Fusion with ARRDC1 or CD63: A Strategy to Enhance p53 Loading into Extracellular Vesicles for Tumor Suppression.

Small extracellular vesicles (sEVs) have emerged as promising therapeutic agents and drug delivery vehicles. Targeted modification of sEVs and their contents using genetic modification strategies is one of the most popular methods. This study investigated the effects of p53 fusion with arrestin domain-containing protein 1 (ARRDC1) and CD63 on the generation of sEVs, p53 loading efficiency, and therapeutic efficacy. Overexpression of either ARRDC1-p53 (ARP) or CD63-p53 (CDP) significantly elevated p53 mRNA and protein levels. The incorporation of ARRDC1 and CD63 significantly enhanced HEK293T-sEV biogenesis, evidenced by significant increases in sEV-associated proteins TSG101 and LAMP1, resulting in a boost in sEV production. Importantly, fusion with ARRDC1 or CD63 substantially increased the efficiency of loading both p53 fusion proteins and its mRNA into sEVs. sEVs equipped with ARP or CDP significantly enhanced the enrichment of p53 fusion proteins and mRNA in p53-null H1299 cells, resulting in a marked increase in apoptosis and a reduction in cell proliferation, with ARP-sEVs demonstrating greater effectiveness than CDP-sEVs. These findings underscore the enhanced functionality of ARRDC1- and CD63-modified sEVs, emphasizing the potential of genetic modifications in sEV-based therapies for targeted cancer treatment.

Magnetic resonance imaging-based lymph node radiomics for predicting the metastasis of evaluable lymph nodes in rectal cancer.

BACKGROUND: Lymph node (LN) staging in rectal cancer (RC) affects treatment decisions and patient prognosis. For radiologists, the traditional preoperative assessment of LN metastasis (LNM) using magnetic resonance imaging (MRI) poses a challenge. AIM: To explore the value of a nomogram model that combines Conventional MRI and radiomics features from the LNs of RC in assessing the preoperative metastasis of evaluable LNs. METHODS: In this retrospective study, 270 LNs (158 nonmetastatic, 112 metastatic) were randomly split into training (n = 189) and validation sets (n = 81). LNs were classified based on pathology-MRI matching. Conventional MRI features [size, shape, margin, T2-weighted imaging (T2WI) appearance, and CE-T1-weighted imaging (T1WI) enhancement] were evaluated. Three radiomics models used 3D features from T1WI and T2WI images. Additionally, a nomogram model combining conventional MRI and radiomics features was developed. The model used univariate analysis and multivariable logistic regression. Evaluation employed the receiver operating characteristic curve, with DeLong test for comparing diagnostic performance. Nomogram performance was assessed using calibration and decision curve analysis. RESULTS: The nomogram model outperformed conventional MRI and single radiomics models in evaluating LNM. In the training set, the nomogram model achieved an area under the curve (AUC) of 0.92, which was significantly higher than the AUCs of 0.82 (P < 0.001) and 0.89 (P < 0.001) of the conventional MRI and radiomics models, respectively. In the validation set, the nomogram model achieved an AUC of 0.91, significantly surpassing 0.80 (P < 0.001) and 0.86 (P < 0.001), respectively. CONCLUSION: The nomogram model showed the best performance in predicting metastasis of evaluable LNs.

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants.

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in nasal tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variant revealed that SARS-CoV-2 WA1 or Delta infect a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possessed broader cellular invasion capacity into the submucosa, while Omicron displayed enhanced nasal respiratory infection and longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon were more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa were accompanied by a decline of phagocytosis-related genes. Further, robust basal stem cell activation contributed to neuroepithelial regeneration and restored ACE2 expression postinfection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration after infection. The shifting characteristics of viral infection at the airway portal provide insight into the variability of COVID-19 clinical features, particularly long COVID, and may suggest differing strategies for early local intervention.

A multiserological line assay to potentially discriminate current from past Helicobacter pylori infection.

