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.

The management pattern and outcomes of chronic thromboembolic pulmonary hypertension: rationale and design for a Chinese real-world study.

BACKGROUND: Chronic thromboembolic pulmonary hypertension (CTEPH) is a progressive pulmonary vascular disorder with substantial morbidity and mortality, also a disease underdiagnosed and undertreated. It is potentially curable by pulmonary endarterectomy (PEA) in patients with surgically accessible thrombi. Balloon pulmonary angioplasty (BPA) and targeted medical therapy are options for patients with distal lesions or persistent/recurrent pulmonary hypertension after PEA. There is an urgent need to increase the awareness of CTEPH. Qualified CTEPH centers are still quite limited. Baseline characteristics, management pattern and clinical outcome of CTEPH in China needs to be reported. METHODS AND DESIGN: The CHinese reAl-world study to iNvestigate the manaGEment pattern and outcomes of chronic thromboembolic pulmonary hypertension (CHANGE) study is designed to provide the multimodality treatment pattern and clinical outcomes of CTEPH in China. Consecutive patients who are ≥ 14 year-old and diagnosed with CTEPH are enrolled. The diagnosis of CTEPH is confirmed in right heart catheterization and imaging examinations. The multimodality therapeutic strategy, which consists of PEA, BPA and targeted medical therapy, is made by a multidisciplinary team. The blood sample and tissue from PEA are stored in the central biobank for further research. The patients receive regular follow-up every 3 or 6 months for at least 3 years. The primary outcomes include all-cause mortality and changes in functional and hemodynamic parameters from baseline. The secondary outcomes include the proportion of patients experiencing lung transplantation, the proportion of patients experiencing heart and lung transplantation, and changes in health-related quality of life. Up to 31 December 2023, the study has enrolled 1500 eligible patients from 18 expert centers. CONCLUSIONS: As a real-world study, the CHANGE study is expected to increase our understanding of CTEPH, and to fill the gap between guidelines and the clinical practice in the diagnosis, assessment and treatment of patients with CTEPH. REGISTRATION NUMBER IN CLINICALTRIALS.GOV: NCT05311072.

Empirical and simulated investigation of the solid waste reverse supply chain: A complex adaptive system perspective.

Solid waste is increasing rapidly worldwide. In this study, the solid waste (household waste, construction and demolition waste and industrial waste) management systems are treated as reverse supply chain to analyze the critical operational issues based on complex adaptive system theory. At the single-layer, the complexity of the various nodes at a layer arises from rational decision-making and behavioral heterogeneity. The solid waste generation layer is employed as an example to investigate the complexity of node behavioral decisions. Regression analysis results reveal that both endogenous (Attitude, Subjective norm, and Perceived behavioral control) and exogenous factors (Economic incentive, Government supervision, Technical support) positively influence sorting behavior. The effect of Economic incentive (ß=0.327P<0.001) and Attitude (ß=0.249P<0.001) on sorting behavior are the largest. In the multi-layer system, different layers communicate with each other through the material and financial flows and have cross-layer impacts. An agent-based model is developed to investigate the multi-layer feedforward influence mechanism of changes in key layers (e.g., sorting rate, disposal rate) and the material and financial flows adaptive adjustment direction of the solid waste reverse supply chain. High rate of participation and accuracy of source sorting can shorten material flow paths and reduce storage and transportation costs. The increase in disposal rate encourages the transition of solid waste from backfill to resource utilization. This study provides a practice reference for solid waste reverse supply chain and related enterprises managers.

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.

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.

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.

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.

MiRNA let-7b promotes the development of hypoxic pulmonary hypertension by targeting ACE2.

