one of the dominant amino acid dependencies of AML cells. Through RNA-seq, we found that the two nucleoside analogs 8-chloro-adenosine (8CA) and 8-amino-adenosine (8AA) significantly suppress the C/M pathway in AML cells, and methionine-adenosyltransferase-2A (MAT2A) is one of most significantly downregulated genes. Additionally, mass spectrometry analysis revealed that Venetoclax (VEN), a BCL-2 inhibitor recently approved by the FDA for AML treatment, significantly decreases the intracellular level of methionine in AML cells. Based on these findings, we hypothesized that combining 8CA or 8AA with VEN can efficiently target the Methionine-MAT2A-S-adenosyl-methionine (SAM) axis in AML. Our results demonstrate that VEN and 8CA/8AA synergistically decrease the SAM biosynthesis and effectively target AML cells both in vivo and in vitro. These findings suggest the promising potential of combining 8CA/8AA and VEN for AML treatment by inhibiting Methionine-MAT2A-SAM axis and provide a strong rationale for our recently activated clinical trial.

Therapeutic application of human type 2 innate lymphoid cells via induction of granzyme B-mediated tumor cell death.

The therapeutic potential for human type 2 innate lymphoid cells (ILC2s) has been underexplored. Although not observed in mouse ILC2s, we found that human ILC2s secrete granzyme B (GZMB) and directly lyse tumor cells by inducing pyroptosis and/or apoptosis, which is governed by a DNAM-1-CD112/CD155 interaction that inactivates the negative regulator FOXO1. Over time, the high surface density expression of CD155 in acute myeloid leukemia cells impairs the expression of DNAM-1 and GZMB, thus allowing for immune evasion. We describe a reliable platform capable of up to 2,000-fold expansion of human ILC2s within 4 weeks, whose molecular and cellular ILC2 profiles were validated by single-cell RNA sequencing. In both leukemia and solid tumor models, exogenously administered expanded human ILC2s show significant antitumor effects in vivo. Collectively, we demonstrate previously unreported properties of human ILC2s and identify this innate immune cell subset as a member of the cytolytic immune effector cell family.

Prognostic biomarker SYK and its correlation with immune infiltrates in glioma.

The tumor microenvironment (TME) provides excellent conditions for the development of glioma. The present study sought to identify the prognostic factors of glioma that could be used to improve the prognosis of patients with this disease. In the present study, Cell-type Identification by Estimating Relative Subsets of RNA Transcripts (CIBERSORT) and Estimation of Stromal and Immune cells in Malignant Tumor tissues using Expression data calculations were employed to estimate the ratio of tumor-infiltrating immune cells and the quantity of immune and stromal components in 698 glioma cases from the Cancer Genome Atlas database. In addition, certain differentially expressed genes were studied by Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses and single genes associated with prognosis were identified by protein-protein interaction (PPI) network and Cox combined analysis. The immune and stromal scores of the TME were significantly associated with glioma patient survival. By using the PPI network and Cox regression analyses, spleen tyrosine kinase (SYK) was eventually identified as the best prognostic factor for patients with glioma. In addition, Gene Set Enrichment Analysis and CIBERSORT analyses were employed. The former indicated that the high-expression SYK group genes were mainly enriched in immune-related activities. The latter revealed that SYK expression was positively associated with T cell cluster of differentiation 4 memory resting and monocytes. The aforementioned experimental analyses provided the theoretical basis for the biological prediction of SYK. The data indicated that SYK contributed to immune predictors in patients with glioma by facilitating the shift of the TME from immune dominance to metabolic activity. Finally, reverse transcription-quantitative PCR and western blotting were used to verify the single gene expression in glioma cells. This may provide prognostic value for the treatment of glioma.

The crosstalk between ferroptosis and anti-tumor immunity in the tumor microenvironment: molecular mechanisms and therapeutic controversy.