OBJECTIVES: Early diagnosis is important in controlling Helicobacter pylori-induced gastritis and progression to gastric malignancy. Serological testing is an efficient non-invasive diagnostic method, but currently does not allow differentiation between active and past infections. To fill this diagnostic gap we investigated the diagnostic value of a panel of ten H. pylori-specific antibodies in individuals with different H. pylori infection status within a German population. METHODS: We used the recomLine Helicobacter IgG 2.0 immunoblotting assay to analyse ten H. pylori-specific antibodies in serum samples collected from 1108 volunteers. From these, 788 samples were used to build exposure and infection status models and 320 samples for model validation. H. pylori infection status was verified by histological examination. We applied logistic regression to select antibodies correlated to infection status and developed, with independent validation, discriminating models and risk scores. Receiving operating characteristic analysis was performed to assess the accuracy of the discriminating models. RESULTS: Antibody reactivity against cytotoxin-associated gene A (CagA), H. pylori chaperone (GroEL), and hook-associated protein 2 homologue (FliD) was independently associated with the risk of H. pylori exposure with ORs and 95% CIs of 99.24 (46.50-211.80), 46.17 (17.45-122.17), and 22.16 (8.46-55.04), respectively. A risk score comprising these three selected antibodies differentiated currently H. pylori infected or eradicated participants from negatives with an area under the curve of 0.976 (95% CI: 0.965-0.987) (Model 1). Seropositivity for vacuolating cytotoxin A (VacA), GroEL, FliD, H. pylori adhesin A (HpaA), and γ-glutamyl transpeptidase (gGT) was associated with a current infection with an area under the curve of 0.870 (95% CI: 0.837-0.903), which may help discriminate currently infected patients from eradicated ones (Model 2). DISCUSSION: The recomLine assay is sensitive and specific in determining H. pylori infection and eradication status and thus represents a valuable tool in the management of H. pylori infection.

A noninvasive multianalytical approach establishment for risk assessment and gastric cancer screening.

Effective screening and early detection are critical to improve the prognosis of gastric cancer (GC). Our study aims to explore noninvasive multianalytical biomarkers and construct integrative models for preliminary risk assessment and GC detection. Whole genomewide methylation marker discovery was conducted with CpG tandems target amplification (CTTA) in cfDNA from large asymptomatic screening participants in a high-risk area of GC. The methylation and mutation candidates were validated simultaneously using one plasma from patients at various gastric lesion stages by multiplex profiling with Mutation Capsule Plus (MCP). Helicobacter pylori specific antibodies were detected with a recomLine assay. Integrated models were constructed and validated by the combination of multianalytical biomarkers. A total of 146 and 120 novel methylation markers were found in CpG islands and promoter regions across the genome with CTTA. The methylation markers together with the candidate mutations were validated with MCP and used to establish a 133-methylation-marker panel for risk assessment of suspicious precancerous lesions and GC cases and a 49-methylation-marker panel as well as a 144-amplicon-mutation panel for GC detection. An integrated model comprising both methylation and specific antibody panels performed better for risk assessment than a traditional model (AUC, 0.83 and 0.63, P < .001). A second model for GC detection integrating methylation and mutation panels also outperformed the traditional model (AUC, 0.82 and 0.68, P = .005). Our study established methylation, mutation and H. pylori-specific antibody panels and constructed two integrated models for risk assessment and GC screening. Our findings provide new insights for a more precise GC screening strategy in the future.

Adsorption and desorption of flavonoids on activated carbon impregnated with different metal ions.

