Research on the correction method for radiotherapy verification plans based on displaced electronic portal imaging device.

BACKGROUND: It has been observed that under the single isocenter conditions, the potential shifts of the electronic portal imaging devices (EPID) may be introduced when executing portal dosimetry (PD) plans for bilateral breast cancer, pleural mesothelioma, and lymphoma. These shifts are relative to the calibration positions of EPID and result in significant discrepancies in the plan verification results. PURPOSE: To explore methods including correction model and specific correction matrices to revise the data obtained from displaced EPID. METHODS: Two methods, the correction model and the specific correction matrices, were applied to correct the data. Five experiments were designed and conducted to build correction model and to validate the effectiveness of these two methods. Gamma passing rates were calculated and data profiles along X-axis and Y-axis were captured. RESULTS: The gamma passing rates for the EPID-displaced IMRT validation plans after applying correction model, along with the application of specific correction matrices to VMAT and IMRT validation plans, exhibit results that are comparable to the cases with non-displaced EPID. Except for the VMAT plans applied correction model which showed larger discrepancies (0.041 ± 0.028, 0.049 ± 0.030), the other three exhibit minimal differences in discrepancy values. In all profiles, the corrected data from displaced EPID exhibit a high level of agreement with data obtained from non-displaced EPID. Good consistency is observed in actual application of the correction model and the specific correction matrices between gamma passing rates of data corrected and those of non-displaced data. CONCLUSIONS: The proposed methods involving correction model and specific correction matrices can correct the data collected from the displaced EPID, and the gamma passing rates of the corrected data show results that are comparable to some extent with those of non-displaced data. Particularly, the results corrected by specific correction matrices closely resemble the data from non-displaced EPID.

CT imaging-based radiomics signatures improve prognosis prediction in postoperative colorectal cancer.

OBJECTIVE: To investigate the use of non-contrast-enhanced (NCE) and contrast-enhanced (CE) CT radiomics signatures (Rad-scores) as prognostic factors to help improve the prediction of the overall survival (OS) of postoperative colorectal cancer (CRC) patients. METHODS: A retrospective analysis was performed on 65 CRC patients who underwent surgical resection in our hospital as the training set, and 19 patient images retrieved from The Cancer Imaging Archive (TCIA) as the external validation set. In training, radiomics features were extracted from the preoperative NCE/CE-CT, then selected through 5-fold cross validation LASSO Cox method and used to construct Rad-scores. Models derived from Rad-scores and clinical factors were constructed and compared. Kaplan-Meier analyses were also used to compare the survival probability between the high- and low-risk Rad-score groups. Finally, a nomogram was developed to predict the OS. RESULTS: In training, a clinical model achieved a C-index of 0.796 (95% CI: 0.722-0.870), while clinical and two Rad-scores combined model performed the best, achieving a C-index of 0.821 (95% CI: 0.743-0.899). Furthermore, the models with the CE-CT Rad-score yielded slightly better performance than that of NCE-CT in training. For the combined model with CE-CT Rad-scores, a C-index of 0.818 (95% CI: 0.742-0.894) and 0.774 (95% CI: 0.556-0.992) were achieved in both the training and validation sets. Kaplan-Meier analysis demonstrated a significant difference in survival probability between the high- and low-risk groups. Finally, the areas under the receiver operating characteristics (ROC) curves for the model were 0.904, 0.777, and 0.843 for 1, 3, and 5-year survival, respectively. CONCLUSION: NCE-CT or CE-CT radiomics and clinical combined models can predict the OS for CRC patients, and both Rad-scores are recommended to be included when available.

SLCO4A1-AS1 promotes colorectal tumourigenesis by regulating Cdk2/c-Myc signalling.

