Reprogramming of glutamine metabolism and its impact on immune response in the tumor microenvironment.

Metabolic reprogramming and immune escape play a major role in tumorigenesis. Increasing number of studies have shown that reprogramming of glutamine metabolism is a putative determinant of the anti-tumor immune response in the tumor microenvironment (TME). Usually, the predatory uptake of glutamine by tumor cells in the TME results in the limited utilization of glutamine by immune cells and affects the anti-tumor immune response. The cell-programmed glutamine partitioning also affects the anti-tumor immune response. However, the reprogramming of glutamine metabolism in tumors modulates immune escape by regulating tumor PD-L1 expression. Likewise, the reprogramming of glutamine metabolism in the immune cells also affects their immune function. Additionally, different types of glutamine metabolism inhibitors extensively regulate the immune cells in the TME while suppressing tumor cell proliferation. Herein, we discuss how metabolic reprogramming of tumor and immune cells regulates anti-tumor immune responses, as well as functional changes in different immune cells in the context of targeting tumor glutamine metabolism, which can better explain the potential of targeting glutamine metabolism in combination with immunotherapy for cancer. Video abstract.

p53 Immunohistochemistry staining patterns and prognosis significance in 212 cases of non-endometrioid endometrial cancer.

OBJECTIVE: To investigate the immunohistochemistry (IHC) staining pattern and prognostic significance of p53 in non-endometrioid endometrial cancer (non-EEC). METHODS: This study retrospectively included 212 non-EEC patients, with histological types including serous carcinoma (SC), clear cell carcinoma (CCC), mixed carcinoma (MC), undifferentiated carcinoma (UC), and carcinosarcoma (CS). p53 IHC was interpreted as normal/wild-type and abnormal/mutant-type, the latter including overexpression, complete absence, and cytoplasmic staining patterns. Moreover, uncommon p53 subclonal/heterogeneous staining patterns were described. Disease-free survival (DFS) and overall survival (OS) were employed as endpoints to evaluate the prognostic significance of p53. RESULTS: In 212 non-EEC cases, 50 (23.6 %) were p53 wild-type, while 162 (76.4 %) displayed abnormal p53 staining. Overexpression was the predominant abnormal p53 staining pattern (122/162), complete absence followed (33/162). All SCs exhibited the mutant p53 staining pattern. The p53 abnormal expression rates in CCC, MC, UC, and CS were 37.5 %, 78.9 %, 35.7 %, and 75.7 %, respectively. Interestingly, of the 12 MC cases with SC components, barring one with p53 subclonal staining, all showed the mutant-type staining. The concordance rate for p53 expression between epithelial and mesenchymal components of CS was 94.3 % (66/70). Kaplan-Meier curves indicated patients with p53 abnormalities had worse DFS compared to those with wild-type p53 (P=0.025). Multivariate Cox regression confirmed that p53 (HR: 2.270, 95 % CI: 1.124-4.586, P=0.022) independently predicted DFS in non-EEC patients, though not for OS. CONCLUSIONS: Non-EEC patients with various histological types exhibit different p53 staining patterns. However, abnormal p53 expression, regardless of histological type, implies a poor DFS in non-EEC patients.

The effects of pulsed electric fields treatment on the structure and physicochemical properties of dialdehyde starch.

The structural and physicochemical properties changes of corn starch oxidized by sodium periodate under the assistance of pulsed electric fields (PEF) were studied. It was found that dialdehyde starch (DAS) particles produced by PEF-assisted oxidation exhibited shrinkage and pits, and had a larger particle size when compared to the control without PEF. The solubility of the DAS (12 kV/cm PEF- assisted oxidation) improved by 70.2% when compared to the native starch. Increment in the strength of the PEF, led to a decrease in the viscosity of the DAS. In addition, the aldehyde group content of the DAS produced by PEF-assisted oxidation exhibited shrinkage and pits, and had a larger particle size when compared to the control increased by 11.6% when compared with the traditional oxidation method. PEF is an effective method to promote oxidation reaction of starch.

Enhanced encapsulation of lutein using soy protein isolate nanoparticles prepared by pulsed electric field and pH shifting treatment.

