Semi-automatic computed tomography angiography quantification assessment is an alternative method to digital subtraction angiography in intracranial stenosis: a multicenter study.

Background: The recent randomized controlled trials studying intracranial atherosclerotic stenosis (ICAS) have used digital subtraction angiography (DSA) to quantify stenosis and enroll patients. However, some disadvantages of DSA such as invasive features, contrast agent overuse, and X-ray radiation overexposure, were not considered in these studies. This study aimed to explore whether computed tomography angiography (CTA) with semi-automatic analysis could be an alternative method to DSA in quantifying the absolute stenotic degree in clinical trials. Methods: Patients with 50-99% ICAS were consecutively screened, prospectively enrolled, and underwent CTA and DSA between March 2021 and December 2021 at 6 centers. This study was registered at www.chictr.org.cn (ChiCTR2100052925). The absolute stenotic degree of ICAS on CTA with semi-automatic analysis was calculated by several protocols using minimal/maximum/mean diameters of stenosis and reference site from a semi-automatic analysis software. Intraclass correlation coefficient (ICC) was used to evaluate the reliabilities of quantifying stenotic degree on CTA. The optimal protocol for quantifying ICAS on CTA was explored. The agreements of quantifying ICAS in calcified or non-calcified lesions and 50-69% or 70-99% stenosis on CTA and DSA were assessed. Results: A total of 191 participants (58.8±10.7 years; 148 men) with 202 lesions were enrolled. The optimal protocol for quantifying ICAS on CTA was calculated as (1 - the minimal diameter of stenosis/the mean diameter of reference) × 100% for its highest agreement with DSA [ICC, 0.955, 95% confidence interval (CI): 0.944-0.966, P<0.001]. Among the 202 lesions, 80.2% (162/202) exhibited severe stenosis on DSA. The accuracy of CTA in detecting severe ICAS was excellent (sensitivity =95.1%, positive predictive value =98.1%). The agreements between DSA and CTA in non-calcified lesions (ICC, 0.960 vs. 0.849) and severe stenosis (ICC, 0.918 vs. 0.841) were higher than those in calcified lesions and moderate stenosis. Conclusions: CTA with semi-automatic analysis demonstrated an excellent agreement with DSA in quantifying ICAS, making it promising to replace DSA for the measurement of absolute stenotic degree in clinical trials.

NanoSHP099-Targeted SHP2 Inhibition Boosts Ly6Clow Monocytes/Macrophages Differentiation to Accelerate Thrombolysis.

Tumor-associated thrombus (TAT) accounts for a high proportion of venous thromboembolism. Traditional thrombolysis and anticoagulation methods are not effective due to various complications and contraindications, which can easily lead to patients dying from TAT rather than the tumor itself. These clinical issues demonstrate the need to research diverse pathways for adjuvant thrombolysis in antitumor therapy. Previously, the phenotypic and functional transformation of monocytes/macrophages is widely reported to be involved in intratribal collagen regulation. This study finds that myeloid deficiency of the oncogene SHP2 sensitizes Ly6Clow monocyte/macrophage differentiation and can alleviate thrombus organization by increasing thrombolytic Matrix metalloproteinase (MMP) 2/9 activities. Moreover, pharmacologic inhibition by SHP099, examined in mouse lung metastatic tumor models, reduces tumor and thrombi burden in tumor metastatic lung tissues. Furthermore, SHP099 increases intrathrombus Ly6Clow monocyte/macrophage infiltration and exhibits thrombolytic function at high concentrations. To improve the thrombolytic effect of SHP099, NanoSHP099 is constructed to achieve the specific delivery of SHP099. NanoSHP099 is identified to be simultaneously enriched in tumor and thrombus foci, exerting dual tumor-suppression and thrombolysis effects. NanoSHP099 presents a superior thrombus dissolution effect than that of the same dosage of SHP099 because of the higher Ly6Clow monocyte/macrophage proportion and MMP2/MMP9 collagenolytic activities in organized thrombi.

Presence, Subtypes, and Prognostic Significance of Tertiary Lymphoid Structures in Urothelial Carcinoma of the Bladder.