Angiotensin-converting enzyme 2 (ACE2) protects against hypoxic pulmonary hypertension (HPH) by inhibiting the proliferation and migration of pulmonary artery smooth muscle cells (PASMCs). Under hypoxia, the hypoxia-inducible factor 1α (HIF-1α) inhibits ACE2 indirectly; however, the underlying mechanism is unclear. In the present study, we found that exposure to chronic hypoxia stimulated microRNA (miRNA) let-7b expression in rat lung via a HIF-1α-dependent pathway. Let-7b downregulated ACE2 expression by directly targeting the coding sequence of ACE2. Our in vitro and in vivo results revealed that let-7b contributed to the pathogenesis of HPH by inducing PASMCs proliferation and migration. Let-7b knockout mitigated right ventricle hypertrophy and pulmonary vessel remodeling in HPH by restoring ACE2 expression. Overall, we demonstrated that HIF-1α inhibited ACE2 expression via the HIF-1α-let-7b-ACE2 axis, which contributed to the pathogenesis of HPH by stimulating PASMCs proliferation and migration. Since let-7b knockout alleviated the development of HPH, let-7b may serve as a potential clinical target for the treatment of HPH.

Transgelin as a therapeutic target to prevent hypoxic pulmonary hypertension.

We previously observed that transgelin was preferentially expressed in human pulmonary arterial smooth muscle cells (PAMSCs) under hypoxia and that the upregulation of transgelin was independent of hypoxia-inducible factor 1α (HIF-1α). Reduced transgelin expression was accompanied by significantly impaired migration ability in vitro. However, the regulation mechanism of transgelin and its function in preventing hypoxic pulmonary hypertension (HPH) was unclear. In the present study, RNA interference with hypoxia-inducible factor 2α (HIF-2α) was employed in human PASMCs. Transgelin expression was diminished in HIF-2α-siRNA-treated cells at both the mRNA and protein levels under hypoxia. However, HIF-2α did not transactivate the transgelin promoter directly. TGF-ß1 concentration in human PASMCs culture medium was higher under hypoxia, and the accumulated TGF-ß1 under hypoxia was regulated by HIF-2α. Furthermore, luciferase and chromatin immunoprecipitation assays indicated that TGF-ß1/Smad3 could bind to the transgelin promoter, resulting in increased transgelin expression. In addition to nonintact cellular migration, inhibition of transgelin expression resulted in impaired proliferation in vitro under hypoxia. A lentiviral vector used to inhibit transgelin expression was constructed and intratracheally instilled in rats 3 wk prior to hypoxia treatment. Our final results indicated that inhibition of transgelin expression locally could attenuate increased right ventricular systolic pressure and its associated cardiac and pulmonary vessel remodeling under hypoxia. Our findings indicate that HIF-2α upregulates transgelin indirectly and that accumulated TGF-ß1 is a mediator in the upregulation of transgelin by HIF-2α under hypoxia. Inhibition of transgelin expression locally could prevent HPH and pulmonary vascular remodeling in vivo.

A novel bismuth-activated Sr3NaSbO6 phosphor with multi-band switchable emission for NUV-pumped LEDs.

Multi-band emission characteristics open up more possibilities for the application of phosphors in LEDs. In this work, a novel Bi3+-activated Sr3NaSbO6 phosphor is developed. The Bi3+ occupation, luminescence properties and application in LEDs of the phosphor are investigated and discussed. There are Sr and Na sites in the crystal structure for Bi3+ substitution, corresponding to two different luminescence centers, which can be excited by commercial UV chips. By changing the excitation wavelength, Bi3+ in the two lattice sites can be excited separately, and a switchable multi-band emission can be obtained accordingly. The blue emission peaks at 450 nm, and the other emission has an ultra-wide full-width at half-maximum of 206 nm, which can cover a wider visible spectrum. All the results show that the phosphor has application prospects in LEDs.

SLC16A3 is a Prognostic Marker and Affects Immune Regulation in Bladder Cancer.

