SAFFRON-104: a phase Ib/II study of sitravatinib alone or with tislelizumab in advanced hepatocellular carcinoma and gastric cancer/gastroesophageal junction cancer.

BACKGROUND: Sitravatinib is a spectrum-selective tyrosine kinase inhibitor targeting TAM (TYRO3, AXL, MER), VEGFR-2, KIT, and MET. SAFFRON-104 (NCT03941873) was a multicohort phase Ib/II study investigating sitravatinib with/without tislelizumab, an anti-programmed cell death protein 1 (PD-1) antibody, in patients with advanced hepatocellular carcinoma (HCC) or gastric cancer/gastroesophageal junction cancer (GC/GEJC). METHODS: Eligible patients had histologically/cytologically confirmed advanced HCC or GC/GEJC. Phase I determined the recommended phase II dose (RP2D) of sitravatinib with/without tislelizumab. Phase II evaluated sitravatinib monotherapy in patients with pretreated HCC, and sitravatinib plus tislelizumab in anti-PD-(L)1-naïve or -treated HCC and anti-PD-(L)1-naïve GC/GEJC. Primary endpoints were safety/tolerability (phase I) and objective response rate (ORR) (phase II). RESULTS: At data cutoff (March 31, 2023), 111 patients were enrolled; 102 were efficacy-evaluable (median study follow-up 9.1 months [range: 0.7-36.9]). The RP2D of sitravatinib was determined as 120 mg orally once daily. In patients receiving sitravatinib monotherapy and sitravatinib in combination with tislelizumab, grade ≥ 3 treatment-related adverse events occurred in 14 (51.9%) and 42 (50.0%) patients, respectively. The ORR was 25% (95% confidence interval [CI]: 8.7-49.1) in patients with pretreated HCC receiving sitravatinib monotherapy. In patients receiving sitravatinib with tislelizumab, the ORR was 11.5% (95% CI 2.4-30.2) with anti-PD-(L)1-naïve HCC, 9.5% (95% CI 1.2-30.4) with anti-PD-(L)1-treated HCC, and 16.1% (95% CI 5.5-33.7) in patients with anti-PD-(L)1-naïve GC/GEJC. CONCLUSIONS: Sitravatinib with/without tislelizumab was generally well tolerated and showed preliminary antitumor activity in patients with advanced HCC and GC/GEJC.

A novel biomarker GATM suppresses proliferation and malignancy of cholangiocarcinoma cells by modulating the JNK/c-Jun signalling pathways.

Background: Cholangiocarcinoma (CCA) is the second most common primary malignancy of the liver and is associated with poor prognosis. Despite the emerging role of glycine amidinotransferase (GATM) in cancer development, its function in CCA remains elusive. This study investigated the biological significance and molecular mechanisms of GATM in CCA. Method: GATM expression was measured using immunohistochemistry and western blotting. Cell proliferation, migration, and invasion were assessed through CCK-8, EdU, clone formation, wound healing, and Transwell assays. Rescue experiments were performed to determine whether the JNK/c-Jun pathway is involved in GATM-mediated CCA development. Immunoprecipitation and mass spectrometry were performed to screen for proteins that interact with GATM. The role of GATM in vivo was investigated according to the xenograft experiment. Result: GATM expression was downregulated in CCA tissues and cells (p < 0.05) and had a significant suppressive effect on CCA cell proliferation, migration, and invasion in vitro as well as on tumour growth in vivo (p < 0.05); conversely, GATM knockdown promoted these phenotypes (p < 0.05). Notably, GATM inhibited the JNK/c-Jun pathway, and JNK activation abrogated GATM's antitumor effects (p < 0.05). Isocitrate dehydrogenase 1 (IDH1) interacts with GATM, and IDH1 knockdown significantly attenuated GATM protein degradation. Overexpression of IDH1 restored the biological function of CCA by reversing the inhibition of JNK/c-Jun pathway phosphorylation by GATM (p < 0.05). Conclusion: GATM acts as a tumour suppressor in CCA by regulating the phosphorylation of the JNK/c-Jun pathway. IDH1 interacted with GATM to regulate CCA progression.

USP49 promotes adenocarcinoma of the esophagogastric junction malignant progression via activating SHCBP1-ß-catenin-GPX4 axis.

