Comprehensive analysis of gene mutations and mismatch repair in Chinese colorectal cancer patients.

BACKGROUND: RAS, BRAF, and mismatch repair (MMR)/microsatellite instability (MSI) are crucial biomarkers recommended by clinical practice guidelines for colorectal cancer (CRC). However, their characteristics and influencing factors in Chinese patients have not been thoroughly described. AIM: To analyze the clinicopathological features of KRAS, NRAS, BRAF, and PIK3CA mutations and the DNA MMR status in CRC. METHODS: We enrolled 2271 Chinese CRC patients at the China-Japan Friendship Hospital. MMR proteins were tested using immunohistochemical analysis, and the KRAS/NRAS/BRAF/PIK3CA mutations were determined using quantitative polymerase chain reaction. Microsatellite status was determined using an MSI detection kit. Statistical analyses were conducted using SPSS software and logistic regression. RESULTS: The KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 44.6%, 3.4%, 3.7%, and 3.9% of CRC patients, respectively. KRAS mutations were more likely to occur in patients with moderate-to-high differentiation. BRAF mutations were more likely to occur in patients with right-sided CRC, poorly differentiated, or no perineural invasion. Deficient MMR (dMMR) was detected in 7.9% of all patients and 16.8% of those with mucinous adenocarcinomas. KRAS, NRAS, BRAF, and PIK3CA mutations were detected in 29.6%, 1.1%, 8.1%, and 22.3% of patients with dMMR, respectively. The dMMR was more likely to occur in patients with a family history of CRC, aged < 50 years, right-sided CRC, poorly differentiated histology, no perineural invasion, and with carcinoma in situ, stage I, or stage II tumors. CONCLUSION: This study analyzed the molecular profiles of KRAS, NRAS, BRAF, PIK3CA, and MMR/MSI in CRC, identifying key influencing factors, with implications for clinical management of CRC.

Impact of chronic kidney disease on left atrial appendage occlusion: A meta-analysis of procedural outcomes and complications.

BACKGROUND: Patients with chronic kidney disease (CKD) experience atrial fibrillation more frequently. The balance of medical management for stroke prevention and bleeding events presents a challenging issue in CKD population. Left atrial appendage occlusion (LAAO) may be an effective solution for stroke prevention in patients who experience frequent bleeding with oral anticoagulants. However, the specific impact of CKD on the procedural success, complications, and outcomes of LAAO implantations remains underexplored. METHODS: We conducted a search of various databases for articles published before October 31, 2023. This search yielded 7 studies, comparing outcomes between CKD and non-CKD cohorts undergoing LAAO implantation. Our analysis focused on CHA2DS2-VASc scores, average eGFR, use of oral anticoagulants, procedural success rates, procedural complications, and associated outcomes. RESULTS: The meta-analysis included data from 2576 patients, with 1131 identified as having CKD. The CKD group also had higher CHA2DS2-VASc scores (4.7 ±â€…1.4 vs 4.0 ±â€…1.5; P < .001) and HAS-BLED scores (3.8 ±â€…1.1 vs 3.1 ±â€…1.0; P < .001) than the non-CKD group. CKD patients showed a nonreduction in procedural success rates and a nonsignificant increase in total complications. The risks of stroke and transient ischemic attack, major bleeding, and cardiovascular mortality were not significantly different between the 2 groups. However, a significantly lower rate of total mortality was observed in the non-CKD group (odds ratio: 0.43; 95% confidence interval, 0.32-0.60). CONCLUSION: While CKD is associated with a nonsignificant decrease in procedural success and a nonsignificant increase in complication risks, the outcomes of LAAO implantation are comparably favorable between CKD and non-CKD groups. Despite similar procedural outcomes, the CKD group exhibited a higher rate of all-cause mortality.

Effects of implantation height on the performance of a redo transcatheter aortic valve replacement using a balloon-expandable valve.