The advent of immunotherapy has significantly reshaped the landscape of cancer treatment, greatly enhancing therapeutic outcomes for multiple types of cancer. However, only a small subset of individuals respond to it, underscoring the urgent need for new methods to improve its response rate. Ferroptosis, a recently discovered form of programmed cell death, has emerged as a promising approach for anti-tumor therapy, with targeting ferroptosis to kill tumors seen as a potentially effective strategy. Numerous studies suggest that inducing ferroptosis can synergistically enhance the effects of immunotherapy, paving the way for a promising combined treatment method in the future. Nevertheless, recent research has raised concerns about the potential negative impacts on anti-tumor immunity as a consequence of inducing ferroptosis, leading to conflicting views within the scientific community about the interplay between ferroptosis and anti-tumor immunity, thereby underscoring the necessity of a comprehensive review of the existing literature on this relationship. Previous reviews on ferroptosis have touched on related content, many focusing primarily on the promoting role of ferroptosis on anti-tumor immunity while overlooking recent evidence on the inhibitory effects of ferroptosis on immunity. Others have concentrated solely on discussing related content either from the perspective of cancer cells and ferroptosis or from immune cells and ferroptosis. Given that both cancer cells and immune cells exist in the tumor microenvironment, a one-sided discussion cannot comprehensively summarize this topic. Therefore, from the perspectives of both tumor cells and tumor-infiltrating immune cells, we systematically summarize the current conflicting views on the interplay between ferroptosis and anti-tumor immunity, intending to provide potential explanations and identify the work needed to establish a translational basis for combined ferroptosis-targeted therapy and immunotherapy in treating tumors.

Artificial intelligence: opportunities and challenges in the clinical applications of triple-negative breast cancer.

Triple-negative breast cancer (TNBC) accounts for 15-20% of all invasive breast cancer subtypes. Owing to its clinical characteristics, such as the lack of effective therapeutic targets, high invasiveness, and high recurrence rate, TNBC is difficult to treat and has a poor prognosis. Currently, with the accumulation of large amounts of medical data and the development of computing technology, artificial intelligence (AI), particularly machine learning, has been applied to various aspects of TNBC research, including early screening, diagnosis, identification of molecular subtypes, personalised treatment, and prediction of prognosis and treatment response. In this review, we discussed the general principles of artificial intelligence, summarised its main applications in the diagnosis and treatment of TNBC, and provided new ideas and theoretical basis for the clinical diagnosis and treatment of TNBC.

Progress in the treatment of urethral adenocarcinoma.

BACKGROUND: Urothelial adenocarcinoma (UA) is a rare subtype of primary urothelial carcinoma, which is more common in women and has a poor prognosis. Because of their low incidence, most of the existing literature is based on case reports and there is a lack of comprehensive literature on this type of tumor. PURPOSE: This article provides a comprehensive and systematic review of the epidemiology, pathological types, treatment, and prognosis of UA. Especially in the treatment section, we reviewed the various treatment methods including surgery, radiotherapy, chemotherapy, immunotherapy and molecular targeted therapy. This review aims to provide a theoretical basis for the clinical diagnosis and management of UA. METHODS: We reviewed the relevant literature of UA from Pubmed. CONCLUSION: There is no standard treatment for UA. Multidisciplinary therapy, including surgery, radiotherapy and chemotherapy, is the current trend. Immunotherapy and molecular targeted therapy will also become viable options for the treatment of UA in future.

Targeting the methionine-methionine adenosyl transferase 2A- S -adenosyl methionine axis for cancer therapy.

PURPOSE OF REVIEW: In this review, we summarize the biological roles of methionine, methionine adenosyl transferase 2A (MAT2A) and S -adenosyl methionine (SAM) in methylation reactions during tumorigenesis. Newly emerged inhibitors targeting the methionine-MAT2A-SAM axis will be discussed. RECENT FINDINGS: SAM is the critical and global methyl-donor for methylation reactions regulating gene expression, and in mammalian cells, it is synthesized by MAT2A using methionine. Recent studies have validated methionine and MAT2A as metabolic dependencies of cancer cells because of their essential roles in SAM biosynthesis. MAT2A inhibition leads to synthetic lethality in methylthioadenosine-phosphorylase (MTAP)-deleted cancers, which accounts for 15% of all cancer types. Of note, remarkable progress has been made in developing inhibitors targeting the methionine-MAT2A-SAM axis, as the first-in-class MAT2A inhibitors AG-270 and IDE397 enter clinical trials to treat cancer. SUMMARY: The methionine-MAT2A-SAM axis plays an important role in tumorigenesis by providing SAM as a critical substrate for abnormal protein as well as DNA and RNA methylation in cancer cells. Targeting SAM biosynthesis through MAT2A inhibition has emerged as a novel and promising strategy for cancer therapy.

Synergy of Venetoclax and 8-Chloro-Adenosine in AML: The Interplay of rRNA Inhibition and Fatty Acid Metabolism.

