CTLs heterogeneity and plasticity: implications for cancer immunotherapy.

Cytotoxic T lymphocytes (CTLs) play critical antitumor roles, encompassing diverse subsets including CD4+, NK, and γδ T cells beyond conventional CD8+ CTLs. However, definitive CTLs biomarkers remain elusive, as cytotoxicity-molecule expression does not necessarily confer cytotoxic capacity. CTLs differentiation involves transcriptional regulation by factors such as T-bet and Blimp-1, although epigenetic regulation of CTLs is less clear. CTLs promote tumor killing through cytotoxic granules and death receptor pathways, but may also stimulate tumorigenesis in some contexts. Given that CTLs cytotoxicity varies across tumors, enhancing this function is critical. This review summarizes current knowledge on CTLs subsets, biomarkers, differentiation mechanisms, cancer-related functions, and strategies for improving cytotoxicity. Key outstanding questions include refining the CTLs definition, characterizing subtype diversity, elucidating differentiation and senescence pathways, delineating CTL-microbe relationships, and enabling multi-omics profiling. A more comprehensive understanding of CTLs biology will facilitate optimization of their immunotherapy applications. Overall, this review synthesizes the heterogeneity, regulation, functional roles, and enhancement strategies of CTLs in antitumor immunity, highlighting gaps in our knowledge of subtype diversity, definitive biomarkers, epigenetic control, microbial interactions, and multi-omics characterization. Addressing these questions will refine our understanding of CTLs immunology to better leverage cytotoxic functions against cancer.

Quantitative Assessment of Myocardial Edema by MR T2 Mapping in Children With Kawasaki Disease.

BACKGROUND: Few studies assessed myocardial inflammation using Cardiovascular Magnetic Resonance Imaging in Kawasaki disease (KD) patients. PURPOSE: To quantify myocardial edema in KD patients using T2 mapping and explore the independent predictors of T2 values. STUDY TYPE: Prospective. SUBJECTS: Ninety KD patients including 40 in acute phase (26 males, 65.0%) and 50 in chronic phase (34 males, 68.0%). Thirty-one healthy volunteers (21 males, 70.0%). FIELD STRENGTH/SEQUENCE: 3.0 T T2-weighted Turbo Spin Echo-Short Time of Inversion Recovery sequence, True fast imaging with steady precession flash sequence and fast low-angle shot 3D spoiled gradient echo sequence. ASSESSMENT: T2 values were compared among KD groups and controls. STATISTICAL TEST: Student's t test and Fisher's exact test; One-way analysis of variance; Pearson correlation analysis; Receiver operating curve analysis; Multivariable linear regression. RESULTS: Global T2 value of KD patients in acute phase was the highest, followed by those of chronic-phase patients and controls (38.83 ± 2.41 msec vs. 37.55 ± 2.28 msec vs. 36.05 ± 1.64 msec). Regional T2 values showed a same trend. There were no significant differences in global and regional T2 values between KD patients with and without coronary artery (CA) dilation, no matter in acute or chronic phase (all KD patients: P = 0.51, 0.51, 0.53, 0.72; acute KD: P = 0.61, 0.37, 0.33, 0.83; chronic KD: P = 0.65, 0.79, 0.62, 0.79). No significant difference was observed in global T2 values between KD patients with Z score > 5.0 and 2.0 < Z score ≤ 5.0 (P = 0.65). Multivariate analysis demonstrated that stage of disease (ß = -0.123) and heart rate (ß = 0.280) were independently associated with global T2 values. DATA CONCLUSION: The degree of myocardial edema was more severe in acute-phase than in chronic-phase KD patients. Myocardial edema persists in patients regardless of the existence or degree of CA dilation. EVIDENCE LEVEL: 2 TECHNICAL EFFICACY: Stage 2.

Psychiatric disorders associated with immune checkpoint inhibitors: a pharmacovigilance analysis of the FDA Adverse Event Reporting System (FAERS) database.