Objective: The use of the transcatheter aortic valve in low-risk patients might lead to a second intervention due to the deterioration of the first 1. Understanding the implantation height is key to an effective redo transcatheter aortic valve replacement treatment. Methods: The effects of implantation height on the performance of a balloon-expandable valve within a self-expandable valve were assessed using hemodynamic testing and particle image velocimetry. The hemodynamic performances, leaflet kinematics, and turbulent shear stresses were measured and compared. Results: When a second balloon-expandable valve was positioned at varying heights relative to the first self-expandable valve, the leaflet motion of the first valve transitioned from free opening and closing to overhanging, and eventually to being entirely pinned to the stent, forming a neo-skirt. When the leaflets of the self-expandable valve could move freely, a decrease in regurgitation fraction was observed, but with an increased pressure gradient across the valve. Flow visualization indicated that the overhanging leaflets disrupted the flow, generating a higher level of turbulence. Conclusions: This study suggests that the overhanging leaflets should be avoided, whereas the other 2 scenarios should be carefully evaluated based on an individual patient's anatomy and the cause of failure of the first valve.

Patient-specific 3D in vitro modeling and fluid dynamic analysis of primary pulmonary vein stenosis.

Introduction: Primary pulmonary vein stenosis (PVS) is a rare congenital heart disease that proves to be a clinical challenge due to the rapidly progressive disease course and high rates of treatment complications. PVS intervention is frequently faced with in-stent restenosis and persistent disease progression despite initial venous recanalization with balloon angioplasty or stenting. Alterations in wall shear stress (WSS) have been previously associated with neointimal hyperplasia and venous stenosis underlying PVS progression. Thus, the development of patient-specific three-dimensional (3D) in vitro models is needed to further investigate the biomechanical outcomes of endovascular and surgical interventions. Methods: In this study, deidentified computed tomography images from three patients were segmented to generate perfusable phantom models of pulmonary veins before and after catheterization. These 3D reconstructions were 3D printed using a clear resin ink and used in a benchtop experimental setup. Computational fluid dynamic (CFD) analysis was performed on models in silico utilizing Doppler echocardiography data to represent the in vivo flow conditions at the inlets. Particle image velocimetry was conducted using the benchtop perfusion setup to analyze WSS and velocity profiles and the results were compared with those predicted by the CFD model. Results: Our findings indicated areas of undesirable alterations in WSS before and after catheterization, in comparison with the published baseline levels in the healthy in vivo tissues that may lead to regional disease progression. Discussion: The established patient-specific 3D in vitro models and the developed in vitro-in silico platform demonstrate great promise to refine interventional approaches and mitigate complications in treating patients with primary PVS.

The small-molecule drug homoharringtonine targets HSF1 to suppress pancreatic cancer progression.

Heat shock factor 1 (HSF1), an essential transcription factor for stress response, is exploited by various tumors to facilitate their initiation, progression, invasion, and migration. Amplification of HSF1 is widely regarded as an indicator in predicting cancer severity, the likelihood of treatment failure and reduced patient survival. Notably, HSF1 is markedly amplified in 40% of pancreatic cancer (PC), which typically have limited treatment options. HSF1 has been proven to be a promising therapeutic target for multiple cancers. However, a direct small molecule HSF1 inhibitor with sufficient bioactivity and reliable safety has not been developed clinically. In this study, we successfully established a high-throughput screening system utilizing luciferase reporter assay specifically designed for HSF1, which leads to the discovery of a potent small molecule inhibitor targeting HSF1. Homoharringtonine (HHT) selectively inhibited PC cell viability with high HSF1 expression and induced a markedly stronger tumor regression effect in the subcutaneous xenograft model than the comparator drug KRIBB11, known for its direct action on HSF1. Moreover, HHT shows promise in countering the resistance encountered with HSP90 inhibitors, which have been observed to increase heat shock response intensity in clinical trials. Mechanistically, HHT directly bound to HSF1, suppressing its expression and thereby inhibiting transcription of HSF1 target genes. In conclusion, our work presents a preclinical discovery and validation for HHT as a HSF1 inhibitor for PC treatment.

Cigarette smoking-related OLC1 overexpression associated with poor prognosis in bladder urothelial carcinoma.