It is known that 8-chloro-adenosine (8-Cl-Ado) is a novel RNA-directed nucleoside analog that targets leukemic stem cells (LSCs). In a phase I clinical trial with 8-Cl-Ado in patients with refractory or relapsed (R/R) AML, we observed encouraging but short-lived clinical responses, likely due to intrinsic mechanisms of LSC resistance. LSC homeostasis depends on amino acid-driven and/or fatty acid oxidation (FAO)-driven oxidative phosphorylation (OXPHOS) for survival. We recently reported that 8-Cl-Ado and the BCL-2-selective inhibitor venetoclax (VEN) synergistically inhibit FAO and OXPHOS in LSCs, thereby suppressing acute myeloid leukemia (AML) growth in vitro and in vivo. Herein, we report that 8-Cl-Ado inhibits ribosomal RNA (rRNA) synthesis through the downregulation of transcription initiation factor TIF-IA that is associated with increasing levels of p53. Paradoxically, 8-Cl-Ado-induced p53 increased FAO and OXPHOS, thereby self-limiting the activity of 8-Cl-Ado on LSCs. Since VEN inhibits amino acid-driven OXPHOS, the addition of VEN significantly enhanced the activity of 8-Cl-Ado by counteracting the self-limiting effect of p53 on FAO and OXPHOS. Overall, our results indicate that VEN and 8-Cl-Ado can cooperate in targeting rRNA synthesis and OXPHOS and in decreasing the survival of the LSC-enriched cell population, suggesting the VEN/8-Cl-Ado regimen as a promising therapeutic approach for patients with R/R AML.

Prognostic value and risk model construction of hypoxic stress-related features in predicting gastric cancer.

OBJECTIVE: Hypoxia promotes tumor progression from multiple aspects, including metabolism, proliferation, migration and angiogenesis. Therefore, a thorough understanding of the impact of hypoxia on gastric adenocarcinoma (STAD) is warranted. The aim of the present study was to find a prognostic model of hypoxia in gastric cancer (GC) and its relationship with the immune microenvironment. METHODS: Distinct hypoxia-related patterns were identified with an unsupervised consensus clustering algorithm in STAD patients from the Gene Expression Omnibus (GEO) and the cancer genome atlas (TCGA) cohorts. The different biological processes among different hypoxia-related clusters were then explored with the algorithm of single sample gene set enrichment analysis. Then hypoxia-related Hub genes were selected by weighted gene co-expression network analysis (WGCNA) prior to the construction of a hypoxia-related gene prognostic model. The model was constructed using multivariate Cox regression analysis, least absolute shrinkage and selection operator (LASSO) regression and univariate Cox regression analysis. The relationship between immune infiltration and hypoxia-related features was analyzed. RESULTS: We identified a hypoxia-related cluster (magenta) by WGCNA and found that different prognosis can be evidently induced by various hypoxia response patterns. LASSO analysis found seven hypoxia-related genes CPZ, LBH, NOX4, NRP1, NOS3, C3orf36 and CDH6, which were then used for the construction of hypoxia-related gene prognostic model. The model was verified by TCGA database and GEO dataset and showing good prognostic value. CONCLUSIONS: A novel hypoxia-related prognostic signature was constructed to predict prognosis and correlate with immune infiltration in STAD. Hypoxia-related prognostic features are expected to be a new prognostic tool for GC.

Therapeutic application of adipose-derived stromal vascular fraction in diabetic foot.

Diabetic foot is one of the severest complications of diabetes. In severe cases, this disease may be lead to amputation or even death due to secondary infection and ischemic necrosis. Since the ineffectiveness of traditional therapy, autologous stem cell transplantation has been used to treat diabetic foot. This simple, safe, and effective therapy is expected to be applied and promoted in the future.In this review, we described the detailed pathogenesis of diabetic foot and the common clinical treatments currently used. We also revealed vascular remodeling as the potential mechanism of therapeutic functions of adipose-derived stromal vascular fraction (SVF) in treating diabetic foot.

The differential expression and potential roles of circular RNAs in children with anti-NMDA receptor encephalitis.