OBJECTIVE: To evaluate the presence and subtypes of tertiary lymphatic structures (TLSs) in urothelial carcinoma of the bladder (UCB) and to analyze their associated clinicopathological characteristics and prognostic significance. METHODS: The study enrolled 580 patients with surgically treated UCB, including 313 non-muscle invasive bladder cancer (NMIBC) and 267 muscle-invasive bladder cancer (MIBC). The presence and subtypes of TLSs were identified by immunohistochemistry (CD20, CD3, Bcl-6, and CD21). TLSs were classified into non-GC (nGC) TLS and GC TLS subtypes based on germinal center (GC) formation. Disease-free survival (DFS) was used as an endpoint outcome to evaluate the prognostic significance of TLS and its subtypes in UCB. RESULTS: TLSs were more common in MIBC than in NMIBC (67.8% vs 48.2%, P < .001), and the tumor-infiltrating lymphocyte (TIL) mean density was significantly higher in MIBC than in NMIBC (24.0% vs 17.5%, P < .001). Moreover, a positive correlation was found between TLS presence and GC structure formation and TIL infiltration in UCB. Endpoint events occurred in 191 patients. Compared to patients with endpoint events, patients without disease progression exhibited higher TIL density and more TLSs (P < .05). Kaplan-Meier curves showed that TLS was associated with better DFS in NMIBC (P = .041) and MIBC (P = .049). However, the Cox multivariate analysis did not demonstrate the prognostic significance of TLS. CONCLUSIONS: TLS is heterogeneous in UCB, and that TLS and GC structures are related to TIL density and prognostic events. However, TLS as a prognostic indicator remains unclear, warranting further investigation.

Incidentally Diagnosed With Pulmonary Embolism in Lung Cancer Patients: Comparison of Clinical Characteristics and Mortality With Symptomatic Pulmonary Embolism.

The purpose of this work was to compare the clinical characteristics, rate of recurrent venous thromboembolism (VTE), bleeding complications and mortality of incidental and symptomatic pulmonary embolism (PE) detected on computed tomography in patients with lung cancer. Clinical data of lung cancer patients with PE were obtained from the Department of Respiratory and Critical Care Medicine of Ningbo First affiliated hospital of Ningbo University during January 2016 and June 2021 and were reviewed retrospectively. We compared clinical and radiological characteristics in lung cancer patients with incidental PE (IPE) and symptomatic PE (SPE) and identified variables associated with the 1-year survival on multivariate Cox analysis. All patients were followed up for 1 year to compare the risks of recurrent VTE, bleeding complications, and mortality. Survival analysis was performed by use of Kaplan-Meier. A total of 223 lung cancer patients with PE were enrolled over the period. Of these, 117 (52%) patients had symptomatic whereas 106 (48%) patients had incidental PE. Those with IPE were more likely to have adenocarcinoma, VTE history, chronic respiratory disease and chemotherapy within 30 days prior to PE, while SPE was more frequently observed in patients with squamous cancer, concomitant VTE, performance status 0-1, chronic heart disease and major surgery within 30 days prior to PE. During 1 year of follow-up, recurrent VTE was diagnosed in 10 patients (9.3%) in lung cancer patients with IPE and 13 patients (11.2%) with SPE. The 12-month cumulative recurrent VTE incidence was 9.6% for patients with incidental and 11.4% for patients with symptomatic PE (P = .61). The 12-month cumulative incidences of major bleeding complications were also comparable in the 2 groups (8.1% for incidental patients and 9.8% for symptomatic patients; P = .62). However, the respective 12-month mortality risks were 34.6% and 30.2% in lung cancer patients with IPE and SPE respectively (P = .03). On multivariate Cox analysis, we found that IPE occurrence was an independent risk factor associated with 1-year mortality in lung cancer patients complicated with PE after adjusting for age and sex (HR 1.517; 95% CI: 1.366-1.684; P = .027). Our findings suggest that lung cancer patients diagnosed with and treated for incidental PE had a similar rate of recurrent VTE, and incidence of hemorrhagic complications, but a significantly higher 1-year cumulative mortality rate after PE compared to those with symptomatic PE. IPE may be a marker of poor prognosis.