AIMS: To explore the clinical significance of OLC1 and cigarette smoking in bladder urothelial carcinoma (UBC). MATERIALS AND METHODS: OLC1 mRNA expression was detected in 106 UBC samples by mRNA array or reverse real-time PCR. OLC1 protein expression in 114 UBC samples was detected by immunohistochemical staining. Wild-type C57BL/6J mice were injected with cigarette smoke condensate (n = 12) or exposed to cigarette smoke (n = 6) to investigate the correlations between cigarette smoking and OLC1 expression using mRNA array. KEY FINDINGS: The mRNA and protein expression of OLC1 were higher in tumor samples (p < 0.01) and significantly correlated with tumor stage (p < 0.05). OLC1 protein expression and smoking history were correlated with disease-free survival (p < 0.05). OLC1 expression was significantly elevated in smoking patients with higher smoking intensity on both mRNA and protein levels (p < 0.05). Cigarette smoke exposure experiments revealed that OLC1 mRNA overexpressed in bladder uroepithelium of mice. SIGNIFICANCE: OLC1 could serve as a potential prognosis biomarker of UBC, especially for smoking patients.

Targeted Rapamycin Delivery via Magnetic Nanoparticles to Address Stenosis in a 3D Bioprinted in Vitro Model of Pulmonary Veins.

Vascular cell overgrowth and lumen size reduction in pulmonary vein stenosis (PVS) can result in elevated PV pressure, pulmonary hypertension, cardiac failure, and death. Administration of chemotherapies such as rapamycin have shown promise by inhibiting the vascular cell proliferation; yet clinical success is limited due to complications such as restenosis and off-target effects. The lack of in vitro models to recapitulate the complex pathophysiology of PVS has hindered the identification of disease mechanisms and therapies. This study integrated 3D bioprinting, functional nanoparticles, and perfusion bioreactors to develop a novel in vitro model of PVS. Bioprinted bifurcated PV constructs are seeded with endothelial cells (ECs) and perfused, demonstrating the formation of a uniform and viable endothelium. Computational modeling identified the bifurcation point at high risk of EC overgrowth. Application of an external magnetic field enabled targeting of the rapamycin-loaded superparamagnetic iron oxide nanoparticles at the bifurcation site, leading to a significant reduction in EC proliferation with no adverse side effects. These results establish a 3D bioprinted in vitro model to study PV homeostasis and diseases, offering the potential for increased throughput, tunability, and patient specificity, to test new or more effective therapies for PVS and other vascular diseases.

Incidence, Risk Factors, and Outcomes of Left Atrial Enlargement in Patients Requiring Right Ventricular Pacing: A Retrospective Study of 461 Cases from 2012 to 2020.

BACKGROUND Long-term right ventricular (RV) pacing has been linked to left atrial enlargement (LAE). The incidence and risk factors associated with significant LAE after RV pacing remain unknown. This retrospective study included 461 patients requiring RV pacing at 2 centers between 2012 and 2020 and aimed to evaluate the incidence, risk factors, outcomes, and complications of LAE. MATERIAL AND METHODS A total of 461 patients with normal-sized pre-implant left atrial dimension and dual-chamber pacing pacemaker implantation for complete atrioventricular block were enrolled. Patients were grouped based on a ≥20% increase from their baseline left atrial dimension by echocardiography, indicating significant LAE, and initial characteristics, echocardiographic data, and outcomes were compared. RESULTS During a mean 7.0±4.9 years follow-up period, 96 patients (20.8%) developed significant LAE, whereas 365 patients did not. In multivariate logistic regression analysis, smaller pre-implant left atrial dimension (OR, 0.776; 95% CI, 0.728-0.828; P<0.001), lower post-implant left ventricular ejection fraction (OR, 0.976; 95% CI, 0.957-0.995; P=0.014), post-implant development of moderate to severe mitral regurgitation (OR, 2.357; 95% CI, 1.172-4.740; P=0.016), and RV pacing duration ≥3.3 years (OR, 1.576; 95% CI, 1.039-2.646; P=0.045) were independent predictors of significant LAE after RV-dependent pacing. There was a significant difference in the incident stroke events between patients without and with significant LAE (9.9% vs 17.7%; log-rank P=0.047). CONCLUSIONS Long-term RV pacing was linked to significant LAE in 20.8% of patients with complete atrioventricular block, with those affected experiencing a higher stroke rate during follow-up.

Exploring the genetic causal association of TIMP3 on CKD and kidney function: a two-sample mendelian randomization.

