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.

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.

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.

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.

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.

p53-responsive CMBL reprograms glucose metabolism and suppresses cancer development by destabilizing phosphofructokinase PFKP.

Aerobic glycolysis is critical for cancer progression and can be exploited in cancer therapy. Here, we report that the human carboxymethylenebutenolidase homolog (carboxymethylenebutenolidase-like [CMBL]) acts as a tumor suppressor by reprogramming glycolysis in colorectal cancer (CRC). The anti-cancer action of CMBL is mediated through its interactions with the E3 ubiquitin ligase TRIM25 and the glycolytic enzyme phosphofructokinase-1 platelet type (PFKP). Ectopic CMBL enhances TRIM25 binding to PFKP, leading to the ubiquitination and proteasomal degradation of PFKP. Interestingly, CMBL is transcriptionally activated by p53 in response to genotoxic stress, and p53 activation represses glycolysis by promoting PFKP degradation. Remarkably, CMBL deficiency, which impairs p53's ability to inhibit glycolysis, makes tumors more sensitive to a combination therapy involving the glycolysis inhibitor 2-deoxyglucose. Taken together, our study demonstrates that CMBL suppresses CRC growth by inhibiting glycolysis and suggests a potential combination strategy for the treatment of CMBL-deficient CRC.

miR-3133 inhibits gastrointestinal cancer progression through activation of Hippo and p53 signalling pathways via multi-targets.

BACKGROUND: Malignant cell growth and chemoresistance, the main obstacles in treating gastrointestinal cancer (GIC), rely on the Hippo and p53 signalling pathways. However, the upstream regulatory mechanisms of these pathways remain complex and poorly understood. METHODS: Immunohistochemistry (IHC), western blot and RT-qPCR were used to analyse the expression of RNF146, miR-3133 and key components of Hippo and p53 pathway. CCK-8, colony formation, drug sensitivity assays and murine xenograft models were used to investigate the effect of RNF146 and miR-3133 in GIC. Further exploration of the upstream regulatory mechanism was performed using bioinformatics analysis, dual-luciferase reporter gene, immunoprecipitation assays and bisulfite sequencing PCR (BSP). RESULTS: Clinical samples, in vitro and in vivo experiments demonstrated that RNF146 exerts oncogenic effects in GIC by regulating the Hippo pathway. Bioinformatics analysis identified a novel miRNA, miR-3133, as an upstream regulatory factor of RNF146. fluorescence in situ hybridization and RT-qPCR assays revealed that miR-3133 was less expressed in gastrointestinal tumour tissues and was associated with adverse pathological features. Functional assays and animal models showed that miR-3133 promoted the proliferation and chemotherapy sensitivity of GIC cells. miR-3133 affected YAP1 protein expression by targeting RNF146, AGK and CUL4A, thus activating the Hippo pathway. miR-3133 inhibited p53 protein degradation and extended p53's half-life by targeting USP15, SPIN1. BSP experiments confirmed that miR-3133 promoter methylation is an important reason for its low expression. CONCLUSION: miR-3133 inhibits GIC progression by activating the Hippo and p53 signalling pathways via multi-targets, including RNF146, thereby providing prognostic factors and valuable potential therapeutic targets for GIC.

Camrelizumab plus rivoceranib versus sorafenib as first-line therapy for unresectable hepatocellular carcinoma (CARES-310): a randomised, open-label, international phase 3 study.