Adenocarcinoma of the esophagogastric junction (AEG) has received widespread attention because of its increasing incidence. However, the molecular mechanism underlying tumor progression remains unclear. Here, we report that the downregulation of Ubiquitin-specific peptidase 49 (USP49) promotes ferroptosis in OE33 and OE19 cells, thereby inhibiting cell proliferation in vitro and in vivo, whereas the overexpression of USP49 had the opposite effect. In addition, USP49 downregulation promoted AEG cell radiotherapy sensitivity. Moreover, overexpression of Glutathione PeroXidase 4 (GPX4) reversed the ferroptosis and proliferation inhibition induced by USP49 knockdown. Mechanistically, USP49 deubiquitinates and stabilizes Shc SH2-domain binding protein 1 (SHCBP1), subsequently facilitating the entry of ß-catenin into the nucleus to enhance GPX4 transcriptional expression. Finally, high USP49 expression was correlated with shorter overall survival in patients with AEG. In summary, our findings identify USP49 as a novel regulator of ferroptosis in AEG cells, indicating that USP49 may be a potential therapeutic target in AEG.

MDM2 inhibitors in cancer immunotherapy: Current status and perspective.

Murine double minute 2 (MDM2) plays an essential role in the cell cycle, apoptosis, DNA repair, and oncogene activation through p53-dependent and p53-independent signaling pathways. Several preclinical studies have shown that MDM2 is involved in tumor immune evasion. Therefore, MDM2-based regulation of tumor cell-intrinsic immunoregulation and the immune microenvironment has attracted increasing research attention. In recent years, immune checkpoint inhibitors targeting PD-1/PD-L1 have been widely used in the clinic. However, the effectiveness of a single agent is only approximately 20%-40%, which may be related to primary and secondary drug resistance caused by the dysregulation of oncoproteins. Here, we reviewed the role of MDM2 in regulating the immune microenvironment, tumor immune evasion, and hyperprogression during immunotherapy. In addition, we summarized preclinical and clinical findings on the use of MDM2 inhibitors in combination with immunotherapy in tumors with MDM2 overexpression or amplification. The results reveal that the inhibition of MDM2 could be a promising strategy for enhancing immunotherapy.

Efficacy and Safety of Iparomlimab, an Anti-PD-1 Antibody, in Patients with Advanced Solid Tumors: A Phase 1c Study.

INTRODUCTION: Iparomlimab (QL1604) is a humanized immunoglobulin G4 mAb against programmed cell death protein 1 (PD-1). Here, we report the preliminary efficacy, safety, pharmacokinetics, and immunogenicity of iparomlimab in patients with advanced solid tumors. METHODS: In this open-label, phase 1c study, patients with advanced or metastatic solid tumors, either failed or had no standard therapies available, were enrolled and received intravenous iparomlimab at 3 mg/kg once every 3 weeks. The primary efficacy endpoint was the objective response rate (ORR) assessed by the investigator per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. RESULTS: Between July 20, 2020, and September 6, 2021, 71 patients were enrolled and received at least one dose of iparomlimab. The ORR was 9.9% (7/71) and disease control rate was 36.6% (26/71). Median duration of response of all responders was 10.7 months [95% confidence interval (CI), 1.4-not estimable]. Additionally, the median time to progression, progression-free survival, and overall survival were 1.4 months (95% CI, 1.4-2.8), 1.4 months (95% CI, 1.4-2.7), and 9.7 months (95% CI, 7.2-15.3), respectively. A total of 52 (73.2%) patients experienced treatment-related adverse events (TRAEs) (grade ≥ 3, 19.7%). The most common TRAE (≥ 10%) was anemia (18.3%). A total of 20 (28.2%) experienced immune-related adverse events (grade ≥ 3, 7.0%). TRAEs leading to discontinuation of study drug occurred in 4 (5.6%) patients, including immune-mediated myocarditis (2 patients), Guillain-Barré syndrome (1 patient), and diarrhea (1 patient). CONCLUSIONS: Iparomlimab showed preliminary clinical activity and had a manageable safety profile in patients with advanced solid tumors. These results support further investigation of iparomlimab as monotherapy or in combination therapy in advanced solid tumors. TRIAL REGISTRATION: ClinicalTrials.gov identifier, NCT05801094. Retrospectively registered in 2023-03-24.

Platelet integrin αIIbß3 plays a key role in venous thrombogenesis in a mouse model.