In this study, soy protein isolate (SPI) was modified by a pulsed electric field (PEF) combined with pH shifting treatment (10 kV/cm, pH 11) to prepare SPI nanoparticles (PSPI11) for efficient loading of lutein. The results showed that when the mass ratio of SPI to lutein was 25:1, the encapsulation efficiency of lutein in PSPI11 increased from 54% to 77%, and the loading capacity increased by 41% compared to the original SPI. The formed SPI-lutein composite nanoparticles (PSPI11-LUTNPs) had smaller, more homogeneous sizes and larger negative charges than SPI7-LUTNPs. The combined treatment favored the unfolding of the SPI structure and could expose its interior hydrophobic groups to bind with lutein. Nanocomplexation with SPIs significantly improved the solubility and stability of lutein, with PSPI11 showing the greatest improvement. As a result, PEF combined with pH shifting pretreatment is an effective method for developing SPI nanoparticles loaded and protected with lutein.

Diagnostic Performance of Dynamic Contrast-Enhanced MRI and 18F-FDG PET/CT for Evaluation of Soft Tissue Tumors and Correlation with Pathology Parameters.

RATIONALE AND OBJECTIVES: To assess the diagnostic performance of dynamic contrast-enhanced (DCE) magnetic resonance imaging (MRI) and fluorine-18-fluorodeoxyglucose (18F-FDG) positron-emission tomography/computed tomography (PET/CT) parameters in evaluating the biological behavior of soft tissue tumors. MATERIALS AND METHODS: We retrospectively analyzed DCE-MRI and 18F-FDG PET/CT parameters in 78 patients with pathology-confirmed soft tissue tumors. A total of 78 patients had undergone DCE-MRI examination, while 24 patients with malignant soft tissue tumor had undergone 18F-FDG PET/CT examination. Microvessel density (MVD) and the Ki-67 labeling index (LI) were detected using immunohistochemistry. Differences in parameters (Ktrans, Kep, Ve, MVD, and Ki-67 LI) between benign and malignant tumors were compared. Differences in parameters (Ktrans, Kep, Ve, MVD, and SUVmax) between high- and low-proliferation malignant tumors (grouped by Ki-67 LI) were compared. Correlation of the DCE-MRI and 18F-FDG PET/CT parameters with MVD and Ki-67 LI was analyzed. RESULTS: Only the Ktrans, Kep, MVD, and Ki-67 LI differed significantly between the benign and malignant soft tissue tumors (all p < 0.001). Only Kep (p = 0.033) and SUVmax (p = 0.001) differed significantly between high- and low-proliferation malignant soft tissue tumors. Ktrans, Kep, and SUVmax correlated positively with MVD (r = 0.805, 0.778, 0.730, respectively; all p < 0.001), and with Ki-67 LI (r = 0.721, 0.685, 0.655, respectively; all p < 0.001). CONCLUSION: DCE-MRI and 18F-FDG PET/CT parameters indicate soft tissue tumor biological behavior and can be used to differentiate between benign and malignant soft tissue tumors and between high- and low-proliferation malignant soft tissue tumors.

Targeted Glucose or Glutamine Metabolic Therapy Combined With PD-1/PD-L1 Checkpoint Blockade Immunotherapy for the Treatment of Tumors - Mechanisms and Strategies.

Immunotherapy, especially PD-1/PD-L1 checkpoint blockade immunotherapy, has led tumor therapy into a new era. However, the vast majority of patients do not benefit from immunotherapy. One possible reason for this lack of response is that the association between tumors, immune cells and metabolic reprogramming in the tumor microenvironment affect tumor immune escape. Generally, the limited amount of metabolites in the tumor microenvironment leads to nutritional competition between tumors and immune cells. Metabolism regulates tumor cell expression of PD-L1, and the PD-1/PD-L1 immune checkpoint regulates the metabolism of tumor and T cells, which suggests that targeted tumor metabolism may have a synergistic therapeutic effect together with immunotherapy. However, the targeting of different metabolic pathways in different tumors may have different effects on tumor immune escape. Herein, we discuss the influence of glucose metabolism and glutamine metabolism on tumor immune escape and describe the theoretical basis for strategies targeting glucose or glutamine metabolism in combination with PD-1/PD-L1 checkpoint blockade immunotherapy.