BACKGROUND: Overexpression of SLC16A3 can contribute to the development of various tumors by regulating metabolism, but a systematic analysis of SLC16A3 in bladder cancer (BC) has been rarely reported. METHODS: We used the BC datasets from public databases to investigate SLC16A3 expression in BC. We first analysed the relationship between SLC16A3 expression and clinical characteristics of 412 bladder cancer patients. After that, gene function analyses and immunocorrelation analyses of SLC16A3 were conducted with the R package. For immunotherapy effect and drug sensitivity analysis, we also used the R package. We also analysed the relation between SLC16A3 expression and 20 m6A modification key genes. Finally, we determined the expression localization of SLC16A3 in bladder cancer by single-cell sequencing analysis using 3,115 BC cells. We further detected the expression of SLC16A3/MCT4 on BC samples by reversed transcriptionquantitative polymerase chain reaction and immunohistochemistry. RESULTS: The SLC16A3 was overexpressed in BC cells, including epithelial cells (p＜0.001). The high SLC16A3 expression level of patients with BC was significantly related to poor prognosis (p＝0.044), and we established a reliable prognosis model for BC patients. Statistically significant associations between SLC16A3 and m6A modification (ALKBH5) gene (p＜0.001), key genes in aerobic glycolysis, M2 macrophage infiltration (p＝0.0058), and immune checkpoint regulation were observed. CONCLUSION: Overexpression of SLC16A3 is an independent prognostic factor in patients with BC. SLC16A3 may influence the immune infiltration of BC by regulating BC metabolism and m6A methylation, which ultimately can lead to the progress of BC. For the detection and therapy of BC, SLC16A3 may be a potent therapeutic target for BC.

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.

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.

Outcomes and Predictors of Response to Pregabalin for the Treatment of Post-Traumatic Trigeminal Neuropathic Pain Following Neuroablative Procedures: A Retrospective Observational Study.

BACKGROUND: Post-traumatic trigeminal neuropathic pain (PTNP) following trigeminal neuralgia (TN)-related neuroablative procedures is relatively rare. Due to the fear of debilitating complications, its treatment has been generally suboptimal. Pregabalin (PGB) has been reported to relieve neuropathic pain. However, the potential role of PGB and the predictors of response of PGB use as a strategy in the treatment of PTNP following TN-related neuroablative procedures have not been identified yet. OBJECTIVES: To report the efficacy and safety of PGB and the identification of predictors of PGB for PTNP following TN-related neuroablative procedures. STUDY DESIGN: Monocentric, retrospective, observational study. SETTING: This study consecutively enrolled patients with PTNP following TN-related neuroablative procedures who were prescribed PGB at Beijing Tiantan Hospital. METHODS: From January 2018 to June 2022, a total of 112 patients were included in this study, of whom 10 were excluded because of incomplete follow-up data and side effects immediately after taking PGB. Final analysis included 102 patients. Demographic data, pain-related baseline data, efficacy of patients with PTNP after one month of PGB evaluated by the Barrow Neurological Institute (BNI) scores for pain, and side effects of PGB were extracted and analyzed. The predictors of pain-relieving effects of PGB were identified by logistic regression analysis. RESULTS: Within one month after the use of PGB alone, 29 out of the 102 (28.4%) patients achieved pain relief with a significant reduction in the BNI scores (P < 0.01). All of the 73 patients who did not respond to PGB monotherapy either switched to other medications (n = 8) or combined additional oral medications to the existing PGB therapy (n = 65). The main side effect of PGB in our study was dizziness. Binary logistic regression analysis showed that longer disease durations (Adjusted odds ratio [OR] = 0.55, 95% confidence interval [CI] 0.43 to 0.72, P = 0.000) and higher Hospital Anxiety and Depression Scale (HADS) scores (Adjusted OR = 0.29, 95% CI 0.10 to 0.87, P = 0.022) were poor predictors of response to PGB. LIMITATIONS: This was a retrospective observational study. Long-term efficacy and safety of PGB in the treatment of PTNP patients were not evaluated. CONCLUSIONS: This study confirms that PGB monotherapy is not a very effective treatment for PTNP following TN-related neuroablative procedures. PGB was more beneficial in patients with shorter disease durations and lower HADS scores. KEY WORDS: Post-traumatic trigeminal neuropathic pain, efficacy, safety, predictor of response, pregabalin.

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.

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.

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.

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.

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.