Venous thrombosis (VT) is a common vascular disease associated with reduced survival and a high recurrence rate. Previous studies have shown that the accumulation of platelets and neutrophils at sites of endothelial cell activation is a primary event in VT, but a role for platelet αIIbß3 in the initiation of venous thrombosis has not been established. This task has been complicated by the increased bleeding linked to partial agonism of current αIIbß3 inhibitory drugs such as tirofiban (Aggrastat ® ). Here, we show that m-tirofiban, an engineered version of tirofiban, is not a partial agonist of αIIbß3. This is based on its cryo-EM structure in complex with human full-length αIIbß3 and its inability to increase expression of an activation-sensitive epitope on platelet αIIbß3. m-tirofiban abolished agonist-induced platelet aggregation ex vivo at concentrations that preserved clot retraction and markedly suppressed the accumulation of platelets, neutrophils, and fibrin on thrombin-activated endothelium in real-time using intravital microscopy in a mouse model of venous thrombogenesis. Unlike tirofiban, however, m-tirofiban did not increase bleeding at the thrombosis-inhibitory dose. These findings establish a key role for αIIbß3 in the initiation of VT, provide a guiding principle for designing potentially safer inhibitors for other integrins, and suggest that pure antagonists of αIIbß3 like m-tirofiban merit further consideration as potential thromboprophylaxis agents in patients at high-risk for VT and hemorrhage.

Central nervous system efficacy of aumolertinib versus gefitinib in patients with untreated, EGFR-mutated, advanced non-small cell lung cancer: data from a randomized phase III trial (AENEAS).

BACKGROUND: The initial randomized, double-blinded, actively controlled, phase III ANEAS study (NCT03849768) demonstrated that aumolertinib showed superior efficacy relative to gefitinib as first-line therapy in epidermal growth factor receptor (EGFR)-mutated advanced non-small cell lung cancer (NSCLC). Metastatic disease in the central nervous system (CNS) remains a challenge in the management of NSCLC. This study aimed to compare the efficacy of aumolertinib versus gefitinib among patients with baseline CNS metastases in the ANEAS study. METHODS: Eligible patients were enrolled and randomly assigned in a 1:1 ratio to orally receive either aumolertinib or gefitinib in a double-blinded fashion. Patients with asymptomatic, stable CNS metastases were included. Follow-up imaging of the same modality as the initial CNS imaging was performed every 6 weeks for 15 months, then every 12 weeks. CNS response was assessed by a neuroradiological blinded, independent central review (neuroradiological-BICR). The primary endpoint for this subgroup analysis was CNS progression-free survival (PFS). RESULTS: Of the 429 patients enrolled and randomized in the ANEAS study, 106 patients were found to have CNS metastases (CNS Full Analysis Set, cFAS) at baseline by neuroradiological-BICR, and 60 of them had CNS target lesions (CNS Evaluable for Response, cEFR). Treatment with aumolertinib significantly prolonged median CNS PFS compared with gefitinib in both cFAS (29.0 vs. 8.3 months; hazard ratio [HR] = 0.31; 95% confidence interval [CI], 0.17-0.56; P < 0.001) and cEFR (29.0 vs. 8.3 months; HR = 0.26; 95% CI, 0.11-0.57; P < 0.001). The confirmed CNS overall response rate in cEFR was 85.7% and 75.0% in patients treated with aumolertinib and gefitinib, respectively. Competing risk analysis showed that the estimated probability of CNS progression without prior non-CNS progression or death was consistently lower with aumolertinib than with gefitinib in patients with and without CNS metastases at baseline. No new safety findings were observed. CONCLUSIONS: These results indicate a potential advantage of aumolertinib over gefitinib in terms of CNS PFS and the risk of CNS progression in patients with EGFR-mutated advanced NSCLC with baseline CNS metastases. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT03849768.

Meta-analysis study of small extracellular vesicle nursing application therapies for healing of wounds and skin regeneration.

We designed and performed this meta-analysis to investigate the impact of the application of extracellular small vesicle therapies on regeneration of skin and wound healing. The findings of this study were computed using fixed or random effect models. The mean differences (MDs), and odds ratio (ORs) with their 95% confidence intervals (CIs) were calculated. In this study, 43 publications were included, encompassing 530 animals with artificial wounds. Small extracellular vesicle therapy had a significant greater rate of wound closure (MD, 24.0; 95% CI, 19.98-28.02, P < 0.001), lower scar width (MD, -191.33; 95%CI, -292.26--90.4, P < 0.001), and higher blood vessel density (MD,36.11; 95%CI, 19.02-53.20, P < 0.001) compared to placebo. Our data revealed that small extracellular vesicle therapy had a significantly higher regeneration of skin and healing of wounds based on the results of wound closure rate, lower scar width, and higher blood vessel density compared to placebo. Future studies with larger sample size are needed.

