Immunotherapy revolutionizing brain metastatic cancer treatment: personalized strategies for transformative outcomes.

Brain metastatic cancer poses a significant clinical challenge, with limited treatment options and poor prognosis for patients. In recent years, immunotherapy has emerged as a promising strategy for addressing brain metastases, offering distinct advantages over conventional treatments. This review explores the evolving landscape of tumor immunotherapy in the context of brain metastatic cancer, focusing on the intricate interplay between the tumor microenvironment (TME) and immunotherapeutic approaches. By elucidating the complex interactions within the TME, including the role of immune cells, cytokines, and extracellular matrix components, this review highlights the potential of immunotherapy to reshape the treatment paradigm for brain metastases. Leveraging immune checkpoint inhibitors, cellular immunotherapies, and personalized treatment strategies, immunotherapy holds promise in overcoming the challenges posed by the blood-brain barrier and immunosuppressive microenvironment of brain metastases. Through a comprehensive analysis of current research findings and future directions, this review underscores the transformative impact of immunotherapy on the management of brain metastatic cancer, offering new insights and opportunities for personalized and precise therapeutic interventions.

Predictive value of metabolism and its heterogeneity parameters measured by preoperative 18 F-FDG PET/CT for mediastinal occult lymph node metastasis in cN0 lung invasive adenocarcinoma.

OBJECTIVE: To explore the potential of intratumoral metabolism and its heterogeneous parameters, as measured by preoperative fluorine-18-fluorodeoxyglucose (18F-FDG) positron emission tomography/computed tomography (PET/CT) imaging, to predict mediastinal occult lymph node metastasis in cN0 lung invasive adenocarcinoma. SUBJECTS AND METHODS: Seventy five patients were consecutively enrolled from January 2018 to December 2022. All patients underwent 18F-FDG PET/CT scans within two weeks before surgery, and had mediastinal lymph node metastasis confirmed by pathologic diagnosis after surgery. Metabolic parameters including the maximum standardized uptake value (SUVmax), mean SUV (SUVmean), maximum average SUV (SUVpeak), tumor metabolic volume (MTV), and metabolic heterogeneity (HF) were measured. The relationship between primary focal metabolism, its heterogeneity parameters, and occult mediastinal lymph node metastasis was analyzed using an independent-sample t-test, analysis of covariance, and Mann-Whitney U test. A multivariate logistic regression model was used to analyze independent risk factors for mediastinal lymph node metastasis, while the receiver operating characteristic (ROC) curve assessed the predictive value of metabolic heterogeneity parameters for mediastinal occult lymph node metastasis. RESULTS: A total of 20 out of 75 patients (26.7%) were pathologically confirmed to have mediastinal lymph node metastasis. Analysis of covariance showed that the SUVmax, SUVmean, SUVpeak and MTV were significantly higher in patients with metastasis than in those without (all P<0.05). The metabolic heterogeneity parameters HF2 and HF3 were significantly higher in patients with mediastinal lymph node metastasis than in those without (P=0.013, 0.001), but not HF1. Multivariate Logistic regression analysis identified that tumor size, SUVmax, SUVpeak, lymph node SUVmax, and HF2 of the primary tumor as independent risk factors for mediastinal lymph node metastasis. Metabolic heterogeneity 3 demonstrated high predictive value for mediastinal occult lymph node metastasis (AUC=0.720, P=0.004). CONCLUSION: Metabolism and heterogeneity, as measured by preoperative 18F-FDG PET/CT in lung invasive adenocarcinoma, potentially have clinical value for predicting mediastinal occult lymph node metastasis.

C5aR2 Deficiency Lessens C5aR1 Distribution and Expression in Neutrophils and Macrophages.