To explore the role of circular RNAs (circRNAs) in pediatric anti-N-methyl-d-aspartate (NMDA) receptor encephalitis, we assessed the profiles of circRNAs and mRNAs in blood leukocytes from anti-NMDA receptor encephalitis patients and healthy controls using microarray analysis. 1196 circRNAs and 719 mRNAs (change ≥2, p < .05) were dysregulated in anti-NMDA receptor encephalitis patients, relative to healthy controls, based on microarray data. Further bioinformatic analysis demonstrated that the host genes of dysregulated circRNAs are primarily associated with receptor internalization. In conclusion, circRNAs may be implicated in the pathogenesis of pediatric anti-NMDA receptor encephalitis.

Expansion and Maintenance of CD133-Expressing Pancreatic Ductal Epithelial Cells by Inhibition of TGF-ß Signaling.

Restoring ß-cell mass by the transplantation of pancreatic islets is an effective diabetes treatment, but it is limited by the shortage of donor organs. CD133-expressing pancreatic ductal epithelial cells (PDECs) have the ability to generate insulin-producing cells. The expansion of these cells is dependent on extrinsic niche factors, but few of those signals have been identified. In this study, CD133-expressing PDECs were purified by sorting from adult wild-type C57BL/6 mice and TGFßRIInull/null mice. Furthermore, using immunofluorescence and transplantation assays, we found that the inhibition of the transforming growth factor-ß (TGF-ß) pathway promoted the expansion of CD133-expressing PDECs for many generations and maintained the ability of CD133-expressing PDECs to generate insulin-producing cells. Moreover, western blot, qRT-PCR, and dual luciferase assays using TGF-ß inhibitors were performed to identify the mechanisms by which TGF-ß signaling regulates proliferation and differentiation. The results showed that the inhibition of TGF-ß signaling enhanced Id2 binding to the promoter region of the cell proliferation repressor p16 and promoted the expansion of CD133-expressing PDECs, and the increased Id2 binding to NeuroD1 decreased the transcription of Pax6 to maintain CD133-expressing PDECs in the Pdx1-expression stage. Taken together, the effect of TGF-ß antagonists on CD133-expressing PDECs reveals a novel paradigm of signaling that explains the balance between the expansion and differentiation of pancreatic duct epithelial progenitors.

α-Ketoglutarate Promotes Pancreatic Progenitor-Like Cell Proliferation.

A major source of ß cell generation is pancreatic progenitor-like cell differentiation. Multiple studies have confirmed that stem cell metabolism plays important roles in self-renewal and proliferation. In the absence of glucose, glutamine provides the energy for cell division and growth. Furthermore, α-ketoglutarate (αKG), a precursor for glutamine synthesis, is sufficient for enabling glutamine-independent cell proliferation. We have demonstrated that αKG contributes to the large-scale proliferation of pancreatic progenitor-like cells that can provide an ample amount of clinically relevant ß cells. We compared the mRNA expression of a subset of genes, the abundance of ATP, reactive oxide species, mitochondrial number, and the colony-forming frequency between mouse pancreatic CD133⁺ and CD133- cells. We employed Real-Time PCR, immunostaining and passage assays to investigate self-renewal and proliferation of pancreatic progenitor-like cells in a 3D culture system in the presence and absence of αKG. The energy metabolism of CD133⁺ cells was more prone to oxidative phosphorylation. However, in the 3D culture system, when αKG was supplemented to the culture medium, the proliferation of the pancreatic progenitor-like cells was significantly elevated. We confirmed that the presence of αKG correlated with the up-regulation of Ten-Eleven Translocation (Tet). αKG can promote the proliferation of pancreatic progenitor-like cells via the up-regulation of Tet.

Nano-loaded human umbilical cord mesenchymal stem cells as targeted carriers of doxorubicin for breast cancer therapy.

The main challenge of anticancer drugs is poor tumor targeting. Now cellular carriers are widely investigated to deliver anticancer agents. As an ideal cellular candidate, human umbilical cord derived mesenchymal stem cells (hUC-MSCs) possess inherent tropism potential to tumor. Here, we constructed hUC-MSCs carrying transferrin-inspired-nanoparticles that contain doxorubicin(hUC-MSCs-Tf-inspired-NPs) to achieve enhanced anti-tumor efficacy and made an evaluation. Results represented that hUC-MSCs-Tf-inspired-NPs not only exhibit the controlled-release property of Tf-inspired-NPs, but also integrate tumor tropism and penetrative abilities of MSCs. The tumor volume of nude mice bearing breast cancer MCF-7 treated with hUC-MSCs-Tf-inspired-NPs, was remarkably reduced compared to those treated with free drug or Tf-inspired-NPs. Thus, Tf-inspired-NPs loaded hUC-MSCs have a potential to deliver anticancer drugs.