Clinical features and treatment outcomes of PD-1 inhibitor therapy in elderly patients (≥ 65 years) with advanced esophageal squamous cell carcinoma: a real-world study.

PURPOSE: This study aims to determine the clinical features and outcomes of PD-1 inhibitor therapy as the initial treatment in patients aged 65 years or older with locally advanced or metastatic esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: The retrospective study conducted a comprehensive analysis of elder patients diagnosed with locally advanced or metastatic ESCC who underwent combined immunochemotherapy in the first affiliated hospital of Nanchang University from January 2019 to January 2023. The main efficacy measures were the objective response rate (ORR) and progression-free survival (PFS). The secondary endpoints were disease control rate (DCR) and overall survival (OS). The evaluation of safety was based on the assessment of adverse events (AEs). RESULTS: A total of 88 patients were enrolled in the study. All patients received PD-1 inhibitors combined with chemotherapy including taxane and platinum as the first-line treatment. The median PFS was 6.2 months (95% CI: 5.1-7.3), and the median OS was 15.3 months (95% CI: 12.9-17.7). The ORR and DCR were 42.0% and 72.7%, correspondingly. 68 (77.3%) patients experienced treatment-related adverse events (TRAEs) of various degrees, with neutrophil count decreased (21, 23.9%) being the most frequent. TRAEs of grade 3 or 4 occurred in 13 (14.8%) patients. CONCLUSION: The study demonstrated that individuals older than 65 years with locally advanced or metastatic ESCC have a survival benefit from the first-line treatment of PD-1 inhibitors combined therapy, with a manageable safety profile.

YTHDF1 regulates immune cell infiltration in gastric cancer via interaction with p53.

The N6-methyladenosine reader YTH N6-methyladenosine RNA binding protein 1 (YTHDF1) has been assessed in several tumor types and holds significance in the tumor microenvironment (TME). Furthermore, p53, an important tumor suppressor, is closely associated with the TME. The present study evaluated the roles of YTHDF1 and p53 in regulating the TME in gastric cancer (GC). Genetic alterations in the YTH domain family were analyzed using the cBioPortal database. Expression of YTHDF1 in GC cells and tissues was assessed using the Tumor Immune Estimation Resource (TIMER), Gene Expression Profiling Interactive Analysis (GEPIA), University of Alabama at Birmingham Cancer data analysis portal and Tumor-Immune System Interactions and Drug Bank (TISIDB) databases, along with reverse-transcription-quantitative PCR and western blotting in GC. The prognostic value of multiple tumors was determined using Kaplan-Meier analysis. Correlation analyses were performed using the TIMER, TISIDB and GEPIA databases. Protein-protein interactions of YTHDF1 were predicted using GeneMANIA and HitPredict, and confirmed using co-immunoprecipitation. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses of the YTHDF1 functional network in GC were performed using LinkedOmics. Genetic alterations revealed that, among the YTH domain family members, YTHDF1 had the highest alteration in GC and was associated with a shorter survival. Additionally, YTHDF1 was significantly negatively associated with the level of CD8+ T cells, B cells, macrophages, dendritic cells (DCs) and neutrophils in GC. Furthermore, tumor associate macrophage-related and DC markers were significantly negatively correlated with YTHDF1 expression, whilst regulatory T cells and T cell exhaustion markers were significantly negatively associated with YTHDF1 expression. In addition, compared with that in p53-nonmutant GC cells, YTHDF1 expression was significantly higher in p53-mutated GC cells, indicating a potential association between YTHDF1 and p53. Analyses using the GeneMANIA and HitPredict databases, and co-immunoprecipitation, demonstrated that YTHDF1 interacted with p53. In conclusion, the findings of the present study indicate that YTHDF1 is associated with a poor prognosis and serves an important role in the TME of GC. We hypothesize, for the first time to the best of our knowledge, that YTHDF1 regulates immune cell infiltration by interacting with p53 in GC, which provides a promising direction for future research.

YB-1 Targeted by miR-509-3-5p Affects Migration and Invasion of Triple­Negative Breast Cancer by Regulating Cellular Epithelial­Mesenchymal Transition.