BACKGROUND: Immunotherapy with immune checkpoint inhibitors combined with an anti-angiogenic tyrosine-kinase inhibitor (TKI) has been shown to improve overall survival versus anti-angiogenic therapy alone in advanced solid tumours, but not in hepatocellular carcinoma. Therefore, a clinical study was conducted to compare the efficacy and safety of the anti-PD-1 antibody camrelizumab plus the VEGFR2-targeted TKI rivoceranib (also known as apatinib) versus sorafenib as first-line treatment for unresectable hepatocellular carcinoma. METHODS: This randomised, open-label, international phase 3 trial (CARES-310) was done at 95 study sites across 13 countries and regions worldwide. Patients with unresectable or metastatic hepatocellular carcinoma who had not previously received any systemic treatment were randomly assigned (1:1) to receive either camrelizumab 200 mg intravenously every 2 weeks plus rivoceranib 250 mg orally once daily or sorafenib 400 mg orally twice daily. Randomisation was done via a centralised interactive response system. The primary endpoints were progression-free survival, as assessed by the blinded independent review committee per Response Evaluation Criteria in Solid Tumours version 1.1, and overall survival in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of the study drugs. We report the findings from the prespecified primary analysis for progression-free survival and interim analysis for overall survival. This study is registered with ClinicalTrials.gov (NCT03764293). FINDINGS: Between June 28, 2019, and March 24, 2021, 543 patients were randomly assigned to the camrelizumab-rivoceranib (n=272) or sorafenib (n=271) group. At the primary analysis for progression-free survival (May 10, 2021), median follow-up was 7·8 months (IQR 4·1-10·6). Median progression-free survival was significantly improved with camrelizumab-rivoceranib versus sorafenib (5·6 months [95% CI 5·5-6·3] vs 3·7 months [2·8-3·7]; hazard ratio [HR] 0·52 [95% CI 0·41-0·65]; one-sided p<0·0001). At the interim analysis for overall survival (Feb 8, 2022), median follow-up was 14·5 months (IQR 9·1-18·7). Median overall survival was significantly extended with camrelizumab-rivoceranib versus sorafenib (22·1 months [95% CI 19·1-27·2] vs 15·2 months [13·0-18·5]; HR 0·62 [95% CI 0·49-0·80]; one-sided p<0·0001). The most common grade 3 or 4 treatment-related adverse events were hypertension (102 [38%] of 272 patients in the camrelizumab-rivoceranib group vs 40 [15%] of 269 patients in the sorafenib group), palmar-plantar erythrodysaesthesia syndrome (33 [12%] vs 41 [15%]), increased aspartate aminotransferase (45 [17%] vs 14 [5%]), and increased alanine aminotransferase (35 [13%] vs eight [3%]). Treatment-related serious adverse events were reported in 66 (24%) patients in the camrelizumab-rivoceranib group and 16 (6%) in the sorafenib group. Treatment-related death occurred in two patients: one patient in the camrelizumab-rivoceranib group (ie, multiple organ dysfunction syndrome) and one patient in the sorafenib group (ie, respiratory failure and circulatory collapse). INTERPRETATION: Camrelizumab plus rivoceranib showed a statistically significant and clinically meaningful benefit in progression-free survival and overall survival compared with sorafenib for patients with unresectable hepatocellular carcinoma, presenting as a new and effective first-line treatment option for this population. FUNDING: Jiangsu Hengrui Pharmaceuticals and Elevar Therapeutics.

Total Lymph Node Yield Is Associated with Prolonged Survival after Neoadjuvant Chemotherapy in ypN0 Gastric Cancer Patients.

INTRODUCTION: Lymph node status after neoadjuvant chemotherapy (NAC) plays the main role in predicting the survival of gastric cancer (GC) patients who underwent curative gastrectomy after NAC. NAC can reduce the number of involved lymph nodes. However, it is unknown whether other variables are associated with the survival outcomes for ypN0 GC patients. It is unknown whether lymph node yield (LNY) has prognostic value in ypN0 GC patients treated with NAC plus surgery. METHODS: In this retrospective study, we reviewed the data of patients treated with NAC plus gastrectomy and identified those with ypN0 disease. The LNY cut-off was calculated using the X-tile program to determine the greatest actuarial survival difference. Patients were categorized into the downstaged N0 (cN+/ypN0) and natural N0 (cN0/ypN0) groups based on nodal status. Multivariate analysis was used to identify the prognostic factors and the association between LNY and prognosis. RESULTS: A total of 211 GC patients with ypN0 status were included. The optimal LNY cut-off was 23. Kaplan-Meier analysis revealed no significant difference in overall survival between the natural and downstaged N0 groups, while ypN0 GC patients with an LNY of ≥24 had significantly longer overall survival than those with an LNY of ≤23. Univariate analysis identified that LNY, cT stage, tumor location, ypT stage, perineural invasion, lymphovascular invasion, tumor size, Mandard tumor regression grade, and extent of gastrectomy were significantly associated with overall survival. Multivariate analysis confirmed that perineural invasion (hazard ratio, 4.246; p < 0.001), lymphovascular invasion (hazard ratio, 2.694; p = 0.048), and an LNY of ≥24 (hazard ratio, 0.394; p = 0.011) were independent prognostic factors. CONCLUSIONS: Patients with natural and downstaged ypN0 GC had similar overall survival after NAC. LNY was an independent prognostic factor in these patients, and an LNY of ≥24 predicted prolonged overall survival.

UTP11 deficiency suppresses cancer development via nucleolar stress and ferroptosis.

The eukaryotic ribosome is essential for cancer cell survival. Perturbation of ribosome biogenesis induces nucleolar stress or ribosomal stress, which restrains cancer growth, as rapidly proliferating cancer cells need more active ribosome biogenesis. In this study, we found that UTP11 plays an important role in the biosynthesis of 18S ribosomal RNAs (rRNA) by binding to the pre-rRNA processing factor, MPP10. UTP11 is overexpressed in human cancers and associated with poor prognoses. Interestingly, depletion of UTP11 inhibits cancer cell growth in vitro and in vivo through p53-depedednt and -independent mechanisms, whereas UTP11 overexpression promotes cancer cell growth and progression. On the one hand, the ablation of UTP11 impedes 18S rRNA biosynthesis to trigger nucleolar stress, thereby preventing MDM2-mediated p53 ubiquitination and degradation through ribosomal proteins, RPL5 and RPL11. On the other hand, UTP11 deficiency represses the expression of SLC7A11 by promoting the decay of NRF2 mRNA, resulting in reduced levels of glutathione (GSH) and enhanced ferroptosis. Altogether, our study uncovers a critical role for UTP11 in maintaining cancer cell survival and growth, as depleting UTP11 leads to p53-dependent cancer cell growth arrest and p53-independent ferroptosis.