Background: With the increasing use of immune checkpoint inhibitors (ICIs) for tumour immunotherapy, the immune-related adverse events (irAEs) caused by their collateral effect on the immune system pose a key challenge for the clinical application of ICIs. Psychiatric adverse events are a class of adverse events associated with ICIs that are realistically observed in the real world. We aim to provide a comprehensive study and summary of psychiatric adverse events associated with ICIs. Methods: We obtained ICI adverse reaction reports during January 2012-December 2021 from the FDA Adverse Event Reporting System (FAERS) database. ICI reports underwent screening to minimize the influence of other adverse reactions, concomitant medications, and indications for medication use that may also contribute to psychiatric disorders. Disproportionality analysis was performed to find psychiatric adverse events associated with ICIs by comparing ICIs with the full FAERS database using the reporting odds ratio (ROR). Influencing factors were explored based on univariate logistic regression analysis. Finally, the Cancer Genome Atlas (TCGA) pan-cancer transcriptome data were combined to explore the potential biological mechanisms associated with ICI-related pAEs. Findings: Reports of psychiatric adverse events accounted for 2.71% of the overall ICI adverse event reports in the FAERS database. Five categories of psychiatric adverse events were defined as ICI-related psychiatric adverse events (pAEs). The median age of reports with ICI-related pAEs was 70 (interquartile range [IQR] 24-95), with 21.54% of reports having a fatal outcome. Cases with indications for lung cancer, skin cancer and kidney site cancer accounted for the majority. The odds of ICI-related pAEs increased in older patients (65-74: OR = 1.44 [1.22-1.70], P < 0.0001: ≥75: OR = 1.84 [1.54-2.20], P < 0.0001). The occurrence of ICI-related pAEs may be related to NOTCH signalling and dysregulation of synapse-associated pathways. Interpretation: This study investigated psychiatric adverse events highly associated with ICI treatment, their influencing factors and potential biological mechanisms, which provides a reliable basis for further in-depth study of ICI-related pAEs. However, as an exploratory study, our findings need to be further confirmed in a large-scale prospective study. Funding: This work was supported by the Natural Science Foundation of Guangdong Province (2018A030313846 and 2021A1515012593), the Science and Technology Planning Project of Guangdong Province (2019A030317020) and the National Natural Science Foundation of China (81802257, 81871859, 81772457, 82172750 and 82172811). Guangdong Basic and Applied Basic Research Foundation (Guangdong - Guangzhou Joint Fouds) (2022A1515111212). This work was supported by Key Research and Development Projects of Sichuan Science and Technology (2022YFS0221, 2022YFS0074, 2022YFS0156 and 2022YFS0378). Sichuan Provincial People's Hospital Hospital Young Talent Fund (2021QN08).

Computed tomography enterography-based multiregional radiomics model for differential diagnosis of Crohn's disease from intestinal tuberculosis.

PURPOSE: To build computed tomography enterography (CTE)-based multiregional radiomics model for distinguishing Crohn's disease (CD) from intestinal tuberculosis (ITB). MATERIALS AND METHODS: A total of 105 patients with CD and ITB who underwent CTE were retrospectively enrolled. Volume of interest segmentation were performed on CTE and radiomic features were obtained separately from the intestinal wall of lesion, the largest lymph node (LN), and region surrounding the lesion in the ileocecal region. The most valuable radiomic features was selected by the selection operator and least absolute shrinkage. We established nomogram combining clinical factors, endoscopy results, CTE features, and radiomic score through multivariate logistic regression analysis. Receiver operating characteristic (ROC) curves and decision curve analysis (DCA) were used to evaluate the prediction performance. DeLong test was applied to compare the performance of the models. RESULTS: The clinical-radiomic combined model comprised of four variables including one radiomic signature from intestinal wall, one radiomic signature from LN, involved bowel segments on CTE, and longitudinal ulcer on endoscopy. The combined model showed good diagnostic performance with an area under the ROC curve (AUC) of 0.975 (95% CI 0.953-0.998) in the training cohort and 0.958 (95% CI 0.925-0.991) in the validation cohort. The combined model showed higher AUC than that of the clinical model in cross-validation set (0.958 vs. 0.878, P = 0.004). The DCA showed the highest benefit for the combined model. CONCLUSION: Clinical-radiomic combined model constructed by combining CTE-based radiomics from the intestinal wall of lesion and LN, endoscopy results, and CTE features can accurately distinguish CD from ITB.