Modification of lysine-260 2-hydroxyisobutyrylation destabilizes ALDH1A1 expression to regulate bladder cancer progression.

ALDH1A1 is one of the classical stem cell markers for bladder cancer. Lysine 2-hydroxyisobutyrylation (Khib) is a newfound modification to modulate the protein expression, and the underlying mechanisms of how ALDH1A1 was regulated by Khib modification in bladder cancer remains unknown. Here, ALDH1A1 showed a decreased K260hib modification, as identified by protein modification omics in bladder cancer. Decreasing ALDH1A1 expression significantly suppressed the proliferation, migration and invasion of bladder cancer cells. Moreover, K260hib modification is responsible for the activity of ALDH1A1 in bladder cancer, which is regulated by HDAC2/3. Higher K260hib modification on ALDH1A1 promotes protein degradation through chaperone-mediated autophagy (CMA), and ALDH1A1 K260hib could sensitize bladder cancer cells to chemotherapeutic drugs. Higher ALDH1A1 expression with a lower K260hib modification indicates a poor prognosis in patients with bladder cancer. Overall, we demonstrated that K260hib of ALDH1A1 can be used as a potential therapeutic target for bladder cancer treatment.

Wearing individualized 3D printed oral stent to protect normal tissues in patients with nasopharyngeal carcinoma during radiotherapy.

PURPOSE: To demonstrate a new individualized 3D printed oral stent in radiotherapy of nasopharyngeal carcinoma (NPC) patients and carry out a comparative analysis combining with clinical case. MATERIAL AND METHODS: Thirty NPC patients treated in our institution from September 2021 to October 2022 were prospectively enrolled. An individualized 3D printed oral stent was designed for each patient, and one set of computed tomography (CT) slices were obtained with /without wearing the oral stent, respectively. After delineation of target volumes and organs at risk (OARs) on the two CT slices, we finished two treatment plans by using the same target objectives, critical constraints and plan setup for each patient. Finally, the dose distribution and other dosimetric parameters of target volumes and OARs between the two plans were compared. RESULTS: Tongue volume and tongue length outside of mouth was 10.4 ± 2.5 cm3 and 2.8 ± 0.6 cm, respectively, distance between dorsal surface of oral tongue and plate increased from 0.3 ± 0.3 cm to 2.2 ± 0.5 cm by wearing the oral stent. For the target volume, there was no significant difference. However, Dmax of tongue, tongue tip and periglottis decreased significantly from 6352.6 ± 259.9 cGy to 5994.9 ± 478.9 cGy, 3499.8 ± 250.6 cGy to 3357.7 ± 158.0 cGy and 6345.5 ± 171.0 cGy to 6133.4 ± 263.3 cGy, respectively (p = 0.000); Dmean of tongue, tongue tip and periglottis decreased significantly from 3714.7 ± 204.2 cGy to 3169.7 ± 200.9 cGy, 3060.8 ± 216.2 cGy to 2509.6 ± 196.7 cGy and 3853.3 ± 224.9 cGy to 3079.3 ± 222.0 cGy, respectively (p = 0.000). CONCLUSION: The individualized 3D printed oral stent can reduce the dose of oral tissues and organs, so as to reduce the oral adverse reactions and improve the compliance of patients and the quality of their life. The technique can be used in radiotherapy of NPC patients.

Synthesis and application of zeolitic imidazolate frameworks-based nucleic acid delivery system in tumor diagnosis and therapy: a review.

Cancer severely threatens human health, which makes it particularly urgent to develop effective strategies for cancer diagnosis and therapy. Gene therapy and nucleic acid-based cancer diagnosis play important roles in cancer theranostic, but their applicability is challenged by the low cellular uptake and enzymatic degradation. In response, safe and efficient carrier metal-organic frameworks (MOFs) have been proposed. Zeolite imidazole frameworks (ZIFs), a promising MOF type, can easily encapsulate negatively charged nucleic acid while offering a high loading efficiency, adjustable structure, and conditional responsiveness (pH, adenosine triphosphate (ATP), or glutathione (GSH)). In this review, we studied recent articles on nucleic acid-loading ZIFs-based nanoplatforms in tumor theranostics on the Pubmed database, with a focus on the synthesis and applications in tumor diagnosis and treatment. The relevant favorable aspects, potential challenges, and future opportunities are also discussed in this review.