Unleashing the potential of combining FGFR inhibitor and immune checkpoint blockade for FGF/FGFR signaling in tumor microenvironment.

BACKGROUND: Fibroblast growth factors (FGFs) and their receptors (FGFRs) play a crucial role in cell fate and angiogenesis, with dysregulation of the signaling axis driving tumorigenesis. Therefore, many studies have targeted FGF/FGFR signaling for cancer therapy and several FGFR inhibitors have promising results in different tumors but treatment efficiency may still be improved. The clinical use of immune checkpoint blockade (ICB) has resulted in sustained remission for patients. MAIN: Although there is limited data linking FGFR inhibitors and immunotherapy, preclinical research suggest that FGF/FGFR signaling is involved in regulating the tumor microenvironment (TME) including immune cells, vasculogenesis, and epithelial-mesenchymal transition (EMT). This raises the possibility that ICB in combination with FGFR-tyrosine kinase inhibitors (FGFR-TKIs) may be feasible for treatment option for patients with dysregulated FGF/FGFR signaling. CONCLUSION: Here, we review the role of FGF/FGFR signaling in TME regulation and the potential mechanisms of FGFR-TKI in combination with ICB. In addition, we review clinical data surrounding ICB alone or in combination with FGFR-TKI for the treatment of FGFR-dysregulated tumors, highlighting that FGFR inhibitors may sensitize the response to ICB by impacting various stages of the "cancer-immune cycle".

Pan-cancer analysis reveals potential of FAM110A as a prognostic and immunological biomarker in human cancer.

Background: Despite great success, immunotherapy still faces many challenges in practical applications. It was previously found that family with sequence similarity 110 member A (FAM110A) participate in the regulation of the cell cycle and plays an oncogenic role in pancreatic cancer. However, the prognostic value of FAM110A in pan-cancer and its involvement in immune response remain unclear. Methods: The Human Protein Atlas (HPA) database was used to detect the expression of FAM110A in human normal tissues, the Tumor Immune Estimation Resource (TIMER) and TIMER 2.0 databases were used to explore the association of FAM110A expression with immune checkpoint genes and immune infiltration, and the Gene Set Cancer Analysis (GSCA) database was used to explore the correlation between FAM110A expression and copy number variations (CNV) and methylation. The LinkedOmics database was used for Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis. Statistical analysis and visualization of data from the The Cancer Genome Atlas (TCGA) or the Genotype-Tissue Expression (GTEx) databases were performed using the R software (version 3.6.3). Clinical samples were validated using immunohistochemistry. Results: FAM110A expression was elevated in most tumor tissues compared with that in normal tissues. CNV and methylation were associated with abnormal FAM110A mRNA expression in tumor tissues. FAM110A affected prognosis and was associated with the expression of multiple immune checkpoint genes and abundance of tumor-infiltrating immune cells across multiple types of cancer, especially in liver hepatocellular carcinoma (LIHC). FAM110A-related genes were involved in multiple immune-related processes in LIHC. Conclusion: FAM110A participates in regulating the immune infiltration and affecting the prognosis of patients in multiple cancers, especially in LIHC. FAM110A may serve as a prognostic and immunological biomarker for human cancer.

Upregulated GPRC5A disrupting the Hippo pathway promotes the proliferation and migration of pancreatic cancer cells via the cAMP-CREB axis.

BACKGROUND: Pancreatic cancer has a high mortality rate worldwide, and is predicted to be third leading cause of death in the near future. However, the regulatory mechanisms that inhibit the progression of pancreatic cancer remain elusive. Currently, exploring the function and mechanisms of GPCRs (G-protein coupled receptors) is an important way to discover promising therapeutic targets for cancer. METHODS: GPRC5A expression was measured using real-time quantitative PCR, immunohistochemistry and western blot assays. Cell proliferation and migration were assessed using CCK-8, clone formation, wound-healing and transwell assays. A cytosolic/nuclear distribution experiment was used to detect the protein location transfer. A xenograft model of pancreatic cancer was established to explore the role of GPRC5A in vivo. RESULTS: GPRC5A expression was increased in pancreatic cancer, and disruption of GPRC5A expression inhibited tumor growth in vivo. Mechanistically, GPRC5A positively regulated the transcription of YAP1 through cAMP-CREB signaling. Moreover, we show that the proliferation and migration induced by GPRC5A in pancreatic cancer could be rescued by inhibiting YAP1 expression. CONCLUSIONS: GPRC5A interacts with the Hippo pathway to promote the progression of pancreatic cancer. These findings reveal an important crosstalk model and provide potential targets for pancreatic cancer therapy.