As another receptor for complement activation product C5a, C5aR2 has been paid much attention these years. Although controversial and complex, its specific signals or roles in modulating the classic receptor C5aR1 have been investigated and gradually revealed. The hypothesis of the heterodimer of C5aR1 and C5aR2 has also been suggested and observed under extremely high C5a concentrations. In this article, we tried to investigate whether C5aR2 would affect C5aR1 expression under normal or inflammatory conditions in WT and C5ar2 -/- mice of C57BL/6 background. We focused on the innate immune cells-neutrophils and macrophages. The mRNA levels of C5ar1 in normal kidney, liver, and the mRNA or protein levels of naïve-bone marrow and peripheral blood leukocytes and peritoneal Mφs were comparable between WT and C5ar2 -/- mice, indicating the technique of C5aR2 knockout did not affect the transcription of its neighboring gene C5aR1. However, the mean fluorescence intensity of surface C5aR1 on naïve circulating C5ar2 -/- neutrophils detected by FACS was reduced, which might be due to the reduced internalization of C5aR1 on C5ar2 -/- neutrophils. In the peritonitis model induced by i.p. injection of thioglycollate, more neutrophils were raised after 10 hr in C5ar2 -/- peritoneal cavity, indicating the antagonism of C5aR2 on C5aR1 signal in neutrophil chemotaxis. After 3 days of thioglycollate injection, the mainly infiltrating macrophages were comparable between WT and C5ar2 -/- mice, but the C5ar1 mRNA and surface or total C5aR1 protein expression were both reduced in C5ar2 -/- macrophages, combined with our previous study of reduced chemokines and cytokines expression in C5ar2 -/- peritoneal macrophages, indicating that C5aR2 in macrophages may cooperate with C5aR1 inflammatory signals. Our article found C5aR2 deficiency lessened C5aR1 distribution and expression in neutrophils and macrophages with different functions, indicating C5aR2 might function differently in different cells.

Neointimal hyperplasia after endoluminal injury in mice is dependent on tissue factor- and angiopoietin-2 dependent interferon gamma production by fibrocytes and macrophages.

Background: The intimal hyperplasia (IH) and vascular remodelling that follows endovascular injury, for instance after post-angioplasty re-stenosis, results in downstream ischaemia and progressive end organ damage. Interferon gamma (IFNγ) is known to play a critical role in this process. In mouse models we have previously shown that fibrocytes expressing tissue factor (TF) are recruited early to the site of injury. Through thrombin generation and protease activated receptor-1 (PAR-1) activation, fibrocytes secrete angiopoietin-2, stimulate neointimal cell proliferation, inhibit apoptosis and induce CXCL-12 production, all of which contribute to the progressive IH that then develops. In this study we investigated the relationship between TF, angiopoietin-2 and IFNγ. Methods and results: IH developing in carotid arteries of wild-type mice 4 weeks after endoluminal injury contained a significant proportion of IFNγ+ fibrocytes and macrophages, which we show, using a previously defined adoptive transfer model, were derived from circulating CD34+ cells. IH did not develop after injury in IFNγ-deficient mice, except after transplantation of WT bone marrow or adoptive transfer of WT CD34+ cells. In vitro, CD34+ cells isolated from post-injury mice did not express IFNγ, but this was induced when provided with FVIIa and FX, and enhanced when prothrombin was also provided: In both cases IFNγ secretion was TF-dependent and mediated mainly through protease activated PAR-1. IFNγ was predominantly expressed by fibrocytes. In vivo, all IFNγ+ neointimal cells in WT mice co-expressed angiopoietin-2, as did the small numbers of neointimal cells recruited in IFNγ-/- mice. Adoptively transferred WT CD34+ cells treated with either an anti-TIE-2 antibody, or with siRNA against angiopoetin-2 inhibited the expression of IFNγ and the development of IH. Conclusion: TF-dependent angiopoietin-2 production by newly recruited fibrocytes, and to a lesser extent macrophages, switches on IFNγ expression, and this is necessary for the IH to develop. These novel findings enhance our understanding of the pathophysiology of IH and expose potential targets for therapeutic intervention.

Anterior Cruciate Ligament Repair Leads to Improved Patient-Reported Outcomes Compared to Anterior Cruciate Ligament Reconstruction.