Triple-negative mouse breast cancer initiating cells show high expression of beta1 integrin and increased malignant features.

Triple-negative breast cancer (TNBC) is a subtype of breast cancer that exhibits aggressive tumor phenotypes, including rapid metastasis and tumor recurrence. Integrins belong to the family of transmembrane glycoproteins involved in regulating cell adhesion, proliferation, and differentiation through cell-cell and cell-extracellular matrix interactions. Aberrant ß1 integrin signaling has been implicated in cancer invasion and metastasis processes. The present work aimed to investigate the role of ß1 integrin in TNBC cancer progression using a mouse 4T1 cell line as a model system. We have sorted a subset of tumor-initiating cells (TICs) from the 4T1 cell line based on CD133 positivity by flow cytometry. RT-PCR and protein analysis studies showed the transcriptional upregulation of ß1 integrin and its downstream target focal adhesion kinase in 4T1-TICs compared to parental 4T1 cells. In addition, the expression of ß1 receptors in TICs is significantly higher than in parental population cells. Furthermore, in vitro cellular assays revealed that CD133+ TICs have higher clonogenic ability, invasion, and sphere formation potential. These findings suggest that ß1 integrin has a potential role in TNBC invasion and metastasis. Hence, ß1 integrin could be a possible factor for future targeted cancer therapies.

Neurosyphilis with ocular involvement and normal magnetic resonance imaging results affirmed by metagenomic next-generation sequencing.

The rapid and accurate identification of pathogenic agents is the key to guide clinicians on diagnosis and medication, especially for intractable diseases, such as neurosyphilis. It is extremely challenging for clinicians to diagnose neurosyphilis with no highly sensitive and specific test available. It is well known that the early transmission and immune evasion ability of Treponema pallidum have earned it the title of "stealth pathogen." Neurosyphilis has complex clinical manifestations, including ocular involvement, which is infrequent and often overlooked, but its neuroimaging results may be normal. Therefore, it is important to find a new test that can detect the presence or absence of Treponema pallidum immediately for the diagnosis of neurosyphilis. We reviewed all the patients admitted to the Sichuan Provincial People's Hospital between 2021 and 2022 who had ocular involvement and whose clinical samples were examined via metagenomic next-generation sequencing (mNGS), and we found 10 candidates for further analysis. The results of magnetic resonance imaging (MRI) were normal for four patients, and three of them met the diagnostic criteria for neurosyphilis confirmed by mNGS. In addition, the results of mNGS from the three patients were further validated using polymerase chain reaction (PCR). Five of the 10 patients had diplopia manifestations; two (20%) experienced abducens nerve palsies, two (20%) had eyelid drooping, and one (10%) had decreased vision. One of the 10 patients (10%) who was HIV positive and five patients had abnormal MRI results. To our knowledge, Treponema pallidum was detected by mNGS in patients with ocular involvement and normal MRI results for the first time. Given this situation, we recommend mNGS as a potential and supplementary tool for the diagnosis and differential diagnosis of neurosyphilis.

Case Report: Diagnosis of vertebral alveolar echinococcosis upon next-generation sequencing in a suspected tuberculosis.

Introduction: Alveolar echinococcosis (AE), caused by larval stages of Echinococcus multilocularis, is a rare zoonotic disease that mainly involves the liver. The diagnosis of extrahepatic AE is usually difficult. Here, we describe a rare case of vertebral alveolar echinococcosis with a suspected history of spinal tuberculosis, diagnosed by metagenomic next-generation sequencing (mNGS). Case Presentation: A 44-year-old woman presented with repetitive neck and back pain, with a surgical history of suspected spinal tuberculosis. Magnetic resonance imaging (MRI) showed cystic masses in the craniocervical junction region and effusion around lumbar vertebrae. Multiple culture tests were performed to detect tuberculosis and other pathogens through puncture of the effusion and of cerebrospinal fluid, but the results were all negative. Finally, mNGS of the effusion fluid was performed and Echinococcus multilocularis were detected. The results were further confirmed by Sanger sequencing. Conclusion: This case emphasizes a role of mNGS in the diagnosis of infectious diseases with unknown pathogen. As a newly emerged sensitive and accurate diagnostic strategy, mNGS provides clinicians an opportunity to clarify pathogens in complicated infectious cases, especially in patients with a history of multiple infections.