The epithelial-mesenchymal transition (EMT) process is closely linked to metastasis of breast cancer. This article elucidates the role of Y-box binding protein-1 (YB-1) on the migration and invasion of triple-negative breast cancer (TNBC) cells by regulating EMT, and the related mechanism. The expression data of YB-1 and miR-509-3-5p in TNBC samples and normal samples were downloaded from the GEO database. The proliferation, migration, invasion, and EMT of TNBC cells were detected by CCK-8 assay, colony formation assay, wound-healing assay, transwell assay, and immunoblotting analyses. The targeted binding of YB-1 and miR-509-3-5p was validated by luciferase reporter experiment. A xenograft mouse model was constructed to investigate the influence of the miR-509-3-5p/YB-1 axis on TNBC tumor growth in vivo. YB-1 was overexpressed, while miR-509-3-5p was underexpressed in TNBC tumor tissues and various cell lines. Silencing YB-1 depressed cell viability, proliferation, motility, and EMT in vitro, and miR-509-3-5p upregulation exerted the same effects. YB-1 was targeted by miR-509-3-5p. The suppressive effects on the phenotypes of TNBC cells caused by overexpressed miR-509-3-5p were attenuated by YB-1 upregulation. In addition, miR-509-3-5p overexpression restrained TNBC tumor growth and downregulated the YB-1-mediated EMT process in vivo. YB-1 targeted by miR-509-3-5p affects motility of TNBC cells by regulating cellular EMT.

Polarization-Sensitive OCT Imaging of Scleral Abnormalities in Eyes With High Myopia and Dome-Shaped Macula.

Importance: The relevance of visualizing scleral fiber orientation may offer insights into the pathogenesis of pathologic myopia, including dome-shaped maculopathy (DSM). Objective: To investigate the orientation and density of scleral collagen fibers in highly myopic eyes with and without DSM by polarization-sensitive optical coherence tomography (PS-OCT). Design, Setting, and Participants: This case series included patients with highly myopic eyes (defined as a refractive error ≥6 diopters or an axial length ≥26.5 mm) with and without a DSM examined at a single site in May and June 2019. Analysis was performed from September 2019 to October 2023. Exposures: The PS-OCT was used to study the birefringence and optic axis of the scleral collagen fibers. Main Outcomes and Measures: The orientation and optic axis of scleral fibers in inner and outer layers of highly myopic eyes were assessed, and the results were compared between eyes with and without a DSM. Results: A total of 72 patients (51 [70.8%] female; mean [SD] age, 61.5 [12.8] years) were included, and 89 highly myopic eyes were examined (mean [SD] axial length, 30.4 [1.7] mm); 52 (58.4%) did not have a DSM and 37 (41.6%) had a DSM (10 bidirectional [27.0%] and 27 horizontal [73.0%]). Among the 52 eyes without DSM, the 13 eyes with simple high myopia had primarily inner sclera visible, displaying radially oriented fibers in optic axis images. In contrast, the entire thickness of the sclera was visible in 39 eyes with pathologic myopia. In these eyes, the optic axis images showed vertically oriented fibers within the outer sclera. Eyes presenting with both horizontal and bidirectional DSMs had clusters of fibers with low birefringence at the site of the DSM. In the optic axis images, horizontally or obliquely oriented scleral fibers were aggregated in the inner layer at the DSM. The vertical fibers located posterior to the inner fiber aggregation were not thickened and appeared thin compared with the surrounding areas. Conclusions and Relevance: This study using PS-OCT revealed inner scleral fiber aggregation without outer scleral thickening at the site of the DSM in highly myopic eyes. Given the common occurrence of scleral pathologies, such as DSM, and staphylomas in eyes with pathologic myopia, recognizing these fiber patterns could be important. These insights may be relevant to developing targeted therapies to address scleral abnormalities early and, thus, mitigate potential damage to the overlying neural tissue.

YAP1-CPNE3 positive feedback pathway promotes gastric cancer cell progression.