BACKGROUND: SLCO4A1-AS1 was found to be upregulated in several cancer types, including colorectal cancer (CRC). However, the detailed roles of SLCO4A1-AS1 in CRC remain to be elucidated. Therefore, we investigated the functions, mechanism, and clinical significance of SLCO4A1-AS1 in colorectal tumourigenesis. METHODS: We measured the expression of SLCO4A1-AS1 in CRC tissues using qRT-PCR and determined its correlation with patient prognosis. Promoter methylation analyses were used to assess the methylation status of SLCO4A1-AS1. Gain- and loss-of-function assays were used to evaluate the effects of SLCO4A1-AS1 on CRC growth in vitro and in vivo. RNA pull-down, RNA immunoprecipitation, RNA-seq, luciferase reporter and immunohistochemistry assays were performed to identify the molecular mechanism of SLCO4A1-AS1 in CRC. RESULTS: SLCO4A1-AS1 was frequently upregulated in CRC tissues based on multiple CRC cohorts and was associated with poor prognoses. Aberrant overexpression of SLCO4A1-AS1 in CRC is partly attributed to the DNA hypomethylation of its promoter. Ectopic SLCO4A1-AS1 expression promoted CRC cell growth, whereas SLCO4A1-AS1 knockdown repressed CRC proliferation both in vitro and in vivo. Mechanistic investigations revealed that SLCO4A1-AS1 functions as a molecular scaffold to strengthen the interaction between Hsp90 and Cdk2, promoting the protein stability of Cdk2. The SLCO4A1-AS1-induced increase in Cdk2 levels activates the c-Myc signalling pathway by promoting the phosphorylation of c-Myc at Ser62, resulting in increased tumour growth. CONCLUSIONS: Our data demonstrate that SLCO4A1-AS1 acts as an oncogene in CRC by regulating the Hsp90/Cdk2/c-Myc axis, supporting SLCO4A1-AS1 as a potential therapeutic target and prognostic factor for CRC.

Sublethal irradiation promotes the metastatic potential of hepatocellular carcinoma cells.

Radiotherapy (RT) represents one of the major treatment methods for cancers. However, many studies have observed that in descendant surviving tumor cells, sublethal irradiation can promote metastatic ability, which is closely related to the tumor microenvironment. We therefore investigated the functions and mechanisms of sublethal irradiated liver nonparenchymal cells (NPCs) in hepatocellular carcinoma (HCC). In this study, primary rat NPCs and McA-RH7777 hepatoma cells were irradiated with 6 Gy X-ray. Conditioned media (CM) from nonirradiated (SnonR), irradiated (SR), or irradiated plus radiosensitizer celecoxib-treated (S[R + D]) NPCs were collected and added to sublethal irradiated McA-RH7777 cells. We showed that CM from sublethal irradiated NPCs significantly promoted the migration and invasion ability of sublethal irradiated McA-RH7777 cells, which was reversed by celecoxib. The differentially expressed genes in differently treated McA-RH7777 cells were enriched mostly in the AMP-activated protein kinase/mammalian target of rapamycin (AMPK/mTOR) signaling pathway. SR increased the migration and invasion ability of HCC cells by inhibiting AMPK/mTOR signaling, which was enhanced by the AMPK inhibitor compound C and blocked by the AMPK activator GSK-621. Analyses of HCC tissues after neoadjuvant radiotherapy confirmed the effects of radiation on the AMPK/mTOR pathway. Cytokine antibody arrays and further functional investigations showed that matrix metalloproteinase-8 (MMP-8) partly mediates the promotion effects of SR on the migration and invasion ability of HCC cells by regulating AMPK/mTOR signaling. In summary, our data indicate that MMP-8 secreted by irradiated NPCs enhanced the migration and invasion of HCC by regulating AMPK/mTOR signaling, revealing a novel mechanism mediating sublethal irradiation-induced HCC metastasis at the level of the tumor microenvironment.

Effect of sequencing of preoperative systemic therapy on patients with locally advanced breast cancer.