Background: Numerous studies have demonstrated a positive association between the level of tissue inhibitor of metalloproteinase 3 (TIMP3) and chronic kidney disease (CKD). Nevertheless, whether those associations reflect causal links still to be determined. This study intended to research the causal relationship of TIMP3 with CKD and markers of kidney function, such as creatinine-based estimated glomerular filtration rate (eGFRcrea), cystatin C-based estimated glomerular filtration rate (eGFRcys), eGFRcrea in diabetics (eGFRcrea (DM)) and eGFRcrea in non diabetics (eGFRcrea (No DM)). Methods: In this study, we investigated the causal relationships between TIMP3 and CKD and kidney function markers using a two-sample Mendelian randomization (MR) technique. We used summary level datasets for TIMP3 and CKD from genome-wide association studies that we were able to access through the study by Suhre K and Pattaro C. Results: We found that TIMP3 had a significant positive causal effect on the risk of CKD (Inverse variance weighted (IVW):odds ratio (OR):0.962, 95% confidence interval (CI): (0.936-0.988),P:0.005). However TIMP3 levels had no significant effect on risk of eGFRcys (PIVW: 0.114),eGFRcrea (PIVW:0.333). After grouping patients based on their diabetes status, we found that genetically higher levels of TIMP3 had a significant impact on eGFRcrea in participants without diabetes (OR:1.003,95%CI (1.001-1.006),P IVW:0.007), but not in participants with diabetes (PIVW = 0.057). Heterogeneity and pleiotropy analyses were carried out to verify the accuracy of the MR findings. Their findings were all not statistically significant. Conclusion: Our study suggests that TIMP3 may be causally associated with CKD and eGFRcrea (No DM)in people of European ancestry. Strategies aimed to increase TIMP3 levels may provide new ways to delay the deterioration of renal function.

Hemodynamics of the VenusP Valve System™-an in vitro study.

This study aims to evaluate the fluid dynamic characteristics of the VenusP Valve System™ under varying cardiac outputs in vitro. A thorough hemodynamic study of the valve under physiological cardiac conditions was conducted and served as an independent assessment of the performance of the valve. Flow fields downstream of the valve near the pulmonary bifurcation were quantitatively studied by two-dimensional Particle Image Velocimetry (PIV). The obtained flow field was analyzed for potential regions of flow stasis and recirculation, and elevated shear stress and turbulence. High-speed en face imaging capturing the leaflet motion provided data for leaflet kinematic modeling. The experimental conditions for PIV studies were in accordance with ISO 5840-1:2021 standard, and two valves with different lengths and different orientations were studied. Results show good hemodynamics performance for the tested valves according to ISO 5840 standard without significant regions of flow stasis. Observed shear stress values are all well below established hemolysis limits.

Sensitivity of Post-TAVR Hemodynamics to the Distal Aortic Arch Anatomy: A High-Fidelity CFD Study.

PURPOSE: Patient-specific simulations of transcatheter aortic valve (TAV) using computational fluid dynamics (CFD) often rely on assumptions regarding proximal and distal anatomy due to the limited availability of high-resolution imaging away from the TAV site and the primary research focus being near the TAV. However, the influence of these anatomical assumptions on computational efficiency and resulting flow characteristics remains uncertain. This study aimed to investigate the impact of different distal aortic arch anatomies-some of them commonly used in literature-on flow and hemodynamics in the vicinity of the TAV using large eddy simulations (LES). METHODS: Three aortic root anatomical configurations with four representative distal aortic arch types were considered in this study. The arch types included a 90-degree bend, an idealized distal aortic arch anatomy, a clipped version of the idealized distal aortic arch, and an anatomy extruded along the normal of segmented anatomical boundary. Hemodynamic parameters both instantaneous and time-averaged such as Wall Shear Stress (WSS), and Oscillatory Shear Index (OSI) were derived and compared from high-fidelity CFD data. RESULTS: While there were minor differences in flow and hemodynamics across the configurations examined, they were generally not significant within our region of interest i.e., the aortic root. The choice of extension type had a modest impact on TAV hemodynamics, especially in the vicinity of the TAV with variations observed in local flow patterns and parameters near the TAV. However, these differences were not substantial enough to cause significant deviations in the overall flow and hemodynamic characteristics. CONCLUSIONS: The results suggest that under the given configuration and boundary conditions, the type of outflow extension had a modest impact on hemodynamics proximal to the TAV. The findings contribute to a better understanding of flow dynamics in TAV configurations, providing insights for future studies in TAV-related experiments as well as numerical simulations. Additionally, they help mitigate the uncertainties associated with patient-specific geometries, offering increased flexibility in computational modeling.