Hippo-Yes-associated protein 1 (YAP1) plays an important role in gastric cancer (GC) progression; however, its regulatory network remains unclear. In this study, we identified Copine III (CPNE3) was identified as a novel direct target gene regulated by the YAP1/TEADs transcription factor complex. The downregulation of CPNE3 inhibited proliferation and invasion, and increased the chemosensitivity of GC cells, whereas the overexpression of CPNE3 had the opposite biological effects. Mechanistically, CPNE3 binds to the YAP1 protein in the cytoplasm, inhibiting YAP1 ubiquitination and degradation mediated by the E3 ubiquitination ligase ß-transducin repeat-containing protein (ß-TRCP). Thereby activating the transcription of YAP1 downstream target genes, which creates a positive feedback cycle to facilitate GC progression. Immunohistochemical analysis demonstrated significant upregulation of CPNE3 in GC tissues. Survival and Cox regression analyses indicated that high CPNE3 expression was an independent prognostic marker for GC. This study elucidated the pivotal involvement of an aberrantly activated CPNE3/YAP1 positive feedback loop in the malignant progression of GC, thereby uncovering novel prognostic factors and therapeutic targets in GC.

TMEM160 promotes tumor immune evasion and radiotherapy resistance via PD-L1 binding in colorectal cancer.

BACKGROUND: The effectiveness of anti-programmed cell death protein 1(PD-1)/programmed cell death 1 ligand 1(PD-L1) therapy in treating certain types of cancer is associated with the level of PD-L1. However, this relationship has not been observed in colorectal cancer (CRC), and the underlying regulatory mechanism of PD-L1 in CRC remains unclear. METHODS: Binding of TMEM160 to PD-L1 was determined by co-immunoprecipitation (Co-IP) and GST pull-down assay.The ubiquitination levels of PD-L1 were verified using the ubiquitination assay. Phenotypic experiments were conducted to assess the role of TMEM160 in CRC cells. Animal models were employed to investigate how TMEM160 contributes to tumor growth.The expression and clinical significance of TMEM160 and PD-L1 in CRC tissues were evaluated by immunohistochemistry(IHC). RESULTS: In our study, we made a discovery that TMEM160 interacts with PD-L1 and plays a role in stabilizing its expression within a CRC model. Furthermore, we demonstrated that TMEM160 hinders the ubiquitination-dependent degradation of PD-L1 by competing with SPOP for binding to PD-L1 in CRC cells. Regarding functionality, the absence of TMEM160 significantly inhibited the proliferation, invasion, metastasis, clonogenicity, and radioresistance of CRC cells, while simultaneously enhancing the cytotoxic effect of CD8 + T cells on tumor cells. Conversely, the upregulation of TMEM160 substantially increased these capabilities. In severely immunodeficient mice, tumor growth derived from lentiviral vector shTMEM160 cells was lower compared with that derived from shNC control cells. Furthermore, the downregulation of TMEM160 significantly restricted tumor growth in immune-competent BALB/c mice. In clinical samples from patients with CRC, we observed a strong positive correlation between TMEM160 expression and PD-L1 expression, as well as a negative correlation with CD8A expression. Importantly, patients with high TMEM160 expression exhibited a worse prognosis compared with those with low or no TMEM160 expression. CONCLUSIONS: Our study reveals that TMEM160 inhibits the ubiquitination-dependent degradation of PD-L1 that is mediated by SPOP, thereby stabilizing PD-L1 expression to foster the malignant progress, radioresistance, and immune evasion of CRC cells. These findings suggest that TMEM160 holds potential as a target for the treatment of patients with CRC.

The role and molecular mechanism of NOP16 in the pathogenesis of nasopharyngeal carcinoma.

We aimed to explore the effects of NOP16 on the pathogenesis of nasopharyngeal carcinoma (NPC) and the related mechanism. In this study, the expression level of NOP16 in NPC tissues and adjacent tissues was measured by qRT-polymerase chain reaction (PCR) and immunohistochemistry (IHC) tests. In the in vitro study, the expression levels of NOP16 and RhoA/phosphatidylinositol 3-kinase (PI3K)/Akt/c-Myc and IKK/IKB/NF-κB signalling pathway-related proteins in NPC cells were measured by qRT-PCR and Western blot (WB). CCK8 assays and colony formation assays were used to detect cell proliferation. Transwell assays were used to detect the migration and invasion ability of NPC cells. Flow cytometry and WB were used to measure the level of apoptosis. For the in vivo study, NPC xenograft models were established in nude mice, and tumour weight and volume were recorded. The expression levels of NOP16 and RhoA/PI3K/Akt/c-Myc signalling pathway-related proteins and mRNAs were measured by immunofluorescence, qRT-PCR and WB experiments. In clinical samples, the results of qRT-PCR and IHC experiments showed that the expression level of NOP16 was significantly increased in NPC tissues. In the in vitro study, the results of qRT-PCR and WB experiments showed that NOP16 was significantly increased in NPC cells. The CCK8 assay, colony formation assay, transwell assay and flow cytometry results showed that knocking out NOP16 inhibited the proliferation, migration and invasion of NPC cells and increased apoptosis. WB results showed that knocking out NOP16 inhibited the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB signalling pathways. These effects were reversed by 740Y-P (PI3K activator). In the in vivo study, knockdown of NOP16 reduced tumour volume and weight and inhibited the RhoA/PI3K/Akt/c-Myc signalling pathway. In conclusion, knockdown of NOP16 inhibited the proliferation, migration and invasion of NPC cells and induced apoptosis by inhibiting the RhoA/PI3K/Akt/c-Myc and IKK/IKB/NF-κB pathways, leading to the malignant phenotype of NPC.