BACKGROUND: The study aims to perform a clinical trial to evaluate the effect of sequencing of systemic therapy on locally advanced breast cancer (LABC). METHODS: LABC patients (n = 733) underwent the combination of external beam radiation therapy, chemotherapy, and breast-conservation surgery with difference sequences. Biopsy followed by histopathological examinations was used to assess treatment responses. The primary end point is ipsilateral local recurrence or death. The secondary end points include the incidence and severity of acute and late side effects, cosmesis, and cumulative incidence of regional recurrence and distant metastasis, and survival. The effects of sequence of therapies on the side effects and treatment outcomes were compared. RESULTS: Patients with preoperative systemic treatment, that is, chemotherapy and radiotherapy performed ahead of surgery, had less fibrosis and pain, and showed higher satisfaction regarding the breast conservation. Preoperative systemic treatment also led to better survival of the patients. CONCLUSIONS: Preoperative systemic therapy is beneficial to alleviate side effects and improve the breast conservation, treatment outcome, and survival of LABC patients.

The poly (ADP-ribose) polymerase inhibitor rucaparib suppresses proliferation and serves as an effective radiosensitizer in cervical cancer.

Objectives Our goal was to investigate the effects of rucaparib on the proliferation of cervical cancer cells and sensitivity to radiotherapy. Methods We used the human cervical cancer cell lines Hela and Siha and evaluated their viability and activity using various methods. Cellular proliferation was assessed by CCK-8 and clonogenic assays after treatment with rucaparib. Cell cycle analysis was performed using propidium iodide staining. Western immunoblotting analysis was used to detect the expression of cyclin D1 and CDK4. Immunofluorescence staining assay was performed to detect the expression of the DNA injury marker ×¥-H2AX after treatment with rucaparib and radiotherapy. Animal experiments were also performed to evaluate tumor size after treatment with rucaparib. Immunohistochemistry was performed to analyze the expression of Ki-67. Results Rucaparib suppressed proliferation, induced G2/M phase arrest, and reduced the expression of cyclin D1 and CDK4 in cervical cancer cells. When rucaparib was combined with radiotherapy in cervical cancer cells, clone formation decreased significantly and G2/M phase arrest was accentuated. The expression of the DNA-damage marker ×¥-H2AX was increased significantly, and rucaparib suppressed tumor growth in vivo. Conclusions Rucaparib exerts significant anti-proliferative effects and can serve as an effective radiosensitizer in cervical cancer, suggesting its candidacy in cervical cancer treatment and worthiness for further investigation.

A Novel Distributed Multitask Fuzzy Clustering Algorithm for Automatic MR Brain Image Segmentation.

Artificial intelligence algorithms have been used in a wide range of applications in clinical aided diagnosis, such as automatic MR image segmentation and seizure EEG signal analyses. In recent years, many machine learning-based automatic MR brain image segmentation methods have been proposed as auxiliary methods of medical image analysis in clinical treatment. Nevertheless, many problems regarding precise medical images, which cannot be effectively utilized to improve partition performance, remain to be solved. Due to the poor contrast in grayscale images, the ambiguity and complexity of MR images, and individual variability, the performance of classic algorithms in medical image segmentation still needs improvement. In this paper, we introduce a distributed multitask fuzzy c-means (MT-FCM) clustering algorithm for MR brain image segmentation that can extract knowledge common among different clustering tasks. The proposed distributed MT-FCM algorithm can effectively exploit information common among different but related MR brain image segmentation tasks and can avoid the negative effects caused by noisy data that exist in some MR images. Experimental results on clinical MR brain images demonstrate that the distributed MT-FCM method demonstrates more desirable performance than the classic signal task method.

Down-regulation of SNX1 predicts poor prognosis and contributes to drug resistance in colorectal cancer.

As a potential tumor suppressor, the detailed clinical application value of sorting nexin 1 (SNX1) has not been elucidated in colorectal cancer (CRC). The aim of the present study was to evaluate the expression of SNX1 in CRC tissues and to determine its correlation with clinicopathologic characteristics and its impact on patient's prognosis. We detected the expression of SNX1 mRNA in 72 CRC patients and SNX1 protein in 237 CRC patients by real-time polymerase chain reaction (RT-PCR) and immunohistochemical staining, respectively. Relationship between the expression of SNX1 and various clinicopathological features in these patients was evaluated. Both the mRNA and protein expression of SNX1 were remarkably decreased in CRC tissues compared with paired non-cancerous tissues, and the down-regulation of SNX1 protein was strongly associated with poor differentiation and poor overall survival (OS) rate of CRC patients. Ectopic SNX1 expression repressed CRC cell growth and promoted tumor sensitivity to most commonly used chemotherapeutic drugs (oxaliplatin and 5-Fluorouracil). In conclusion, overexpression of SNX1 may serve as a new therapeutic strategy for CRC.