Characteristics and 6-Month Mortality of Medical Oncology Patients With Incidental and Symptomatic Pulmonary Embolism: A Single-Institutional Retrospective Longitudinal Analysis.

This study aimed to identify clinical characteristics of cancer patients with incidental pulmonary embolism (IPE) and assess the variables associated with 30-day mortality in cancer patients with PE including symptomatic pulmonary embolism (SPE) and IPE. 6-Month mortality rate in cancer patients with SPE and IPE were also compared. We retrospectively analyzed electronic medical records of cancer patients with newly diagnosed PE between January 2016 and June 2021. We compared clinical and radiological characteristics in cancer patients with IPE and SPE and identified variables associated with the overall 30-day mortality on multivariate analysis. All patients were followed up for 6 months and survival analysis was performed by use of Kaplan-Meier. Five hundred and nine eligible cancer patients with pulmonary embolism were identified during the study period. IPE is associated with lower BMI, colorectal and pancreas cancers, stage III/IV of cancer, recent antiangiogenic therapy, central venous catheter (CVC) and chronic cardiac or respiratory disease compared to SPE. The factors associated with 30-day mortality included poor performance status, lung/pleura or upper gastrointestinal cancers, stage III/IV of cancer, previous VTE, oxygen saturation < 95%, lactic acid > 2 mmol/l and bilateral PE. The overall survival in patients with IPE at 6-month follow-up was similar to those diagnosed with SPE. The present study has allowed the identification of factors associated with 30-day mortality in cancer patients with IPE and SPE. We also found similar mortality rate in cancer patients with IPE compared with patients with SPE at 6-month follow-up.

MiR-522-3p Targets Transcription Factor 4 to Overcome Cisplatin Resistance of Gastric Cells.

Gastric cancer (GC) is a malignancy originating from gastric epithelial tissue. Chemoresistance to cisplatin (DDP) often leads to chemotherapy failure in GC. Previously, miR-522 was found to be associated with chemoresistance in GC cells. Thus, we attempted to clarify miR-522-3p's role underlying chemoresistance of GC cells. RT-qPCR measured the miR-522-3p levels in untreated and DDP-treated AGS cells. RT-qPCR and Western blotting detected transcription factor 4 (TCF4) mRNA and protein levels in GC cells. AGS and AGS/DDP cell proliferation were detected by the colony formation assay. Flow cytometry analysis detected AGS and AGS/DDP cell apoptosis. Bioinformatics and dual luciferase reporter assays predicted and verified the relationship between miR-522-3p and TCF4. Rescue experiments further clarified the regulatory patterns of miR-522-3p/TGF4 in GC cells. miR-522-3p presented a downregulation in GC cells and was positively affected by DDP. TCF4 presented elevation in GC cells and was negatively affected by DDP. Mechanistically, miR-522-3p targeted TCF4 to suppress TCF4 gene expression. miR-522-3p overexpression suppressed GC cell proliferation and resistance to DDP and GC cell apoptosis was facilitated. TCF4 overexpression facilitated GC cell proliferation and resistance to DDP while repressing GC cell apoptosis. TCF4 elevation rescued changes in GC cell proliferation, apoptosis, and chemoresistance due to miR-522-3p overexpression. To sum up, miR-522-3p suppresses GC cell malignancy and resistance to DDP via targeting TCF4. Our research may provide a new biomarker for GC diagnosis and a novel direction for GC chemotherapy.

Predictors of response for percutaneous balloon compression for the treatment of recurrent trigeminal neuralgia following surgical procedures: a retrospective study.