Development of a Nomogram Based on 3D CT Radiomics Signature to Predict the Mutation Status of EGFR Molecular Subtypes in Lung Adenocarcinoma: A Multicenter Study.

Background: This study aimed to noninvasively predict the mutation status of epidermal growth factor receptor (EGFR) molecular subtype in lung adenocarcinoma based on CT radiomics features. Methods: In total, 728 patients with lung adenocarcinoma were included, and divided into three groups according to EGFR mutation subtypes. 1727 radiomics features were extracted from the three-dimensional images of each patient. Wilcoxon test, least absolute shrinkage and selection operator regression, and multiple logistic regression were used for feature selection. ROC curve was used to evaluate the predictive performance of the model. Nomogram was constructed by combining radiomics features and clinical risk factors. Calibration curve was used to evaluate the goodness of fit of the model. Decision curve analysis was used to evaluate the clinical applicability of the model. Results: There were three, two, and one clinical factor and fourteen, thirteen, and four radiomics features, respectively, which were significantly related to each EGFR molecular subtype. Compared with the clinical and radiomics models, the combined model had the highest predictive performance in predicting EGFR molecular subtypes [Del-19 mutation vs. wild-type, AUC=0.838 (95% CI, 0.799-0.877); L858R mutation vs. wild-type, AUC=0.855 (95% CI, 0.817-0.894); and Del-19 mutation vs. L858R mutation, AUC=0.906 (95% CI, 0.869-0.943), respectively], and it has a stable performance in the validation set [AUC was 0.813 (95% CI, 0.740-0.886), 0.852 (95% CI, 0.790-0.913), and 0.875 (95% CI, 0.781-0.929), respectively]. Conclusion: Our combined model showed good performance in predicting EGFR molecular subtypes in patients with lung adenocarcinoma. This model can be applied to patients with lung adenocarcinoma.

Preliminary study on the diagnostic value of cardiac magnetic resonance feature tracking for malignant ventricular arrhythmias in non-ischemic dilated cardiomyopathy.

Background: Patients with nonischemic dilated cardiomyopathy (NIDCM) and malignant ventricular arrhythmia (MVA) often have a poor prognosis and a high risk of sudden cardiac death. Although the diagnosis of MVA is straightforward by electrocardiogram (ECG), the underlying abnormalities of ventricular mechanics in these patients are unknown. This study aims to preliminarily explore the value of cardiac magnetic resonance feature tracking (CMR-FT) for MVA in dilated cardiomyopathy. Methods: In this retrospective study, patients with NIDCM who met inclusion criteria were divided into an MVA group and a non-MVA group (included from January 2018 to September 2021). The interobserver agreement of myocardial strain parameters, including global longitudinal strain (GLS), global circumferential strain (GCS) and global radial strain (GRS), were tested. The GLS, GCS, GRS, left ventricular ejection fraction (LVEF), Tpeak-Tend interval on ECG and brain natriuretic peptide (BNP) were compared between groups. Single-factor and multifactor receiver operating characteristic (ROC) curve analyses were conducted to calculate the area under the ROC curve (AUC), cut-off point, sensitivity, and specificity of these parameters in predicting MVA in NIDCM. Results: A total of 161 NIDCM patients were included (54 in the MVA group). GLS, GCS, and GRS had good interobserver agreement (all intraclass correlation coefficients >0.80). The absolute GLS and GCS, GRS and LVEF were lower in the MVA group than the non-MVA group (P<0.001), Tpeak-Tend and BNP were higher (P<0.001). Single-factor ROC curve analysis showed that GLS, GCS and GRS had certain diagnostic value for MVA (AUC =0.795, 0.802, and 0.754, respectively). Among them, GCS had higher sensitivity and specificity (GCS 0.796/0.776, GLS 0.778/0.757, GRS 0.741/0.692). Multifactor ROC curve analysis showed the combination of GLS and GCS (AUC =0.810), the combination of GCS and GRS (AUC =0.802), the combination of GLS and GRS (AUC =0.787), the combination of GLS, GCS, and GRS (AUC =0.810). Conclusions: The three-dimensional myocardial strain parameters (especially GLS and GCS) measured by CMR-FT had certain diagnostic value and could reflect the underlying abnormality of ventricular mechanics of NIDCM with MVA.