In this study, four metal ions Mg2+, Al3+, Fe3+, and Zn2+ were loaded on the surface of activated carbon by an impregnation method coupled with high-temperature calcination to prepare modified activated carbon. Scanning electron microscopy, specific surface area and pore size analysis, X-ray diffraction, and Fourier infrared spectroscopy were used to evaluate the structure and morphology of the modified activated carbon. The findings show that the modified activated carbon had a large microporous structure and high specific surface area, both of which significantly improved absorbability. This study also investigated the adsorption and desorption kinetics of the prepared activated carbon for three flavonoids with representative structures. The adsorption amounts of quercetin, luteolin, and naringenin in the blank activated carbon reached 920.24 mg g-1, 837.07 mg g-1, and 677.37 mg g-1, while for activated carbon impregnated with Mg, the adsorption amounts reached 976.34 mg g-1, 963.39 mg g-1, and 817.98 mg g-1, respectively; however, the desorption efficiencies of the three flavonoids varied a lot. The differences in desorption rates of naringenin as compared with quercetin and luteolin in the blank activated carbon were 40.13% and 46.22%, respectively, and the difference in desorption rates increased to 78.46% and 86.93% in the activated carbon impregnated with Al. The differences provide a basis for the application of this type of activated carbon in the selective enrichment and separation of flavonoids.

Metabolite Alterations and Interactions with Microbiota in Helicobacter pylori-Associated Gastric Lesions.

Metabolites and their interactions with microbiota may be involved in Helicobacter pylori-associated gastric lesion development. This study aimed to explore metabolite alterations upon H. pylori eradication and possible roles of microbiota-metabolite interactions in progression of precancerous lesions. Targeted metabolomics assays and 16S rRNA gene sequencing were conducted to investigate metabolic and microbial alterations of paired gastric biopsy specimens in 58 subjects with successful and 57 subjects with failed anti-H. pylori treatment. Integrative analyses were performed by combining the metabolomics and microbiome profiles from the same intervention participants. A total of 81 metabolites were significantly altered after successful eradication compared to failed treatment, including acylcarnitines, ceramides, triacylglycerol, cholesterol esters, fatty acid, sphingolipids, glycerophospholipids, and glycosylceramides, with P values of <0.05 for all. The differential metabolites showed significant correlations with microbiota in baseline biopsy specimens, such as negative correlations between Helicobacter and glycerophospholipids, glycosylceramide, and triacylglycerol (P < 0.05 for all), which were altered by eradication. The characteristic negative correlations between glycosylceramides and Fusobacterium, Streptococcus, and Gemella in H. pylori-positive baseline biopsy specimens were further noticed in active gastritis and intestinal metaplasia (P < 0.05 for all). A panel including differential metabolites, genera, and their interactions may help to discriminate high-risk subjects who progressed from mild to advanced precancerous lesions in short-term and long-term follow-up periods with areas under the curve (AUC) of 0.914 and 0.801, respectively. Therefore, our findings provide new insights into the metabolites and microbiota interactions in H. pylori-associated gastric lesion progression. IMPORTANCE In this study, a panel was established including differential metabolites, genera, and their interactions, which may help to discriminate high-risk subjects for progression from mild lesions to advanced precancerous lesions in short-term and long-term follow-up.

The value of cuproptosis-related differential genes in guiding prognosis and immune status in patients with skin cutaneous melanoma.

Background: Skin cutaneous melanoma (SKCM) is one of the most common cutaneous malignancies, which incidence is increasing. Cuproptosis is a new type of programming cell death recently reported, which may affect the progression of SKCM. Method: The mRNA expression data of melanoma were obtained from the Gene Expression Omnibus and the Cancer Genome Atlas databases. We constructed a prognostic model according to the cuproptosis-related differential genes in SKCM. Finally, real-time quantitative PCR was performed to verify the expression of cuproptosis-related differential genes in patients with different stages of cutaneous melanoma. Results: We detected 767 cuproptosis-related differential genes based on 19 cuproptosis-related genes, and screened out 7 differential genes to construct a prognostic model, which including three high-risk differential genes (SNAI2, RAP1GAP, BCHE), and four low-risk differential genes (JSRP1, HAPLN3, HHEX, ERAP2). Kaplan-Meier analysis indicated that SKCM patients with low-risk differential genes signals had better prognosis. The Encyclopedia of Genomes results manifested that cuproptosis-related differential genes are not only involved in T cell receptor signaling channel, natural killer cell mediated cytotoxicity, but also chemokine signaling pathway and B cell receptor signaling pathway. In our risk scoring model, the receiver operating characteristic (ROC) values of the three-time nodes are 0.669 (1-year), 0.669 (3-year) and 0.685 (5-year), respectively. Moreover, the tumor burden mutational and immunology function, cell stemness characteristics and drug sensitivity have significant differences between low-risk group and high-risk group. The mRNA level of SNAI2, RAP1GAP and BCHE in stage Ⅲ+Ⅳ SKCM patients was significantly higher than that in stage Ⅰ+Ⅱ patients, while the level of JSRP1, HAPLN3, HHEX and ERAP2 in stage Ⅰ+Ⅱ SKCM patients was more remarkable higher than that in stage Ⅲ+Ⅳ SKCM patients. Conclusion: In summary, we suggest that cuproptosis can not only regulate the tumor immune microenvironment but also affect the prognosis of SKCM patients, and may offer a basic theory for SKCM patients survival studies and clinical decision-making with potentially therapeutic drugs.