TLR4-dependant immune response, but not hepatitis B virus reactivation, is important in radiation-induced liver disease of liver cancer radiotherapy.

Toll-like receptor 4 (TLR4) is an important trigger of the immune response against hepatitis B virus (HBV) infection and liver injuries. The roles of HBV reactivation versus TLR4-dependant immune response may be critical factors in preventing radiation-induced liver diseases (RILDs) after liver cancer radiotherapy. This study consists of three phases. In the primary phase, livers of mutant TLR4 (TLR4(-)) mice were irradiated with 30 Gy in either the absence or presence of HBV infection. The latter was done by introduction of plasmid pAAV/HBV 1.2. In the advanced phase, RILDs were compared in normal TLR4 (TLR4(+)) versus TLR4(-) mice. In the validation phase, 28 liver cancer patients who had undergone radiotherapy before hepatectomy were enrolled. Liver biopsies near tumors, irradiated with 35-48 Gy, were used to construct tissue microarrays. HBV reactivation, TLR4 expression, and severity of RILDs were studied in both mouse and human. More HBV reactivation, without significant RILD, was observed in irradiated versus unirradiated TLR4(-) mice. RILD scores of TLR4(+) mice were higher than TLR4(-) mice. In humans, serious RILDs tended to develop in patients with high TLR4 expression, but not in patients with low TLR4 or high HBV surface antigen expression. High TLR4 expression was seen in only 2 of 12 HBV-reactive patients, but in HBV-nonreactive patients, it was seen in 6 of 9 (P < 0.03). In summary, RILDs correlated with high TLR4 expression, but not with HBV reactivation, which is inhibited in liver with high TLR4 expression after liver cancer radiotherapy.

Radiotherapy treatment of adrenal gland metastases from hepatocellular carcinoma: clinical features and prognostic factors.

BACKGROUND: The optimal treatment for adrenal metastases from hepatocellular carcinoma (HCC) has not been established. This study analyzed the effects of radiation therapy (RT) for such metastases and identified clinical features and predictors of survival in these patients. METHODS: We retrospectively investigated 55 patients with adrenal metastasis from HCC who had been treated with RT. Radiation doses to the adrenal lesions ranged from 26 to 60 Gy, while the intrahepatic lesions were treated by surgical resection, transarterial chemoembolization (TACE), liver transplantation, and/or RT. RT was conducted to adrenal lesions after their intrahepatic lesions were controlled more than 2 months. The parameters studied included survival rates and tumor responses to RT. The Kaplan-Meier method was used to evaluate survival rate and the Cox regression model was used to identify potential predictors of outcome. RESULTS: The patients treated by RT had adrenal metastasis on the right side (41), the left (6), or on both sides (8). In all 55 patients, the median survival duration was 13.6 months and there was 100% pain relief after completion of RT. Adverse effects were mild to moderate. Unfavorable pretreatment predictors determined by univariate analysis were associated with multiple intrahepatic foci, metastases to additional organs, high γ-glutamyltransferase and alpha-fetoprotein levels, liver function of Child-Pugh classification B and uncontrolled primary HCC. By multivariate analysis, unfavorable predictors were multiple intrahepatic foci, metastases to additional organs and uncontrolled primary HCC. CONCLUSIONS: Radiotherapy as treatment for adrenal metastases in HCC is a good palliative therapy that is associated with reasonable safety. It appears reasonable that such patients should be considered to be treated with radiotherapy. Multiple intrahepatic foci, metastases to additional organs and uncontrolled primary HCC were unfavorable predictors.