Introduction Anterior cruciate ligament (ACL) tears occur frequently in young athletes, and ligament repair and reconstruction are surgical treatments. Although there are suggested benefits for both approaches, there is a lack of direct comparisons between ACL repair and reconstruction.This study aims to compare the mid-term functional outcomes and quality of life measures between patients that have undergone ACL repair versus reconstruction. Methods A retrospective review was conducted for demographic and operative report data of patients who underwent an ACL repair or reconstruction between 2012 and 2018. Patients were contacted over the phone and underwent a Patient-Reported Outcomes Measurement Information System (PROMIS) survey evaluating pain interference, mobility, and function. Patients were excluded from the study if there was an incomplete operative note, missing contact information, or failure to answer phone calls. Results A total of 74 eligible patients were included, with n = 54 in the ACL reconstruction group (73.0%) and n = 20 in the ACL repair group (27.0%). Reconstruction patients had a PROMIS (median (IQR)) physical function score of 22.50 (16.00-59.00), as compared to repair patients' physical function score of 60.00 (21.50-60.00). There was a significant difference favoring repair (p = 0.040). In addition, ACL reconstruction patients had a significantly higher rate of additional procedures, with 63.0% of reconstruction patients receiving an additional operation as compared to 30.0% of repair patients (p = 0.017). The surgery type did not show a significant effect on physical function scores, while additional procedures remained significant in the linear regression analysis. Conclusion Although ACL repair is associated with improved physical function scores as compared to reconstruction in the univariate analysis, surgery type did not show significance when controlling for other variables. Further studies are necessary to compare patients with similar injuries to account for differences in additional procedures, but the results remain promising in assisting with patient-driven treatment decisions.

[Characteristics of Epiphytic Bacterial Community on Submerged Macrophytes in Water Environment Supplemented with Reclaimed Water].

Biofilms attached to submerged macrophytes play an important role in improving the water quality of the water environment supplemented with reclaimed water. In order to explore the effects of reclaimed water quality and submerged macrophyte species on the characteristics of an epiphytic bacterial community, different types of submerged macrophytes were selected as research objects in this study. 16S rRNA high-throughput sequencing technology was used on the epiphytic bacteria and the surrounding environmental samples to analyze the bacterial community structure and functional genes. The results showed that approximately 20%-35% of the nitrogen and phosphorus nutrients were absorbed and utilized in the water environment supplemented with reclaimed water. However, the COD, turbidity, and chroma of the downstream water were significantly increased. The bacterial community of the biofilms attached to submerged macrophytes was significantly different from that in the surrounding environment (soil, sediment, and water body) and in the activated sludge that was treated by reclaimed water. In terms of bacterial community diversity, the richness and diversity were significantly lower than those of soil and sediment but higher than those of plankton bacteria in water. In terms of bacterial community composition, dominant genera and corresponding abundances were also different from those of other samples. The main dominant bacterial genera were Sphingomonas, Aeromonas, Pseudomonas, and Acinetobacter, accounting for 7%-40%, respectively. Both macrophyte species and the quality of reclaimed water (BOD5, TN, NH4+-N, and TP) could affect the bacterial community. However, the effect of water quality of the bacterial community was greater than that of macrophytes species. Additionally, the quality of reclaimed water also affected the abundance of functional genes in the bacterial community, and the relative abundance of nitrogen and phosphorus cycling functional genes was higher in areas with higher nitrogen and phosphorus concentrations.

[Clinical features and genetic analysis of a child with Central core disease due to compound heterozygous variants of RYR1 gene].