Gastric cancer-associated long non-coding RNA profiling and noninvasive biomarker screening based on a high-risk population cohort.

BACKGROUND: Effective noninvasive biomarkers of gastric cancer (GC) are critical for early detection and improvement of prognosis. We performed genome-wide long non-coding RNA (lncRNA) microarray analysis to identify and validate novel GC biomarkers depending on a high-risk population cohort. METHODS: LncRNA profiles were described using the Human LncRNA Microarray between GC and control plasma samples. The differential candidate lncRNAs were validated in two stages by quantitative reverse transcription polymerase chain reaction (qRT-PCR). We further evaluated the joint effect between the GC-associated lncRNA and Helicobacter pylori (H. pylori) infection on the risk of cardia and non-cardia GC, respectively. RESULTS: Different lncRNA expression profiles were identified between GC and control plasma with a total of 1206 differential lncRNAs including 470 upregulated and 736 downregulated in GC compared with the control group. The eight significantly upregulated lncRNAs (RP11-521D12.1, AC011995.3, RP11-5P4.3, RP11-244 K5.6, RP11-422 J15.1, CTD-2306 M5.1, CTC-428G20.2, and AC009133.20) in GC cases both in the present study and a similar microarray screening study by our collaborative team were selected for a two-stage validation. After the large sample size validation, the subjects with higher expression of RP11-244 K5.6 showed a significantly increased risk of GC with an adjusted odds ratio (OR) as 2.68 and 95% confidence interval (CI) as 1.15-6.24. Joint effects between RP11-244 K5.6 expression and H. pylori infection on the risk of GC were evaluated with no statistical significance. CONCLUSIONS: Our study found different lncRNA expression profiles between GC and control plasma and preliminarily identified RP11-244 K5.6 as a potential noninvasive biomarker for GC screening.

Melanoma molecular subtyping and scoring model construction based on ligand-receptor pairs.

Melanoma is a malignancy of melanocytes, responsible for a high percentage of skin cancer mortality. Ligand-Receptor pairs, a type of cellular communication, are essential for tumor genesis, growth, metastasis, and prognosis. Yet, the role of Ligand-Receptor pairs in melanoma has not been fully elucidated. Our research focused on the function of Ligand-Receptor pairs in melanoma prognosis. We screened 131 melanoma prognosis corresponded ligand-receptor pairs by analyzing the TCGA data of melanoma and the 2293 LR pairs retrieved from the connectomeDB2020 database. And further developed subtypes of melanoma according to the expression of these ligand-receptor pairs by Consensus Clustering. Then we using lasso cox regression and stepwise multivariate regression analysis established a ligand-receptor pairs-based scoring model for the evaluation of melanoma prognosis. Our study demonstrated that the ligand-receptor pairs are vital to the molecular heterogeneity of melanoma, and characterized three different melanoma ligand-receptor pairs subtypes. Among them, the C3 subtype showed a better prognosis, while the C1 subtype exhibited a low prognosis state. And our analysis then found out that this could be related to the differed activation and inhabitation of the cell cycle and immune-related pathways. Using lasso cox regression and stepwise multivariate regression analysis, we further identified 9 key ligand-receptor pairs and established a scoring model that effectively correlated with the prognosis, immune pathways, and therapy of melanoma, showing that the LR.score model was a trustworthy and independent biomarker for melanoma prognosis evaluation. In sum, we found that ligand-receptor pairs are significantly associated with the prognosis and therapy of melanoma. And our ligand-receptor-based scoring model showed potential for the evaluation of melanoma prognosis and immune therapy outcome prediction, which is crucial to the survival for the patients.