Recurrent trigeminal neuralgia (TN) after surgical procedures can be rather difficult to treat, and standardized treatment measures are not available yet. It is unclear whether percutaneous balloon compression (PBC) can be used as the preferred surgical treatment for postoperative recurrent TN. To determine the efficacy of PBC and identify the predictors of response of PBC for the treatment of recurrent TN following TN-related surgeries, we retrospectively collected and analyzed the data of patients with recurrent TN following surgical treatments who underwent PBC under three-dimensional computed tomography (3D-CT) guidance at the Department of Pain Management of Beijing Tiantan Hospital, Capital Medical University from January 2018 to January 2022. We found, within 1 month after PBC, that the total efficacy of PBC on recurrent TN following TN-related surgeries was 86.7%. Based on the effectiveness of PBC 1 month postoperatively, patients were divided into the effective group (130, 86.7%) and the ineffective group (20, 13.3%). Fourteen (10.8%) patients in the effective group had undergone RFT before, which was significantly lower than that in the ineffective group (6, 30%, p = 0.02). Multivariate logistic regression analysis showed that previous RFT alone (OR = 0.20, 95%CI 0.06-0.66, P = 0.01) was an independent predictor of the negative response of PBC. Thus, PBC was found to be a moderately effective and safe treatment for recurrent TN after TN-related surgery. However, previous RFT procedures may predict a slightly worse outcome after PBC.

New insights into the prognosis of intraocular malignancy: Interventions for association mechanisms between cancer and diabetes.

The intraocular malignancies, which mostly originate from the retina and uvea, exhibit a high incidence of blindness and even death. Uveal melanoma (UM) and retinoblastoma (RB) are the most common intraocular malignancies in adults and children, respectively. The high risks of distant metastases lead to an extremely poor prognosis. Nowadays, various epidemiological studies have demonstrated that diabetes is associated with the high incidence and mortality of cancers, such as liver cancer, pancreatic cancer, and bladder cancer. However, the mechanisms and interventions associated with diabetes and intraocular malignancies have not been reviewed. In this review, we have summarized the associated mechanisms between diabetes and intraocular malignancy. Diabetes mellitus is a chronic metabolic disease characterized by prolonged periods of hyperglycemia. Recent studies have reported that the abnormal glucose metabolism, insulin resistance, and the activation of the IGF/insulin-like growth factor-1 receptor (IGF-1R) signaling axis in diabetes contribute to the genesis, growth, proliferation, and metastases of intraocular malignancy. In addition, diabetic patients are more prone to suffer severe complications and poor prognosis after radiotherapy for intraocular malignancy. Based on the common pathogenesis shared by diabetes and intraocular malignancy, they may be related to interventions and treatments. Therefore, interventions targeting the abnormal glucose metabolism, insulin resistance, and IGF-1/IGF-1R signaling axis show therapeutic potentials to treat intraocular malignancy.

Case report: apatinib plus selexipag as a novel therapy for pulmonary tumor thrombotic microangiopathy accompanied by pulmonary hypertension associated with gastric carcinoma.

RATIONALE: PTTM is a rare but fatal disease, characterized by endothelial intimal proliferation and pulmonary hypertension due to micro-vascular remodeling. In view of the poor prognosis, new effective strategies are urgently required. PATIENT CONCERNS AND DIAGNOSIS: A 51-year-old woman was admitted to hospital for acute progressive dyspnea and dry cough. Clinical tests revealed hypercoagulable state and signs of severe pulmonary hypertension, without evidence of pulmonary embolism on contrast-enhanced CT. CT showed interlobular septal thickening and diffuse ground-glass opacity. Lung perfusion scan indicated multiple segment defect. Further right heart catherization proved a significant increase in pulmonary vascular resistance. INTERVENTIONS: A combination therapy of apatinib and selexipag was administered for treatment of PTTM. The conventional therapies of ventilation, anticoagulation and diuretic medicines were initiated after admission. OUTCOMES: Symptoms of PTTM were ameliorated with a reduction in pulmonary artery pressure. The resolution of interlobular septal thickening and ground-glass opacity on CT constituted the clinical benefits from treatment. LESSONS: Patient with PTTM will benefit from the combination strategy of apatinib, a VEGF-receptor antagonist, and selexipag, an oral prostacyclin receptor agonist.

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.

Immunosuppression Induced by Glutamine Deprivation Occurs via Activating PD-L1 Transcription in Bladder Cancer.