Discovery of the Highly Selective and Potent STAT3 Inhibitor for Pancreatic Cancer Treatment.

Signal transducer and activator of transcription 3 (STAT3) is an attractive cancer therapeutic target. Unfortunately, targeting STAT3 with small molecules has proven to be very challenging, and for full activation of STAT3, the cooperative phosphorylation of both tyrosine 705 (Tyr705) and serine 727 (Ser727) is needed. Further, a selective inhibitor of STAT3 dual phosphorylation has not been developed. Here, we identified a low nanomolar potency and highly selective small-molecule STAT3 inhibitor that simultaneously inhibits both STAT3 Tyr705 and Ser727 phosphorylation. YY002 potently inhibited STAT3-dependent tumor cell growth in vitro and achieved potent suppression of tumor growth and metastasis in vivo. More importantly, YY002 exhibited favorable pharmacokinetics, an acceptable safety profile, and superior antitumor efficacy compared to BBI608 (STAT3 inhibitor that has advanced into phase III trials). For the mechanism, YY002 is selectively bound to the STAT3 Src Homology 2 (SH2) domain over other STAT members, which strongly suppressed STAT3 nuclear and mitochondrial functions in STAT3-dependent cells. Collectively, this study suggests the potential of small-molecule STAT3 inhibitors as possible anticancer therapeutic agents.

Prevalence of coccidia in lagomorphs in China between 1981 and 2023: A systematic review and meta-analysis.

Lagomorpha coccidiosis, caused by coccidia, is a prevalent disease affecting rabbits, hares and pikas. This meta-analysis aimed to estimate the pooled prevalence of coccidia infection in lagomorphs and identify potential risk factors. A systematic search of six databases yielded 102 studies published between 1981 and 2023. The pooled prevalence of Eimeriidae, Sarcocystidae and Cryptosporidiidae in lagomorphs was 76.4%, 6.2% and 3.9%, respectively. Rabbits had the highest prevalence of Eimeriidae (76.8%) and Sarcocystidae (7.4%), while pikas had the highest prevalence of Cryptosporidiidae (6.2%). Juvenile rabbits exhibited the highest prevalence of Eimeriidae (84.6%) and Cryptosporidiidae (9.9%). Northwest China had the highest prevalence of Eimeriidae (87.8%). Over time, the prevalence of Eimeriidae declined (Coefficient: -0.0062; P<0.05), but remained high (65.0%) in the past five years. Our findings highlight the prevalence of Eimeriidae infection in lagomorphs and the need for further research on Sarcocystidae and Cryptosporidiidae infections. We emphasize the importance of developing lagomorpha coccidia vaccines and implementing vaccination schedules for juvenile rabbits to mitigate coccidia infections.

MeIS: DNA methylation-based immune response signatures for thyroid nodule diagnostics.

CONTEXT: Accurately distinguishing between benign thyroid nodules (BTNs) and papillary thyroid cancers (PTCs) with current conventional methods poses a significant challenge. OBJECTIVE: We identify DNA methylation markers of immune response-related genes for distinguishing BTNs and PTCs. METHODS: In this study, we analyzed a public reduced representative bisulfite sequencing (RRBS) dataset and revealed distinct methylation patterns associated with immune signals in PTCs and BTNs. Based on these findings, we developed a diagnostic classifier named as the Methylation-based Immune Response Signature (MeIS), which was composed of fifteen DNA methylation markers associated with immune response-related genes. We validated the MeIS's performance in two independent cohorts: ZS's retrospective cohort (50 PTC and 18 BTN surgery-leftover samples) and ZS's preoperative cohort (31 PTC and 30 BTN fine-needle aspiration (FNA) samples). RESULTS: The MeIS classifier demonstrated significant clinical promise, achieving AUCs of 0.96, 0.98, 0.89 and 0.90 in the training set, validation set, ZS's retrospective cohort, and ZS's preoperative cohort, respectively. For the cytologically indeterminate thyroid nodules, in the ZS's retrospective cohort, MeIS exhibited a sensitivity of 91% and a specificity of 82%; in the ZS's preoperative cohort, MeIS achieved a sensitivity of 84% and a specificity of 74%. Additionally, combining MeIS and BRAFV600E detection improved the detecting performance of cytologically indeterminate thyroid nodules, yielding sensitivities of 98% and 87%, and specificities of 82% and 74% in the ZS's retrospective cohort and ZS's preoperative cohort, respectively. CONCLUSIONS: The fifteen markers we identified can be employed to improve the diagnostic of cytologically indeterminate thyroid nodules.