Phase 1b/2 study of penpulimab (AK105), an antiprogrammed cell death-1 immunoglobulin G1 antibody, in advanced or metastatic solid tumors (AK105-204).

BACKGROUND: Penpulimab, a new-generation antiprogrammed cell death-1 immunoglobulin G1 monoclonal antibody, was engineered to optimize receptor occupancy and eliminate fragment crystallizable γ-mediated effector function. In this multicenter, phase 1b/2, multicohort study, the objective was to investigate the efficacy, safety, and immunogenicity of penpulimab in advanced solid tumors. METHODS: Patients who had unresectable, advanced solid tumors were enrolled from six centers and received 200 mg penpulimab on day 1 every 2 weeks for up to 24 months. The primary end point was the objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors, version criteria 1.1. RESULTS: Between September 2, 2019, and January 1, 2020, 65 patients were enrolled and received penpulimab. At the time of data cutoff (May 11, 2022), the median follow-up was 12.6 months (range, 1.1-28.6 months). The ORR was 12.3 (95% confidence interval [CI], 5.5%-22.8%), with three (4.6%) complete responses and five (7.7%) partial responses. Twelve patients (18.5%) achieved stable disease, resulting in a disease control rate of 30.8% (95% CI, 19.9%-43.4%). The median duration of response was not reached (95% CI, 6.70 months to not estimable). In all cohorts, the median progression-free survival was 1.74 months (95% CI, 1.41-2.69 months), and the median overall survival was 16.59 months (95% CI, 7.82-22.18 months). Grade 3 or greater treatment-related adverse events and immune-related adverse events occurred in 9.2% and 27.7% of patients, respectively. Positive antidrug antibody responses to penpulimab were observed in one patient (1.8%). CONCLUSIONS: Penpulimab showed promising antitumor activity with an acceptable safety profile, offering a potential new treatment approach for solid tumors. These findings supported the evaluation of penpulimab's durable activity and safety, as monotherapy or in combination therapy, in specific malignancies.

Anaplastic Lymphoma Kinase (ALK) Inhibitors Show Activity in Colorectal Cancer With ALK Rearrangements: Case Series and Literature Review.

Anaplastic lymphoma kinase (ALK) rearrangement is a well-known driver oncogene detected in approximately 5% of non-small cell lung cancer. However, ALK rearrangement is much less frequent in other solid tumors outside the lungs, such as colorectal cancer (CRC); thus, the optimal management of CRC with ALK rearrangements has yet to be established. In this report, we describe 2 cases of ALK-positive CRC, both of which benefited from ALK tyrosine kinase inhibitor (ALK-TKI) therapy. Case 1 was a postoperative patient with poorly differentiated colon adenocarcinoma, who was diagnosed with metastatic relapse shortly after surgery. Both fluorouracil, leucovorin, and oxaliplatin (FOLFOX) and bevacizumab combined with 5-fluorouracil, l-leucovorin, and irinotecan (FOLFIRI) proved ineffective against the disease. The patient was then treated with ensartinib, as the CAD-ALK fusion gene was detected by genomic analysis. The patient was initially treated with ensartinib monotherapy for 9 months, then with ensartinib combined with local radiotherapy and fruquintinib for another 4 months for isolated hilar hepatic lymph node metastasis. The patient experienced disease progression with an acquired ALK G1202R resistance mutation that responded well to lorlatinib. Case 2 involved a 72-year-old man with advanced colon cancer (pT4bN2aM1b, stage IV) harboring an EML4-ALK fusion. The patient underwent resection of the right colon tumor due to intestinal obstruction, but the disease continued to progress after 12 courses of FOLFIRI and bevacizumab chemotherapy. However, the patient responded remarkably well to alectinib. Our report emphasizes the importance of gene detection in the treatment of malignant tumors, and the significance of ALK mutations in CRC.