Allium vegetable intake associated with the risk of incident gastric cancer: a continuous follow-up study of a randomized intervention trial.

BACKGROUND: Allium vegetable components have antibacterial, antioxidative, and immune modulation properties, thus potentially exhibiting antitumor effects. Despite evidence from case-control studies, prospective studies linking allium vegetables with gastric cancer (GC) have been sparse. OBJECTIVE: In a prospective study, we examined whether allium vegetable intake would change the risk of GC occurrence and whether the associations would be modified by vitamin supplementation, garlic supplementation, and Helicobacter pylori (H. pylori) treatment. METHODS: The study was conducted on the basis of the Shandong Intervention Trial, a randomized, placebo-controlled, factorial-designed trial (1995-2003) in a well-recognized high-risk area for GC in China. Participants were continuously followed up to December 2017 for 22.3 y (1995-2017). A total of 3229 subjects were included, with information on the intake of allium vegetables (garlic vegetables and scallions), collected by structured questionnaires in 1994. The associations of total and individual allium vegetable intake with the risk of GC were examined, respectively. RESULTS: During the follow-up, 144 incident cases of GC were identified. Garlic vegetable intake was associated with a decreased risk of incident GC (P-trend = 0.02; OR: 0.83; 95% CI: 0.70, 0.98, per 1 kg/y increment), whereas scallion intake showed no association (P-trend = 0.80). An inverse association of the risk of GC with total allium vegetable and garlic vegetable intake was particularly stronger among those receiving the placebo for vitamin supplementation or garlic supplementation, indicating potential effect modifications by nutritional supplementation on allium vegetable intake and the risk of developing GC. Similar findings were found for analyses of the combined prevalence of dysplasia or GC. CONCLUSIONS: We found a significant reduction in the risk of developing GC with increasing dietary intake of allium vegetables, particularly garlic vegetables. The findings add to the literature on the potential inverse association of garlic vegetable intake with the risk of GC, therefore holding public health implications for dietary recommendations. This trial was registered at clinicaltrials.gov as NCT00339768.

Urine proteomic signatures predicting the progression from premalignancy to malignant gastric cancer.

BACKGROUND: Early detection of gastric cancer (GC) remains challenging. We aimed to examine urine proteomic signatures and identify protein biomarkers that predict the progression of gastric lesions and risk of GC. METHODS: A case-control study was initially designed, covering subjects with GC and gastric lesions of different stages. Subjects were aged 40-69 years, without prior diagnosis of renal or urological diseases. We enrolled a total of 255 subjects, with 123 in the discovery stage from Linqu, China, a high-risk area for GC and 132 in the validation stage from Linqu and Beijing. A prospective study was further designed for a subset of 60 subjects with gastric lesions, which were followed for 297-857 days. FINDINGS: We identified 43 differentially expressed urine proteins in subjects with GC vs. mild or advanced gastric lesions. Baseline urinary levels of ANXA11, CDC42, NAPA and SLC25A4 were further positively associated with risk of gastric lesion progression. Three of them, except for SLC25A4, also had higher expression in GC than non-GC tissues. Integrating these four proteins showed outstanding performance in predicting the progression of gastric lesions (AUC (95% CI): 0.92 (0.83-1.00)) and risk of GC (AUC (95% CI): 0.81 (0.73-0.89) and 0.84 (0.77-0.92) for GC vs. mild or advanced gastric lesions respectively). INTERPRETATION: This study revealed distinct urine proteomic profiles and a panel of proteins that may predict the progression of gastric lesions and risk of GC. These biomarkers in a non-invasive approach may have translational significance for defining high-risk populations of GC and its early detection. FUNDING: Funders are listed in the Acknowledgement.