Few studies have reported whether nutrients in the tumor microenvironment can regulate the expression of PD-L1. Since tumor cells are often situated in a low-glutamine environment, we investigated PD-L1 expression under glutamine deprivation in bladder cancer cells. PD-L1 expression and the activation of the EGFR/MEK/ERK/c-Jun signaling pathway under glutamine deprivation were investigated by qPCR, Western blot, and immunofluorescence analyses. C-Jun-mediated transcriptional regulation of the PD-L1 gene was assessed by ChIP. PD-L1 expression and activation of the EGFR/MEK/ERK/c-Jun signaling pathway were assessed in T24 cells, TCCSUP cells and BALB/c mice with or without glutamine supplementation. Additionally, the impact of PD-L1 expression under glutamine deprivation on the function of T cells was investigated by ELISA. The expression of PD-L1 and EGFR/MEK/ERK/c-Jun pathway activation were elevated by glutamine deprivation, and c-Jun was enriched in the enhancer region of PD-L1. The expression of PD-L1 was considerably impaired by inhibiting the EGFR/MEK/ERK/c-Jun pathway and was elevated by activating this signaling pathway. In addition, the elevated PD-L1 expression and MEK/ERK/c-Jun signaling pathway activation were reduced by glutamine supplementation in vitro and in vivo. PD-L1 upregulation by glutamine deprivation in bladder cancer cells could reduce IFN-γ production by T cells. The expression of PD-L1 was upregulated under glutamine deprivation through the EGFR/MEK/ERK/c-Jun pathway to impair T cell function.

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.

Identification of NTRK3 as a potential prognostic biomarker associated with tumor mutation burden and immune infiltration in bladder cancer.

BACKGROUND: Bladder cancer (BLCA) is a common malignant tumor of urinary system with high morbidity and mortality. In recent years, immunotherapy has played a significant role in the treatment of BLCA. Tumor mutation burden (TMB) has been reported to be a powerful biomarker for predicting tumor prognosis and efficacy of immunotherapy. Our study aimed to explore the relationship between TMB, prognosis and immune infiltration to identify the key genes in BLCA. METHODS: Clinical information, somatic mutation and gene expression data of BLCA patients were downloaded from The Cancer Genome Atlas (TCGA) database. Patients were divided into high and low TMB groups according to their calculated TMB scores. Gene Set Enrichment Analysis (GSEA) was performed to screen for significantly enriched pathways. Differentially expressed genes (DEGs) between the two groups were identified. Univariate Cox analysis and Kaplan-Meier survival analysis were applied for screening key genes. Immune infiltration was performed for TMB groups and NTRK3. RESULTS: Higher TMB scores were related with poor survival in BLCA. After filtering, 36 DEGs were identified. NTRK3 had the highest hazard ratio and significant prognostic value. Co-expressed genes of NTRK3 were mainly involved in several pathways, including DNA replication, basal transcription factors, complement and coagulation cascades, and ribosome biogenesis in eukaryotes. There was a significant correlation among TMB scores, NTRK3 expression and immune infiltration. CONCLUSIONS: Our results suggest that NTRK3 is a TMB-related prognostic biomarker, which lays the foundation for further research on the immunomodulatory effect of NTRK3 in BLCA.

Glucose metabolism involved in PD-L1-mediated immune escape in the malignant kidney tumour microenvironment.

Programmed death receptor-ligand 1 (PD-L1) plays a crucial role in immune evasion by tumour cells. Most tumour cells exhibit energy dependency and acquire energy from glycolysis. However, the relationship between glucose metabolism and PD-L1 expression remains unclear. In this study, changes in PD-L1 expression in renal carcinoma cells were evaluated during glucose deficiency and recovery, and PD-L1 could inversely regulate glycolysis. In addition, the possible signalling pathways activated by a low level of glucose to regulate PD-L1 were tested experimentally. The results showed that glucose deficiency could upregulate PD-L1 expression in two renal cancer cell lines, 786-O and OS-RC-2. Although the native levels of PD-L1 differed in the two cell lines, the upregulated PD-L1 expression was repristinated after glucose recovery. Moreover, epidermal growth factor receptor (EGFR) expression was upregulated in both cell lines with glucose deficiency. The use of an EGFR inhibitor reversed the upregulation of PD-L1 expression induced by glucose deficiency and inhibited the phosphorylation of extracellular regulated protein kinases 1 and 2 (ERK1/2). EGFR activated by epidermal growth factor (EGF) induced PD-L1 expression and ERK1/2 phosphorylation. Furthermore, an ERK1/2 inhibitor inhibited the phosphorylation of c-Jun and decreased the elevated PD-L1 expression induced by glucose deficiency. In addition, this study also showed that 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFK-2/FBPase 3 or PFKFB3) mediated upregulation of the level of glycolysis to improve the adverse environment through PD-L1 induction. Therefore, glucose metabolism can regulate the expression of PD-L1 through the EGFR/ERK/c-Jun pathway in renal cancer, and elevated PD-L1 can also regulate glycolysis by improving the expression of PFKFB3. The findings of this study could provide a new multiple target treatment for renal cell carcinoma (RCC) therapy.