OBJECTIVE: To explore the clinical features and genetic etiology of a child with Central core disease (CCD). METHODS: A child with CCD who was treated at the Children's Hematology Department of the First Affiliated Hospital of Zhengzhou University in February 2022 was selected as the study subject. Muscle biopsy was performed. Peripheral blood samples were collected from the child and his parents for the extraction of genomic DNA. The child was subjected to whole exome sequencing (WES), and candidate variant was verified by Sanger sequencing. RESULTS: The child, a 12-year-old boy, had manifested motor retardation, facial weakness, ptosis, pectus carinatum, scoliosis, etc. Muscle biopsy showed that the central nucleus muscle fibers and atrophic muscle fibers were mainly type I. WES revealed that the child has harbored c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene. Sanger sequencing confirmed that they were inherited from his mother and father, respectively. Based on the guidelines from the American College of Medical Genetics and Genomics, both variants were considered as likely pathogenic (PS4+PM1+PM2_Supporting+PP3；PM1+PM2_Supporting+PM3+PP3). CONCLUSION: By combining his clinical manifestation and results of muscle pathology and genetic testing, the child was diagnosed with CCD, which may be attributed to the c.10561G>A (p.G3521S) and c.3448T>C (p.C1150R) compound heterozygous variants of the RYR1 gene.

Minisci-Type Dehydrogenative Coupling of N-Heteroaromatic Rings with Inert C(sp3)-H Enabled by a Visible-Light-Catalyzed Intermolecular Hydrogen Atom Transfer Process.

The Minisci-type dehydrogenative coupling of N-heteroaromatic rings with inert C-H or Si-H partners via visible-light-catalyzed hydrogen atom transfer has been reported. This methodology allows the coupling reactions to be carried out in water as a solvent under air atmospheric conditions with visible-light illumination. A wide range of inert C-H and Si-H partners could be directly coupled with various N-aromatic heterocycles to deliver products in good to excellent yields.

Age-Related Changes in Hepatic Lipid Metabolism and Abdominal Adipose Deposition in Yellow-Feathered Broilers Aged from 1 to 56 Days.

The objective of this study was to evaluate the age-related changes in hepatic lipid metabolism, adipocyte hyperplasia, hypertrophy, and lipid metabolism in the abdominal adipose tissue of yellow-feathered broilers. Blood, liver, and abdominal adipose samples were collected on days 1, 7, 14, 21, 28, 35, 42, 49, and 56. Body, liver, and abdominal weight increased (p < 0.05) with age-related changes. The triacylglycerol content peaked on day 14, and total cholesterol content peaked on day 56. The adipocyte diameter and area peaked on day 56, and total DNA content peaked on day 7. The age-related changes in hepatic lipogenesis-related gene (ChREBP, SREBP-1c, ACC, FAS, SCD1) expression mainly occurred during days 1 to 21, hepatic lipolysis-related gene (CPT1, LPL, ApoB) expression mainly occurred during days 1 to 14, and abdominal adipose-deposition-related gene (PPARα, CPT1, LPL, PPARγ, C/EBPß) expression occurred during days 1 to 14. These results demonstrated a dynamic pattern of hepatic lipid metabolism and abdominal adipose deposition in yellow-feathered broilers, which provides practical strategies to regulate hepatic lipid metabolism and reduce abdominal adipose deposition in yellow-feathered broilers.

Toxicity and inhibition mechanism of gallic acid on physiology and fermentation performance of Escherichia coli.

Gallic acid is a natural phenolic acid that has a stress inhibition effect on Escherichia coli. This study by integrates fermentation characteristics and transcriptional analyses to elucidate the physiological mechanism of E. coli 3110 response to gallic acid. Compared with the control (without stress), the cell growth was severely retarded, and irregular cell morphology appeared in the case of high levels of gallic acid stress. The glucose consumption of E. coli was reduced successively with the increase of gallic acid content in the fermentation medium. After 20 h of gallic acid stress, cofactor levels (ATP, NAD+ and NADH) of E. coli 3110 were similarly decreased, indicating a more potent inhibitory effect of gallic acid on E. coli. The transcriptional analysis revealed that gallic acid altered the gene expression profiles related to five notable differentially regulated pathways. The genes related to the two-component system were up-regulated, while the genes associated with ABC-transporter, energy metabolism, carbon metabolism, and fatty acid biosynthesis were down-regulated. This is the first report to comprehensively assess the toxicity of gallic acid on E. coli. This study has implications for the efficient production of phenolic compounds by E. coli and provides new ideas for the study of microbial tolerance to environmental stress and the identification of associated tolerance targets.