Quantitative CT imaging features for COVID-19 evaluation: The ability to differentiate COVID-19 from non- COVID-19 (highly suspected) pneumonia patients during the epidemic period.

OBJECTIVES: COVID-19 and Non-Covid-19 (NC) Pneumonia encountered high CT imaging overlaps during pandemic. The study aims to evaluate the effectiveness of image-based quantitative CT features in discriminating COVID-19 from NC Pneumonia. MATERIALS AND METHODS: 145 patients with highly suspected COVID-19 were retrospectively enrolled from four centers in Sichuan Province during January 23 to March 23, 2020. 88 cases were confirmed as COVID-19, and 57 patients were NC. The dataset was randomly divided by 3:2 into training and testing sets. The quantitative CT radiomics features were extracted and screened sequentially by correlation analysis, Mann-Whitney U test, the least absolute shrinkage and selection operator (LASSO) logistic regression (LR) and backward stepwise LR with minimum AIC methods. The selected features were used to construct the LR model for differentiating COVID-19 from NC. Meanwhile, the differentiation performance of traditional quantitative CT features such as lesion volume ratio, ground glass opacity (GGO) or consolidation volume ratio were also considered and compared with Radiomics-based method. The receiver operating characteristic curve (ROC) analysis were conducted to evaluate the predicting performance. RESULTS: Compared with traditional CT quantitative features, radiomics features performed best with the highest Area Under Curve (AUC), sensitivity, specificity and accuracy in the training (0.994, 0.942, 1.0 and 0.965) and testing sets (0.977, 0.944, 0.870, 0.915) (Delong test, P < 0.001). Among CT volume-ratio based models using lesion or GGO component ratio, the model combining CT lesion score and component ratio performed better than others, with the AUC, sensitivity, specificity and accuracy of 0.84, 0.692, 0.853, 0.756 in the training set and 0.779, 0.667, 0.826, 0.729 in the testing set. The significant difference of the most selected wavelet transformed radiomics features between COVID-19 and NC might well reflect the CT signs. CONCLUSIONS: The differentiation between COVID-19 and NC could be well improved by using radiomics features, compared with traditional CT quantitative values.

Single-Cell Analysis Reveals Spatial Heterogeneity of Immune Cells in Lung Adenocarcinoma.

The impacts of the tumor microenvironment (TME) on tumor evolvability remain unclear. A challenge for nearly all cancer types is spatial heterogeneity, providing substrates for the emergence and evolvability of drug resistance and leading to unfavorable prognosis. Understanding TME heterogeneity among different tumor sites would provide deeper insights into personalized therapy. We found 9,992 cell profiles of the TME in human lung adenocarcinoma (LUAD) samples at a single-cell resolution. By comparing different tumor sites, we discovered high TME heterogeneity. Single-sample gene set enrichment analysis (ssGSEA) was utilized to explore functional differences between cell subpopulations and between the core, middle and edge of tumors. We identified 8 main cell types and 27 cell subtypes of T cells, B cells, fibroblasts and myeloid cells. We revealed CD4+ naive T cells in the tumor core that express high levels of immune checkpoint molecules and have a higher activity of immune-exhaustion signaling. CD8+ T cell subpopulations in the tumor core correlate with the upregulated activity of transforming growth factor-ß (TGF-ß) and fibroblast growth factor receptor (FGFR) signaling and downregulated T cell activity. B cell subtypes in the tumor core downregulate cytokine production. In this study, we revealed that there was immunological heterogeneity in the TME of patients with LUAD that have different ratios of immune cells and stromal cells, different functions, and various degrees of activation of immune-related pathways in different tumor parts. Therefore, clarifying the spatial heterogeneity of the tumor in the immune microenvironment can help clinicians design personalized treatments.