Recombinant canstatin inhibits the progression of hepatocellular carcinoma by repressing the HIF-1α/VEGF signaling pathway.

Hepatocellular carcinoma (HCC), a hypervascular tumor, is the most frequent primary malignant tumor of the liver. Angiogenesis inhibitors, such as endogenous angiogenesis inhibitors, are essential for HCC therapy and have generated significant interest owing to their safety, efficacy, and multitargeting attributes. Canstatin is an angiogenesis inhibitor derived from the basement membrane and exerts anti-tumor effects. However, the inhibitory effects and underlying mechanisms of action of canstatin on HCC remain unclear. Therefore, in this study, HepG2 and Huh7 cells were used to investigate the inhibitory effects of recombinant canstatin on HCC cells. Subsequently, the biosafety and inhibitory effects of recombinant canstatin on tumor growth were investigated in a xenograft animal model of liver cancer. Canstatin inhibited the growth of liver cancer cells by regulating their proliferation, apoptosis, and migration. Additionally, it suppressed the occurrence and progression of HCC by modulating the HIF-1α/VEGF signaling pathway. In mice, canstatin exerted no discernible harmful side effects and suppressed the growth of HCC subcutaneous xenograft tumors. Overall, our findings shed light on the molecular pathways underlying canstatin-induced HCC cell death that may help develop novel HCC treatments.

External-beam radiotherapy after transarterial chemoembolization (TACE) versus TACE alone for treatment of inoperable HCC: A randomized phase III trial.

PURPOSE: To compare the outcomes of transarterial chemoembolization (TACE) alone with those of TACE combined with external-beam radiotherapy (EBRT) in patients with hepatocellular carcinoma (HCC) in a multicenter randomized study. METHODS AND MATERIALS: From 2017 to 2022, 74 HCC patients with tumors confined to the liver without vascular invasion were treated with either TACE only (TACE group, 39 patients) or TACE combined with EBRT (TACE+EBRT group, 35 patients). The primary outcome measured was overall survival (OS). Secondary outcomes included progression-free survival (PFS), local tumor control (LC), and the assessment of treatment-related toxicity. RESULTS: Due to slow accrual, the trial was closed prematurely after enrolling 74 patients. All patients received two cycles of TACE before randomization. The TACE and TACE+EBRT groups showed comparable patient and tumor characteristics. The TACE group underwent an median of 3 TACE cycles, and the TACE+EBRT group received two cycles of TACE and a median of 5,500 cGy in 15 fractions. For the TACE group, the median LC duration was 13.1 months, while for the TACE+EBRT group, the median LC was not achieved (P<0.001). The PFS was recorded at 11.6 months in the TACE group compared to 15.4 months in the TACE+EBRT group (P=0.072). The median OS reached 36.8 months for the TACE group and extended to 47.1 months for the TACE+EBRT group (P=0.654). The incidence of toxicity was comparable between both groups. CONCLUSIONS: Although the number of patients enrolled in this clinical trial did not meet expectations. TACE combined with EBRT was shown to be more effective than TACE alone in improving local control (LC) without increasing toxicity, while PFS and OS was slightly improved. TACE+EBRT can be used as a standard treatment option for patients with inoperable but confined intrahepatic HCC.

New insights into the characteristic skin microorganisms in different grades of acne and different acne sites.