Predictors of pathologic complete response in patients with residual flat mucosal lesions after neoadjuvant chemoradiotherapy for locally advanced rectal cancer.

Objective: The accurate prediction of tumor response to neoadjuvant chemoradiotherapy (nCRT) remains challenging. Few studies have investigated pathologic complete response (ypCR) prediction in patients with residual flat mucosal lesions after treatment. This study aimed to identify variables for predicting ypCR in patients with residual flat mucosal lesions after nCRT for locally advanced rectal cancer (LARC). Methods: Data of patients with residual flat mucosal lesions after nCRT who underwent radical resection between 2009 and 2015 were retrospectively collected from the LARC database at Peking University Cancer Hospital. Univariate and multivariate analyses of the association between clinicopathological factors and ypCR were performed, and a nomogram was constructed by incorporating the significant predictors. Results: Of the 246 patients with residual flat mucosal lesions included in the final analysis, 56 (22.8%) had ypCR. Univariate and multivariate analyses showed that pretreatment cT stage (pre-cT) ≤T2 (P=0.016), magnetic resonance tumor regression grade (MR-TRG) 1-3 (P=0.001) and residual mucosal lesion depth =0 mm (P<0.001) were associated with a higher rate of ypCR. A nomogram was developed with a concordance index (C-index) of 0.759 and the calibration curve showed that the nomogram model had good predictive consistency. The follow-up time ranged from 3.0 to 113.3 months, with a median follow-up time of 63.77 months. The multivariate Cox regression model showed that the four variables in the nomogram model were not risk factors for disease-free survival (DFS) or overall survival (OS). Conclusions: Completely flat mucosa, early cT stage and good MR-TRG were predictive factors for ypCR instead of DFS or OS in patients with LARC with residual flat mucosal lesions after nCRT. Endoscopic mucosal re-evaluation before surgery is important, as it may contribute to decision-making and facilitate nonoperative management or organ preservation.

Effectiveness and safety of stem cell therapy for diabetic foot: a meta-analysis update.

BACKGROUND: Diabetic foot (DF) is one of the most common and serious complications of diabetes mellitus (DM), which brings great psychological and economic pressure to patients. This study aimed to evaluate the efficacy of stem cells in the treatment of diabetic foot. METHODS: All relevant studies in Cochrane, Embase, PubMed, Web of Science, China National Knowledge Infrastructure, and WanFang databases were systematically searched for meta-analysis. The outcomes consisted of ulcer or wound healing rate, amputation rate, new vessels, ankle-brachial index (ABI), transcutaneous oxygen pressure (TcPO2), pain-free walking distance, and rest pain score. Dichotomous outcomes were described as risk ratios (RR) with 95% confidence intervals (CIs), while continuous data were presented as standardized mean differences (SMDs) with 95% CIs. Statistical analysis was performed with RevMan 5.3 software. RESULTS: A total of 14 studies with 683 participants were included in the meta-analysis. Meta-analysis showed that stem cell therapy was more effective than conventional therapy in terms of ulcer or wound healing rate [OR = 8.20 (5.33, 12.62)], improvement in lower extremity ischemia(new vessels) [OR = 16.48 (2.88, 94.18)], ABI [MD = 0.13 (0.04, 0.08)], TcO2[MD = 4.23 (1.82, 6.65)], pain-free walking distance [MD = 220.79 (82.10, 359.48)], and rest pain score [MD = - 1.94 (- 2.50, - 1.39)], while the amputation rate was significantly decreased [OR = 0.19 (0.10, 0.36)]. CONCLUSIONS: The meta-analysis of the current studies has shown that stem cells are significantly more effective than traditional methods in the treatment of diabetic foot and can improve the quality of life of patients after treatment. Future studies should conduct large-scale, randomized, double-blind, placebo-controlled, multicenter trials with high-quality long-term follow-up to demonstrate the most effective cell types and therapeutic parameters for the treatment of diabetic foot.

Plasma lipids signify the progression of precancerous gastric lesions to gastric cancer: a prospective targeted lipidomics study.