Targeted delivery of doxorubicin by nano-loaded mesenchymal stem cells for lung melanoma metastases therapy.

Poor antigenic presentation of tumor tissues and a lack of specific targets currently limit the success of nanoparticle delivery system. Cellular carrier technique has been recently explored extensively as a substitutive or supplement for traditional targeting delivery system. Here, we demonstrate the usage of mesenchymal stem cells (MSCs) loaded with doxorubicin containing polymer nanoparticles in pulmonary melanoma metastases therapy, as a modified technique of targeted delivery system. The characterizations of prepared nanoparticles and MSCs sensitivity to DOX and PLGA-DOX were measured. In vitro tumor tropism, and in vivo distributions of nanoparticles loaded MSCs were also investigated. The findings have demonstrated that, the modified system not only integrates the controlled-release property of nanoparticles but also exhibits tumor tropism and penetrative characteristics of MSCs. Furthermore, the in vitro and in vivo anti-tumor study has demonstrated that drug loaded MSCs had potent efficacy in lung melanoma metastases treatment.

[Descriptive study on the epidemiology of lung cancer in coal-producing area in eastern Yunnan, China].

BACKGROUND AND OBJECTIVE: Xuanwei county is located at Late Permian coal-accumulating area in eastern Yunnan and western Guizhou, China. The lung cancer mortality rate in Xuanwei county is among the highest in China and has been attributed to exposure to indoor smoky coal emissions that contain very high levels of polycyclic aromatic hydrocarbons (PAHs). Recent years, the pollution and the higher mortality rate of lung cancer has been watched in the area around Xuanwei, and there is no report about whether the epidemic levels and the pathogen of lung cancer in other area of eastern Yunnan is similar to that in xuanwei. The aim of this study is to epidemic levels and cause of lung cancer in coal-producing area in the east of Yunnan province. METHODS: 382 study units (nature villages) were selected by stratified cluster random sampling from coalproducing area in eastern Yunnan province, China. The villagers who were aged 30-79 years with no history of lung cancer were enrolled. All the participants received an initial single-view posterior-anterior chest radiograph and administered a questionnaire survey (which involves the information of demography, household and fuel use, lifestyle, tobacco and occupational exposure history, family and personal medical history, etc. The subjects with a positive screen by chest x-ray underwent to have a computed tomography scan of the chest and biopsy examination. The confidence interval of the standardized rate ratio were adopted to evaluate the statistical significance of differences in different regions. RESULTS: 52,833 villagers were surveyed and screened with X-ray. 604 of them were suspicious lung cancer with an initial chest radiograph, 541 underwent CT scan (362 were diagnosed by CT and 109 were diagnosed by histology). The adjusted positive rates for lung cancer screening with CT is 763.08 per 100,000, the age-standardized rate (ASR) with the world standard population is 426.28 per 100,000 (95% confidence interval=381.51/10 per 100,000 to 471.05 per 100,000), 482.78 per 100,000 for man, 387.98 per 100,000 for woman, male-to-female (M:F) rate ratios is 1.24. The intensity of lung cancer had significant difference between different study units. The ASR for lung cancer screening from A, B, C to D areas decreased in turn, and the area A was the highest of all, which was 6.97 times higher than the lowest area D, and the ratio between male and female was increased gradually. The positive rate for lung cancer was related to the distribution of coal and in direct proportion to the amount of smoky coal burning, but not associated with smokeless coal combustion. There are above 80% residents who burned "smoky" coal in indoor firepits which generated very high levels of air pollution. Lung cancer mortality of family members has the same distribution to positive rates of lung cancer screening, and they are in proportion to each other. 85% men smoke 16.12 cigarettes per day, averagely. About 50% of them did the job like coking, mining coal and so forth. Smoking rate of woman is 1.37%, they always did housework such as cooking, raising pigs and so on. Though the smoking and occupational hazard factors were not the major reasons for women to get lung cancer, they were possible reasons for men. CONCLUSIONS: In coal-producing area in eastern Yunnan, China, [corrected] lung cancer was associated with exposure to smoky coal emissions and family susceptibility. Smoking, coking and mining were not the major risk factors lead to lung cancer for women.