Background: The increasing maturity of sequencing technology provides a convenient approach to studying the role of skin microorganisms in acne pathogenesis. However, there are still too few studies about the skin microbiota of Asian acne patients, especially a lack of detailed analysis of the characteristics of the skin microbiota in the different acne sites. Methods: In this study, a total of 34 college students were recruited and divided into the health, mild acne, and severe acne groups. The bacterial and fungal flora of samples were separately detected by 16S and 18S rRNA gene sequencing. The biomarkers of different acne grades and different acne sites [forehead, cheek, chin, torso (including chest and back)] were excavated. Results and Discussion: Our results indicated that there was no significant difference in species diversity between groups. The genera like Propionibacterium, Staphylococcus, Corynebacterium, and Malassezia, which have a relatively high abundance in the skin microbiota and were reported as the most acne-associated microbes, were no obvious differences between groups. On the contrary, the abundance of less reported Gram-negative bacteria (Pseudomonas, Ralstonia, and Pseudidiomarina) and Candida has a significant alteration. Compared with the health group and the mild group, in the severe group, the abundance of Pseudomonas and Ralstonia sharply reduced while that of Pseudidiomarina and Candida remarkably raised. Moreover, different acne sites have different numbers and types of biomarkers. Among the four acne sites, the cheek has the greatest number of biomarkers including Pseudomonas, Ralstonia, Pseudidiomarina, Malassezia, Saccharomyces, and Candida, while no biomarker was observed for the forehead. The network analysis indicated that there might be a competitive relationship between Pseudomonas and Propionibacterium. This study would provide a new insight and theoretical basis for precise and personalized acne microbial therapy.

Mitigating misalignment in MRI-to-CT synthesis for improved synthetic CT generation: an iterative refinement and knowledge distillation approach.

Objective.Deep learning has shown promise in generating synthetic CT (sCT) from magnetic resonance imaging (MRI). However, the misalignment between MRIs and CTs has not been adequately addressed, leading to reduced prediction accuracy and potential harm to patients due to the generative adversarial network (GAN)hallucination phenomenon. This work proposes a novel approach to mitigate misalignment and improve sCT generation.Approach.Our approach has two stages: iterative refinement and knowledge distillation. First, we iteratively refine registration and synthesis by leveraging their complementary nature. In each iteration, we register CT to the sCT from the previous iteration, generating a more aligned deformed CT (dCT). We train a new model on the refined 〈dCT, MRI〉 pairs to enhance synthesis. Second, we distill knowledge by creating a target CT (tCT) that combines sCT and dCT images from the previous iterations. This further improves alignment beyond the individual sCT and dCT images. We train a new model with the 〈tCT, MRI〉 pairs to transfer insights from multiple models into this final knowledgeable model.Main results.Our method outperformed conditional GANs on 48 head and neck cancer patients. It reduced hallucinations and improved accuracy in geometry (3% ↑ Dice), intensity (16.7% ↓ MAE), and dosimetry (1% ↑γ3%3mm). It also achieved <1% relative dose difference for specific dose volume histogram points.Significance.This pioneering approach for addressing misalignment shows promising performance in MRI-to-CT synthesis for MRI-only planning. It could be applied to other modalities like cone beam computed tomography and tasks such as organ contouring.

Application value of 3D pCASL in early assessment of potential radiation encephalopathy in nasopharyngeal carcinoma patients undergoing radiotherapy.

OBJECTIVE: The study explores the application value of three-dimensional arterial spin labeling magnetic resonance imaging (3D pCASL) in early assessment of radiation encephalopathy (REP) in patients with nasopharyngeal carcinoma (NPC). METHODS: A retrospective analysis of 39 cases of NPC was performed. Routine enhanced MRI scan and 3D pCASL imaging were used to examine the apparent diffusion coefficient (ADC) and brain blood flow (CBF) before and after treatment with intensity-modulated radiotherapy (IMRT). Dosimetric analysis of irradiation was performed. Receiver operating characteristic curve (ROC) was used to analyze diagnostic performance of two imaging methods. RESULTS: There was no statistically significant difference between the two methods for the measurement of temporal white matter ADC, but statistically significant difference was found in CBF. 3D pCASL imaging showed more sensitivity, specificity and higher accuracy than conventional MRI enhanced scan in showing REP. The maximum dose of the temporal lobe was at the enhanced area. CONCLUSION: The present study demonstrates that 3D pCASL scan at month 3 can reflect blood flow perfusion differences in NPC patients after IMRT and can accurately assess the possibility of REP at early stage. Enhanced areas have a higher probability of REP than the surrounding areas. ADVANCES IN KNOWLEDGE: There is few magnetic resonance angiography studies used to evaluate arterial circulation on its application on potential REP after radiotherapy for NPC. In our study, we evaluate the application value of 3D pCASL in the early assessment of potential REP in patients with NPC after radiotherapy. The study was to provide an improved understanding of the early specific characteristics on MRI imaging and evolution of potential radiation encephalopathy using 3D pCASL technique, which can quantitatively evaluate the changes of blood flow in tissues at early stage and help to diagnose and treat potential radiation encephalopathy as early as possible.

