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.

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.

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.

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.

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.

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.

Characteristics and Prevalence of Staphyloma Edges at Different Ages in Highly Myopic Eyes.

Purpose: The purpose of this study was to determine the characteristics of staphyloma edges in highly myopic eyes and how they progress. Methods: We conducted a cross-sectional analysis using baseline data and a longitudinal study with follow-up data from 256 patients (447 eyes) with high myopia, with a mean (SD) follow-up of 3.79 (0.78) years. Participants were divided into four age groups: children (<13), youth (13-24), mature (25-59), and elderly (>60). Ultrawide-field swept-source optical coherence tomography was used to analyze staphyloma edges, which were divided into four areas: nasal to the optic disc (OD), superior to the macula, inferior to the macula, and temporal to the macula. Results: Staphylomas were significantly more prevalent in the mature (42.49%) and the elderly (51.35%) groups than in the children (13%) and youth (9%) groups. Staphyloma edges were predominantly superior to the macula in the mature and elderly groups. In contrast, staphylomas were rare in children and youth, with their edges mainly located nasal to the OD. The edges of staphylomas located superior and temporal to the macula were more likely to be associated with myopic traction maculopathy. During the follow-up period, 11 new staphyloma edges developed primarily in the mature group (64%). Additionally, 12 edges had an increased degree of protrusion over time, with most cases occurring in the mature (75%) group. Conclusions: The prevalence and location of staphyloma edges show significant variations depending on age. As time progresses, staphyloma edges manifest at distinct sites and increase their protrusion, potentially playing a role in the emergence of fundus complications.

LONGITUDINAL CHANGES OF POSTERIOR VORTEX VEINS IN HIGHLY MYOPIC EYES DETERMINED BY RETROSPECTIVE ANALYSES OF INDOCYANINE GREEN ANGIOGRAMS.

PURPOSE: To assess the longitudinal changes of the posterior vortex veins (VVs) in highly myopic (HM) eyes. METHODS: The medical records of 1,730 consecutive HM eyes that had undergone indocyanine green angiography were studied. Eyes that had posterior VVs and had undergone at least two indocyanine green angiography examinations with a minimum interval of 3 years were selected from this group. RESULTS: Ninety-one eyes of 78 patients met the inclusion criteria. A total of 124 posterior VVs were identified. Over an average interval of 7.8 ± 5.0 years, 41 (33.1%) of the 124 posterior VVs had marked changes consisting mainly of an attenuation of vessels in 36 posterior VVs (87.8%) and alterations in the drainage course in 16 posterior VVs (39.0%). Fifteen posterior VVs had both types of changes. Most of the attenuations of the vessels occurred for smaller branches, but a complete loss of the entire trunk was seen in three eyes. Additionally, four eyes had posterior VV changes in association with changes of peripheral VVs. CONCLUSION: Posterior VV in highly myopic eyes can undergo changes with increasing time. The associated factors included the development and progression of myopic maculopathy lesions. In some cases, the blood drainage shifted from posterior VV to peripheral VV by forming anastomotic channels.

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.

Machine Learning Models for Predicting Long-Term Visual Acuity in Highly Myopic Eyes.