How to optimize the Radiology protocol during the global COVID-19 epidemic: Keypoints from Sichuan Provincial People's Hospital.

Currently, the COVID-19 pneumonia epidemic is spreading worldwide. Pulmonary imaging plays an important role. The pulmonary imaging (chest computed tomography and Digital radiography) are indispensable for definitive diagnosis and reexamination. It should be noted that nosocomial infection is not uncommon. Many cases including health workers are infected. This is the experience of our radiology department's protocols during the outbreak, we used this protocol to cope with the COVID-19 in Sichuan Province， besides，there is zero infection for health workers during the whole epidemic. So, we would like to share our experience to other radiologists to avoid the nosocomial infection as low as possible. We have six key points for updating the protocol in the epidemic period of COVID-19: 1. Triage system: three-level triage, 2. Maximum Protection Principle, 3. Technical operation principle: careful, fast and stable, 4. Radiologist's Responsibility and Notice, 5. Disinfection measures of machine room, 6. Hospital information construction, network office, accelerate the sharing of imaging, and carry out MDT consultation.

Experimental study of detection of nodules showing ground-glass opacity and radiation dose by using anthropomorphic chest phantom: digital tomosynthesis and multidetector CT.

OBJECTIVE: The purpose of this study was to compare chest digital tomosynthesis (DTS) and multidetector computed tomography (MDCT) for the detection of pulmonary ground-glass opacity (GGO) nodules and estimation of radiation dose using an anthropomorphic chest phantom and simulated nodules. MATERIALS AND METHODS: A male anthropomorphic chest phantom equipped with thermoluminescent dosimeters and simulated pulmonary nodules showing GGO was scanned by MDCT and DTS. The organic radiation doses were recorded and converted into effective doses. The density, diameter, and position of pulmonary nodules were reviewed; and the sensitivities of nodule detection were compared using the Fisher exact test. The radiation dose levels of DTS and MDCT were compared using paired t tests. RESULTS: The sensitivities of nodule detection by DTS and MDCT were 60% and 80%, respectively (P < 0.05), whereas the sensitivities of detection of -630-Hounsfield unit (HU) GGO nodules were 73.3% and 86.7%, respectively (P > 0.05), and the detection sensitivities of 5- and 8-mm diameter -800 HU GGO nodules were 33.3% and 58.3%, respectively (P < 0.05). The effective doses of DTS and MDCT were 0.65 and 7.71 mSv, respectively, and the mean effective dose of DTS for the chest was 91.6% lower than that of MDCT. CONCLUSION: Multidetector computed tomography is preferable to DTS for the detection of GGO pulmonary nodules. Although the detection sensitivities of DTS and MDCT were similar for the nodules with a density of -630 HU, the detection sensitivity of MDCT was significantly superior to that of DTS for the 5- and 8-mm nodules with a density of -800 HU. The mean effective dose of DTS to the chest was significantly lower than that of MDCT.

Organ dose evaluation for multi-slice spiral CT scans based on China Sichuan chest anthropomorphic phantom measurements.

The authors measured organ radiation doses during multi-slice computed tomography (MSCT) chest scans using a China Sichuan anthropomorphic phantom (CDP-1C). Chest CT images from live volunteers based on automatic tube current modulation (ATCM) techniques were similar to those obtained using the CDP-1C phantom, indicating that the phantom accurately modelled the anatomic structure and X-ray absorbance of the human torso. Indeed, attenuation values differed by <5%. Organ radiation doses were measured using thermoluminescence dosemeters in the CDP-1C. With increased noise index, the CT dose index, the dose-length product and the average organ dose all decreased. Thus, the CDP-1C phantom can also assess dose levels during CT examinations in Chinese patients. The noise index (based on ATCM techniques) should be set to 8.5 or higher to reduce X-ray exposure while maintaining appropriate resolution for diagnosis.