Increased di-(2-ethylhexyl) phthalate exposure poses a differential risk for adult asthma clusters.

BACKGROUND: DEHP, a common plasticizer known for its hormone-disrupting properties, has been associated with asthma. However, a significant proportion of adult asthma cases are "non-atopic", lacking a clear etiology. METHODS: In a case-control study conducted between 2011 and 2015, 365 individuals with current asthma and 235 healthy controls from Kaohsiung City were enrolled. The control group comprised individuals without asthma, Type 2 Diabetes Mellitus (T2DM), hypertension, or other respiratory/allergic conditions. The study leveraged asthma clusters (Clusters A to F) established in a prior investigation. Analysis involved the examination of urinary DEHP metabolites (MEHP and MEHHP), along with the assessment of oxidative stress, sphingolipid metabolites, and inflammatory biomarkers. Statistical analyses encompassed Spearman's rank correlation coefficients, multiple logistic regression, and multinomial logistic regression. RESULTS: Asthma clusters (E, D, C, F, A) exhibited significantly higher ORs of MEHHP exposures compared to the control group. When considering asthma-related comorbidities (T2DM, hypertension, or both), patients without comorbidities demonstrated significantly higher ORs of the sum of primary and secondary metabolites (MEHP + MEHHP) and MEHHP compared to those with asthma comorbidities. A consistent positive correlation between urinary HEL and DEHP metabolites was observed, but a consistent negative correlation between DEHP metabolites and selected cytokines was identified. CONCLUSION: The current study reveals a heightened risk of MEHHP and MEHP + MEHHP exposure in specific asthma subgroups, emphasizing its complex relationship with asthma. The observed negative correlation with cytokines suggests a new avenue for research, warranting robust evidence from epidemiological and animal studies.

MHD-Net: Memory-Aware Hetero-Modal Distillation Network for Thymic Epithelial Tumor Typing With Missing Pathology Modality.

Fusing multi-modal radiology and pathology data with complementary information can improve the accuracy of tumor typing. However, collecting pathology data is difficult since it is high-cost and sometimes only obtainable after the surgery, which limits the application of multi-modal methods in diagnosis. To address this problem, we propose comprehensively learning multi-modal radiology-pathology data in training, and only using uni-modal radiology data in testing. Concretely, a Memory-aware Hetero-modal Distillation Network (MHD-Net) is proposed, which can distill well-learned multi-modal knowledge with the assistance of memory from the teacher to the student. In the teacher, to tackle the challenge in hetero-modal feature fusion, we propose a novel spatial-differentiated hetero-modal fusion module (SHFM) that models spatial-specific tumor information correlations across modalities. As only radiology data is accessible to the student, we store pathology features in the proposed contrast-boosted typing memory module (CTMM) that achieves type-wise memory updating and stage-wise contrastive memory boosting to ensure the effectiveness and generalization of memory items. In the student, to improve the cross-modal distillation, we propose a multi-stage memory-aware distillation (MMD) scheme that reads memory-aware pathology features from CTMM to remedy missing modal-specific information. Furthermore, we construct a Radiology-Pathology Thymic Epithelial Tumor (RPTET) dataset containing paired CT and WSI images with annotations. Experiments on the RPTET and CPTAC-LUAD datasets demonstrate that MHD-Net significantly improves tumor typing and outperforms existing multi-modal methods on missing modality situations.

Multi-object distance determination by analysis of CoC variation for dynamic structured light.