Importance: High myopia is a global concern due to its escalating prevalence and the potential risk of severe visual impairment caused by pathologic myopia. Using artificial intelligence to estimate future visual acuity (VA) could help clinicians to identify and monitor patients with a high risk of vision reduction in advance. Objective: To develop machine learning models to predict VA at 3 and 5 years in patients with high myopia. Design, Setting, and Participants: This retrospective, single-center, cohort study was performed on patients whose best-corrected VA (BCVA) at 3 and 5 years was known. The ophthalmic examinations of these patients were performed between October 2011 and May 2021. Thirty-four variables, including general information, basic ophthalmic information, and categories of myopic maculopathy based on fundus and optical coherence tomography images, were collected from the medical records for analysis. Main Outcomes and Measures: Regression models were developed to predict BCVA at 3 and 5 years, and a binary classification model was developed to predict the risk of developing visual impairment at 5 years. The performance of models was evaluated by discrimination metrics, calibration belts, and decision curve analysis. The importance of relative variables was assessed by explainable artificial intelligence techniques. Results: A total of 1616 eyes from 967 patients (mean [SD] age, 58.5 [14.0] years; 678 female [70.1%]) were included in this analysis. Findings showed that support vector machines presented the best prediction of BCVA at 3 years (R2 = 0.682; 95% CI, 0.625-0.733) and random forest at 5 years (R2 = 0.660; 95% CI, 0.604-0.710). To predict the risk of visual impairment at 5 years, logistic regression presented the best performance (area under the receiver operating characteristic curve = 0.870; 95% CI, 0.816-0.912). The baseline BCVA (logMAR odds ratio [OR], 0.298; 95% CI, 0.235-0.378; P < .001), prior myopic macular neovascularization (OR, 3.290; 95% CI, 2.209-4.899; P < .001), age (OR, 1.578; 95% CI, 1.227-2.028; P < .001), and category 4 myopic maculopathy (OR, 4.899; 95% CI, 1.431-16.769; P = .01) were the 4 most important predicting variables and associated with increased risk of visual impairment at 5 years. Conclusions and Relevance: Study results suggest that developing models for accurate prediction of the long-term VA for highly myopic eyes based on clinical and imaging information is feasible. Such models could be used for the clinical assessments of future visual acuity.

BIDL: a brain-inspired deep learning framework for spatiotemporal processing.

Brain-inspired deep spiking neural network (DSNN) which emulates the function of the biological brain provides an effective approach for event-stream spatiotemporal perception (STP), especially for dynamic vision sensor (DVS) signals. However, there is a lack of generalized learning frameworks that can handle various spatiotemporal modalities beyond event-stream, such as video clips and 3D imaging data. To provide a unified design flow for generalized spatiotemporal processing (STP) and to investigate the capability of lightweight STP processing via brain-inspired neural dynamics, this study introduces a training platform called brain-inspired deep learning (BIDL). This framework constructs deep neural networks, which leverage neural dynamics for processing temporal information and ensures high-accuracy spatial processing via artificial neural network layers. We conducted experiments involving various types of data, including video information processing, DVS information processing, 3D medical imaging classification, and natural language processing. These experiments demonstrate the efficiency of the proposed method. Moreover, as a research framework for researchers in the fields of neuroscience and machine learning, BIDL facilitates the exploration of different neural models and enables global-local co-learning. For easily fitting to neuromorphic chips and GPUs, the framework incorporates several optimizations, including iteration representation, state-aware computational graph, and built-in neural functions. This study presents a user-friendly and efficient DSNN builder for lightweight STP applications and has the potential to drive future advancements in bio-inspired research.

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.

Risk assessment and disease burden of extreme precipitation on hospitalizations for acute aortic dissection in a subtropical coastal Chinese city.

Background: Extreme precipitation events are becoming more frequent due to climate change. The present study aimed to explore the impacts of extreme precipitation on hospitalizations for acute aortic dissection (AAD) and to identify susceptible populations and quantify the corresponding disease burden. Methods: The present study used a distributed lag nonlinear model (DLNM) with a quasi-Poisson function to investigate the association between extreme precipitation (≥95th percentile) and the risk of hospitalizations for AAD from 2015 to 2020 in Shantou, Guangdong Province, China. Results: The significant adverse effects of extreme precipitation (relative to no precipitation) on daily AAD hospitalizations lasted from lag 5 [relative risk (RR): 1.0318, 95% confidence interval (CI): 1.0067-1.0575] to lag 9 (RR: 1.0297, 95% CI: 1.0045-1.0555) and reached its maximum at lag 7 (RR: 1.0382, 95% CI: 1.0105-1.0665). Males and older adult individuals (≥60 years) were more susceptible to extreme precipitation. A total of 3.68% (118 cases) of AAD hospitalizations were due to extreme precipitation. Conclusion: Extreme precipitation was significantly correlated with AAD hospitalizations. Government departments should actively implement extreme precipitation intervention measures to strengthen the protection of males and the older adult (≥60 years) and effectively reduce AAD hospitalizations.