IRF7 and IFIT2 in mediating different hemorrhage outcomes for non-small cell lung cancer after bevacizumab treatment.

Background: Lung cancer has some of the highest morbidity and mortality worldwide among cancers, with non-small cell lung cancer (NSCLC) accounting for 85% of lung cancer diagnoses. Severe pulmonary hemorrhage (PH) is a serious potential adverse event in the treatment of lung cancer with bevacizumab. Significant clinical differences have been observed between patients with lung adenocarcinoma (LUAD) and those with lung squamous cell carcinoma (LUSC) after bevacizumab treatment; however, the underlying causes is unclear and requires further study. Methods: First, tumor tissues from LUAD and LUSC patients were stained with antibodies targeting CD31 and CD34 to assess the difference in microvessel density (MVD). Tube formation assays were performed using HMEC-1 cells cocultured with lung cancer cells. Single-cell sequencing data obtained from lung cancer tissues were then downloaded and analyzed to identify differentially expressed genes related to angiogenesis in LUAD and LUSC tumors. Real-time polymerase chain reaction, immunofluorescence analysis, small interfering RNA analysis, and enzyme-linked immunosorbent assay were performed to clarify the underlying causes. Results: The MVD of LUAD tissues was higher than that of LUSC tissues. Additionally, endothelial cells cocultured with LUAD cells had a higher MVD than did those cocultured with LUSC cells. Although bevacizumab mainly targets vascular endothelial growth factor (VEGF), the expression of VEGF in LUSC and LUAD cells was not significantly different (P>0.05). Further experiments showed that interferon regulatory factor 7 (IRF7) and interferoninduced protein with tetratricopeptide repeats 2 (IFIT2) were differentially expressed between LUSC and LUAD tumors. Higher IRF7 levels and lower IFIT2 levels in LUAD tumors were associated with higher MVD in LUAD tissues, which may be responsible for the different hemorrhage outcomes after bevacizumab treatment. Conclusions: Our data indicated that IRF7 and IFIT2 may account for the differential hemorrhage outcomes in patients with NSCLC after bevacizumab treatment, revealing a new mechanism underlying bevacizumab-induced pulmonary hemoptysis.

Low-dose radiotherapy promotes the formation of tertiary lymphoid structures in lung adenocarcinoma.

Purpose: A tertiary lymphoid structure (TLS) refers to an organized infiltration of immune cells that is linked to a positive prognosis and improved response to immunotherapy. However, methods that promote TLS formation are limited and challenging to implement in clinical settings. In this study, we aimed to promote the formation and maturation of TLSs in lung adenocarcinoma (LUAD) by combining low-dose radiotherapy (LDRT) with immunotherapy. Methods: Tissue sections from 198 patients who had undergone surgery were examined. Risk factors for patient survival were assessed, and the relationship between TLSs and five-year survival was analyzed. The Kras-LSL-G12D spontaneous lung cancer mouse model was used to screen the optimal irradiation dose (0/1/2 Gy whole lung irradiation) for promoting TLS formation. LDRT combined with anti-PD-1 was used to promote the formation and maturation of TLSs. Results: TLS+, TLSHigh, TLS+GC+ and CD8High within TLS+ were associated with a favorable prognosis. LDRT increased the formation of early TLSs in the Kras-LSL-G12D lung cancer mouse model. In addition, LDRT combined with anti-PD-1 treatment can significantly improve the maturity of TLSs in mouse LUAD, resulting in greater antitumor effects. This antitumor effect was strongly associated with the number of CD8+ T cells within the TLSs. Conclusion: We successfully applied LDRT combined with PD-1 inhibitor therapy for the first time, which increased both the quantity and maturity of TLSs in lung cancer. This approach achieved a promising antitumor effect.