Rationale: Gastric cancer (GC) is preceded by a stepwise progression of precancerous gastric lesions. Distinguishing individuals with precancerous gastric lesions that have progression potential to GC is an important need. Perturbated lipid metabolism, particularly the dysregulation of de novo lipogenesis, is involved in gastric carcinogenesis. We conducted the first prospective lipidomics study exploring lipidomic signatures for the risk of gastric lesion progression and early GC. Methods: Our two-stage study of targeted lipidomics enrolled 400 subjects from the National Upper Gastrointestinal Cancer Early Detection Program in China, including 200 subjects of GC and different gastric lesions in the discovery and validation stages. Of validation stage, 152 cases with gastric lesions were prospectively followed for the progression of gastric lesions for a median follow-up of 580 days (interquartile range 390-806 days). We examined the lipidomic signatures associated with the risk of advanced gastric lesions and their progression to GC. Our published tissue proteomic data were referred to further investigate highlighted lipids with their biologically related protein expression in gastric mucosa. Results: We identified 11 plasma lipids significantly inversely associated with the risk of gastric lesion progression and GC occurrence. These lipids were integrated as latent profiles to identify 5 clusters of lipid expression that had distinct risk of gastric lesion progression. The latent profiles significantly improved the ability to predict the progression potential of gastric lesions (AUC: 0.82 vs 0.68, Delong's P = 4.6×10-4) and risk of early GC (AUC: 0.81 vs 0.55, P = 6.3×10-5). Significant associations were found between highlighted lipids, their biologically correlated proteins and the risk of GC, supporting the role of the pathways involving monocarboxylic acid metabolism and lipid transport and catabolic process in GC. Conclusions: Our study revealed the lipidomic signatures associated with the risk of gastric lesion progression and GC occurrence, exhibiting translational implications for GC prevention.

Evolution of nasal and olfactory infection characteristics of SARS-CoV-2 variants.

SARS-CoV-2 infection of the upper airway and the subsequent immune response are early, critical factors in COVID-19 pathogenesis. By studying infection of human biopsies in vitro and in a hamster model in vivo, we demonstrated a transition in tropism from olfactory to respiratory epithelium as the virus evolved. Analyzing each variants revealed that SARS-CoV-2 WA1 or Delta infects a proportion of olfactory neurons in addition to the primary target sustentacular cells. The Delta variant possesses broader cellular invasion capacity into the submucosa, while Omicron displays longer retention in the sinonasal epithelium. The olfactory neuronal infection by WA1 and the subsequent olfactory bulb transport via axon is more pronounced in younger hosts. In addition, the observed viral clearance delay and phagocytic dysfunction in aged olfactory mucosa is accompanied by a decline of phagocytosis related genes. Furthermore, robust basal stem cell activation contributes to neuroepithelial regeneration and restores ACE2 expression post-infection. Together, our study characterized the nasal tropism of SARS-CoV-2 strains, immune clearance, and regeneration post infection. The shifting characteristics of viral infection at the airway portal provides insight into the variability of COVID-19 clinical features and may suggest differing strategies for early local intervention.

Health-Related Quality of Life in Patients With Locally Advanced Gastric Cancer Undergoing Perioperative or Postoperative Adjuvant S-1 Plus Oxaliplatin With D2 Gastrectomy: A Propensity Score-Matched Cohort Study.