Exposure to low humidex increases the risk of hip fracture admissions in a subtropical coastal Chinese city.

OBJECTIVE: The adverse impacts of meteorological factors on human health have attracted great attention. However, no studies have investigated the nonlinear effects of humidex on hip fractures (HF), particularly in middle-aged and older adults. This study aimed to quantify the impacts of humidex, a comprehensive index of temperature and relative humidity, on HF admissions. METHODS: Daily HF admissions, meteorological variables and air pollutants in the subtropical coastal city of Shantou, China, from 2015 to 2020 were collected. A generalized linear regression model combined with a distributed lag nonlinear model was applied to explore the exposure-lag-response relationship between humidex and HF admissions. Subgroup analyses were also conducted by gender, age and season. Attributable fractions (AF) and attributable numbers (AN) were used to represent the burden of disease. RESULTS: A total of 6200 HF admissions were identified during the study period. Taking the median humidex (31.9) as a reference, the single-day lag effects of low humidex (13, 2.5th percentile) were significant at lag 0 [relative risk (RR) = 1.145, 95 % confidence interval (CI): 1.041-1.259] to lag 2 (RR = 1.049, 95 % CI: 1.010-1.089). The cumulative lag effects of low humidex were significant at lag 0-0 (RR = 1.145, 95 % CI: 1.041-1.259) to lag 0-6 (RR = 1.258, 95 % CI: 1.010-1.567) and reached a maximum at lag 0-3 (RR = 1.330, 95 % CI: 1.113-1.590). High humidex (44, 97.5th percentile) was not associated with the risk of HF. Females and people over the age of 75 appeared to be more susceptible to low humidex. In addition, the adverse effects of low humidex were more pronounced in the cold season. The AF and AN of low humidex on HF admissions were 24.8 % (95 % CI: 10.2-37.1 %) and 1538, respectively. CONCLUSION: Low humidex was associated with an increased risk of HF admissions. The government should take timely measures to prevent people from being exposed to low humidex to effectively reduce HF admissions.

Key roles of autophagosome/endosome maturation mediated by Syntaxin17 in methamphetamine-induced neuronal damage in mice.

BACKGROUND: Autophagic defects are involved in Methamphetamine (Meth)-induced neurotoxicity. Syntaxin 17 (Stx17), a member of the SNARE protein family, participating in several stages of autophagy, including autophagosome-late endosome/lysosome fusion. However, the role of Stx17 and potential mechanisms in autophagic defects induced by Meth remain poorly understood. METHODS: To address the mechanism of Meth-induced cognitive impairment, the adenovirus (AV) and adeno-associated virus (AAV) were injected into the hippocampus for stereotaxis to overexpress Stx17 in vivo to examine the cognitive ability via morris water maze and novel object recognition. In molecular level, the synaptic injury and autophagic defects were evaluated. To address the Meth induced neuronal damage, the epidermal growth factor receptor (EGFR) degradation assay was performed to evaluate the degradability of the "cargos" mediated by Meth, and mechanistically, the maturation of the vesicles, including autophagosomes and endosomes, were validated by the Co-IP and the GTP-agarose affinity isolation assays. RESULTS: Overexpression of Stx17 in the hippocampus markedly rescued the Meth-induced cognitive impairment and synaptic loss. For endosomes, Meth exposure upregulated Rab5 expression and its guanine-nucleotide exchange factor (GEF) (immature endosome), with a commensurate decreased active form of Rab7 (Rab7-GTP) and impeded the binding of Rab7 to CCZ1 (mature endosome); for autophagosomes, Meth treatment elicited a dramatic reduction in the overlap between Stx17 and autophagosomes but increased the colocalization of ATG5 and autophagosomes (immature autophagosomes). After Stx17 overexpression, the Rab7-GTP levels in purified late endosomes were substantially increased in parallel with the elevated mature autophagosomes, facilitating cargo (Aß42, p-tau, and EGFR) degradation in the vesicles, which finally ameliorated Meth-induced synaptic loss and memory deficits in mice. CONCLUSION: Stx17 decrease mediated by Meth contributes to vesicle fusion defects which may ascribe to the immature autophagosomes and endosomes, leading to autophagic dysfunction and finalizes neuronal damage and cognitive impairments. Therefore, targeting Stx17 may be a novel therapeutic strategy for Meth-induced neuronal injury.