Haemodynamic analysis of adult patients with moyamoya disease: CT perfusion and DSA gradings.

OBJECT: Moyamoya disease (MMD) is a common and chronic progressive stenotic-occlusive cerebrovascular disease in Eastern Asia. To evaluate the hemispheric haemodynamic status of adult patients with MMD, we explored the potential risk factors of hemispheric perfusion alterations with CT perfusion (CTP) and DSA. METHODS: We retrospectively reviewed 44 male and 44 female (176 hemispheres) adult patients with MMD who had both DSA and CTP. Data on cerebral blood perfusion (CBF), cerebral blood volume (CBV), mean transmit time (MTT), time to peak (TTP) of cerebral hemisphere and cerebellum were gathered and difference of relative haemodynamic parameters between different subgroups were assessed with independent sample t analysis, one-way analysis of variance and general linear regression analysis. RESULTS: Parameters in regional CBF (rCBF) of frontal, temporal lobe and basal ganglia in female was more superior than male. rCBF, regional MTT (rMTT) and regional TTP (rTTP) in adult MMD patients with haemorrhage were superior than the ischaemic. With the increase of age, significant difference could be seen in rCBF and rCBV of thalamus. However, with progress of arterial stenosis, significant difference could only be obsevrved in rCBV, rMTT and rTTP, whereas rCBF had no significant difference. For increase of moyamoya vessels, significant decrease of rCBF could be seen in temporal and parietal lobe. With the increase of compensatory artery numbers, no significant difference could be seen in rCBF parameters (p>0.05). CONCLUSIONS: In adult MMD patients, age, gender and clinical type were potential risk factors for the change of cerebral perfusion. When arterial stenosis is worsened, moyamoya vessels could alter perfusion of temporal and parietal lobe, but not frontal lobe. Extracranial/intracranial compensatory arteries could maintain microcirculation stability in frontal lobe and basal ganglia, indicating that the protection from extracranial compensatory arteries, a theoretic base for surgery treatment if necessary.

Establishment and Validation of a Prognostic Risk Model for Autophagy-Related Genes in Clear Cell Renal Cell Carcinoma.

BACKGROUND: Autophagy plays an essential role in tumorigenesis. At present, due to the unclear role of autophagy in renal clear cell carcinoma, we studied the potential value of autophagy-related genes (ARGs) in renal clear cell carcinoma (ccRCC). METHODS: We obtained all ccRCC data from The Cancer Genome Atlas (TCGA). We extracted the expression data of ARGs for difference analysis and carried out biological function analysis on the different results. The autophagy risk model was constructed. The 5-year survival rate was assessed using the model, and the predictive power of the model was evaluated from multiple perspectives. Cox regression analysis was use to assess whether the model could be an independent prognostic factor. Finally, the correlation between the model and clinical indicators is analyzed. RESULTS: The patients were divided into the high-risk group and low-risk group according to the median of autophagy risk score, and the results showed that the prognosis of the low-risk group was better than that of a high-risk group. The validation results of external data sets show that our model has good predictive value for ccRCC patients. The model can be an independent prognostic factor. Finally, the results show that our model has a stable predictive ability. CONCLUSION: The autophagy gene model we constructed can be used as an excellent prognostic indicator for ccRCC. Our study provides the possibility of individualized and precise treatment for ccRCC patients.