Background: Some high-quality clinical trials have proven the efficacy and safety of perioperative and postoperative S-1 with oxaliplatin (peri-SOX and post-SOX) for patients with locally advanced gastric cancer (LAGC) undergoing D2 gastrectomy. However, little is known about how health-related quality of life (HRQOL) changes over time in patients receiving peri-SOX or post-SOX chemotherapy. Methods: A prospective observational cohort (NCT04408859) identified 151 eligible patients with LAGC who underwent D2 gastrectomy with at least six cycles of peri-SOX or post-SOX chemotherapy from 2018 to 2020. HRQOL was assessed using the EROTC QLQ-C30 and its gastric module, QLQ-STO22, at indicated measurements, including the baseline, 1st, 3rd, 6th and 12th month after initiation of therapy. Baseline characteristics, therapeutic effects, and longitudinal HRQOL were compared between the peri-SOX and post-SOX groups after propensity score matching. HRQOL changes over time and the risk factors for scales with severe deterioration were further analyzed. Results: No statistically significant differences in longitudinal HRQOL were observed between patients in the peri-SOX and post-SOX groups, with comparable surgical outcomes and adverse chemotherapy events. Scales of social functioning, abnormal taste, and anxiety improved earlier in the peri-SOX group than in the post-SOX group. Score changes in both groups indicated that general deterioration and slower recovery usually occurred in the scales of physical, social, and role functioning, as well as symptoms of fatigue, reflux, diarrhea, and anxiety. Conclusion: Peri-SOX showed a longitudinal HRQOL comparable to post-SOX in patients with LAGC who underwent D2 gastrectomy. The peri-SOX group had better performance in social functioning, abnormal taste, and anxiety at some measurements.

Beneficial effects of endoscopic screening on gastric cancer and optimal screening interval: a population-based study.

BACKGROUND : The effectiveness of endoscopic screening on gastric cancer has not been widely investigated in China and the screening interval of repeated screening has not been determined. METHODS : In a population-based prospective study, we included 375,800 individuals, 14,670 of whom underwent endoscopic screening (2012-2018). We assessed the associations between endoscopic screening and risk of incident gastric cancer and gastric cancer-specific mortality, and examined changes in overall survival and disease-specific survival following screening. The optimal screening interval for repeated endoscopy for early detection of gastric cancer was explored. RESULTS : Ever receiving endoscopic screening significantly decreased the risk of invasive gastric cancer (age- and sex-adjusted relative risk [RR] 0.69, 95 % confidence interval [CI] 0.52-0.92) and gastric cancer-specific mortality (RR 0.33, 95 %CI 0.20-0.56), particularly for noncardia gastric cancer. Repeated screening strengthened the beneficial effect on invasive gastric cancer-specific mortality of one-time screening. Among invasive gastric cancers, screening-detected individuals had significantly better overall survival (RR 0.18, 95 %CI 0.13-0.25) and disease-specific survival (RR 0.18, 95 %CI 0.13-0.25) than unscreened individuals, particularly for those receiving repeated endoscopy. For individuals with intestinal metaplasia or low grade intraepithelial neoplasia, repeated endoscopy at an interval of < 2 years, particularly within 1 year, significantly enhanced the detection of early gastric cancer, compared with repeated screening after 2 years (P-trend = 0.02). CONCLUSION : Endoscopic screening prevented gastric cancer occurrence and death, and improved its prognosis in a population-based study. Repeated endoscopy enhanced the effectiveness. Screening interval should be based on gastric lesion severity.

Sox2 regulates globose basal cell regeneration in the olfactory epithelium.

BACKGROUND: In the olfactory epithelium, mitotically active globose basal cells (GBCs) continuously replenish olfactory sensory neurons (OSNs) lost throughout life. Although an essential role of the transcription factor Sox2 in expanding olfactory progenitors/stem cells has been shown, its precise role in olfactory GBCs remain incompletely understood. METHODS: We characterized the Sox2 expression in olfactory GBCs in normal conditions and in a lesion-regeneration model using a Lgr5EGFP-IRES-creERT2 strain. During GBC-mediated regeneration, genetic deletion of sox2 and lineage tracing experiments were performed to examine the function of Sox2 in the progeny of Lgr5-EGFP+ GBCs. RESULTS: Over 95% of Lgr5-EGFP+ GBCs express Sox2 in normal or regeneration conditions. Loss of Sox2 dramatically reduces the cell number in each lineage traced cluster. In the progeny of Lgr5-EGFP+ GBCs, loss of Sox2 significantly decreased the portion of OMP+ OSNs. However, the generation of sustentacular cells was unchanged. CONCLUSIONS: Our observations support an essential role of Sox2 in adult olfactory regeneration, likely acting on neuronal-lineage GBCs.