Colorectal Cancer-Derived Small Extracellular Vesicles Promote Tumor Immune Evasion by Upregulating PD-L1 Expression in Tumor-Associated Macrophages.

Tumor-associated macrophages (TAMs) are one of the most abundant cell types in colorectal cancer (CRC) tumor microenvironment (TME). Recent studies observed complicated "cross-talks" between cancer cells and macrophages in TME. However, the underlying mechanisms are still poorly elucidated. Here, PD-L1 levels are very low in CRC cells but highly abundant in TAMs, and a specific PD-L1+CD206+ macrophage subpopulation are identified, which is induced by tumor cells and associated with a poor prognosis. Mechanistic investigations reveal that CRC cells can secrete small extracellular vesicles (sEVs) taken up by macrophages that induce M2 like polarization and PD-L1 expression, resulting in increased PD-L1+CD206+ macrophage abundance and decreased T cell activity in CRC TME. sEV-derived miR-21-5p and miR-200a are identified as key signaling molecules mediating the regulatory effects of CRC on macrophages. Further studies reveal that CRC-derived miR-21-5p and miR-200a synergistically induces macrophage M2 like polarization and PD-L1 expression by regulating the PTEN/AKT and SCOS1/STAT1 pathways, resulting in decreased CD8+ T cell activity and increased tumor growth. This study suggests that inhibiting the secretion of specific sEV-miRNAs from CRC and targeting PD-L1 in TAMs may serve as novel methods for CRC treatment as well as a sensitization method for anti-PD-L1 therapy in CRC.

Caffeine does not enhance radiosensitivity of normal liver tissue in vivo.

The aim of this study was to determine whether caffeine enhanced radiosensitivity of normal liver tissue in a rat radiation-induced liver disease model. Buffalo rat McA-RH7777 hepatocellular cancer cells and BRL3A normal liver cells were irradiated, and cell cycle distribution and apoptosis rates were analyzed. A rat model of radiation-induced liver disease was established, rats were randomized into four groups: control; caffeine alone; irradiation (IR) alone; and caffeine plus IR (Caff + IR) group. Apoptosis rates in normal rat liver tissue after IR were evaluated by TUNEL staining and caspase-3 Western blot. Transaminase activity was measured and histopathological examination was done after IR. Caffeine abrogated IR-induced G2 phase arrest (Caff + IR vs. IR: 40.9 ± 4.0 vs. 60.7 ± 5.5%, at 12 h after IR) and increased apoptosis rates (Caff + IR vs. IR: 56.1 ± 6.8 vs. 35.5 ± 4.0%, at 72 h after IR) in McA-RH7777 cells, but did not affect IR-induced G2 phase arrest and apoptosis rates at any time point after IR in BRL3A cells. Caffeine did not enhance apoptosis, transaminase activity, or histopathological injury of normal rat liver tissue at any time points after IR. This study suggests that caffeine might not enhance radiosensitivity of normal liver tissue in vivo. In an earlier study, we reported that caffeine enhanced radiosensitivity of human hepatocellular cancer in a nude mice model. Together, these results offer feasibility of clinical application.

Identification of Epileptic EEG Signals Through TSK Transfer Learning Fuzzy System.

We propose a new model to identify epilepsy EEG signals. Some existing intelligent recognition technologies require that the training set and test set have the same distribution when recognizing EEG signals, some only consider reducing the marginal distribution distance of the data while ignoring the intra-class information of data, and some lack of interpretability. To address these deficiencies, we construct a TSK transfer learning fuzzy system (TSK-TL) based on the easy-to-interpret TSK fuzzy system the transfer learning method. The proposed model is interpretable. By using the information contained in the source domain and target domains more effectively, the requirements for data distribution are further relaxed. It realizes the identification of epilepsy EEG signals in data drift scene. The experimental results show that compared with the existing algorithms, TSK-TL has better performance in EEG recognition of epilepsy.