A multi-object distance determination method can be achieved by 932 nm structured light with one camera as the data receiver. The structured light generated by a liquid crystal on silicon spatial light modulator (LCoS-SLM) facilitates dynamic image projection on targets. A series of moving light strip images were captured and collected for data analysis. This method lifted the limitation of single-object distance determination and the limitation of the angle requirement between the camera and the light source in the triangulation method. The average error of this method was approximately 3% in the range of 700 mm to 1900 mm away from LCoS-SLM without further optimization. It provides a potential compact design for indoor multi-object distance determination in the future.

Regulation of regulatory T cells and tumor-associated macrophages in gastric cancer tumor microenvironment.

INTRODUCTION: Despite advancements in the methods for prevention and early diagnosis of gastric cancer (GC), GC continues to be the fifth in incidence among major cancers and the third most common cause of cancer-related death. The therapeutic effects of surgery and drug treatment are still unsatisfied and show notable differences according to the tumor microenvironment (TME) of GC. METHODS: Through screening Pubmed, Embase, and Web of Science, we identified and summarized the content of recent studies that focus on the investigation of Helicobacter pylori (Hp) infection, regulatory T cells (Tregs), and tumor-associated macrophages (TAMs) in the TME of GC. Furthermore, we searched and outlined the clinical research progress of various targeted drugs in GC treatment including CTLA-4, PD-1\PD-L1, and VEGF/VEGFR. RESULTS: In this review, the findings indicate that Hp infection causes local inflammation and leads to immunosuppressive environment. High Tregs infiltration in the TME of GC is associated with increased induction and recruitment; the exact function of infiltrated Tregs in GC was also affected by phenotypes and immunosuppressive molecules. TAMs promote the development and metastasis of tumors, the induction, recruitment, and function of TAMs in the TME of gastric cancer are also regulated by various factors. CONCLUSION: Discussing the distinct tumor immune microenvironment (TIME) of GC can deepen our understanding on the mechanism of cancer immune evasion, invasion, and metastasis, help us to reduce the incidence of GC, and guide the innovation of new therapeutic targets for GC eventually.

5-Methoxytryptophan enhances the sensitivity of sorafenib on the inhibition of proliferation and metastasis for lung cancer cells.

BACKGROUND: Lung cancer is a leading cause of cancer-related mortality worldwide, and effective therapies are limited. Lung cancer is a leading cause of cancer-related mortality worldwide with limited effective therapy. Sorafenib is a multi-tyrosine kinase inhibitor frequently used to treat numerous types of malignant tumors. However, it has been demonstrated that sorafenib showed moderate antitumor activity and is associated with several side effects in lung cancer, which restricted its clinical application. This study aimed to examine the antitumor effect of the combination treatment of sorafenib and 5-methoxytryptophan (5-MTP) on cell growth and metastasis of Lewis lung carcinoma (LLC) cells. METHOD: The anticancer effect of the combination treatment of sorafenib and 5-MTP was determined through cytotoxicity assay and colony forming assays. The mechanism was elucidated using flow cytometry and western blotting. Wound healing and Transwell assays were conducted to evaluate the impact of the combination treatment on migration and invasion abilities. An in vivo model was employed to analyze the effect of the combination treatment on the tumorigenic ability of LLC cells. RESULT: Our results demonstrated that the sorafenib and 5-MTP combination synergistically reduced viability and proliferation compared to sorafenib or 5-MTP treatment alone. Reduction of cyclin D1 expression was observed in the sorafenib alone or combination treatments, leading to cell cycle arrest. Furthermore, the sorafenib-5-MTP combination significantly increased the inhibitory effect on migration and invasion of LLC cells compared to the single treatments. The combination also significantly downregulated vimentin and MMP9 levels, contributing to the inhibition of metastasis. The reduction of phosphorylated Akt and STAT3 expression may further contribute to the inhibitory effect on proliferation and metastasis. In vivo, the sorafenib-5-MTP combination further reduced tumor growth and metastasis compared to the treatment of sorafenib alone. CONCLUSIONS: In conclusion, our data indicate that 5-MTP sensitizes the antitumor activity of sorafenib in LLC cells in vitro and in vivo, suggesting that sorafenib-5-MTP has the potential to serve as a therapeutic option for patients with lung cancer.