Association of Perioperative Skeletal Muscle Index Change With Outcome in Colorectal Cancer Patients.

BACKGROUND: The association between perioperative changes in the skeletal muscle index (SMI) and colorectal cancer (CRC) outcomes remains unclear. We aim to explore perioperative change patterns of SMI and evaluate their effects on long-term outcomes in CRC patients. METHODS: This retrospective cohort study included Stage I-III CRC patients who underwent curative resection between 2012 and 2019. SMI at the third lumbar vertebra level was calculated using computed tomography scans. Optimal cut-off values for SMI were defined separately for males and females and classified as high or low preoperatively and at 3, 6, 9 and 12 months postoperatively. SMI status was further categorized into different perioperative SMI change patterns: highpre-highpost, highpre-lowpost, lowpre-highpost and lowpre-lowpost. The association with recurrence-free survival (RFS) and overall survival (OS) was examined using Cox proportional hazards models. RESULTS: A total of 2222 patients (median [interquartile range] age, 60.00 [51.00-68.00] years; 1302 (58.60%) men; 222 (9.99%) with preoperative low SMI) were evaluated. During a median follow-up of 60 months, 375 patients (16.88%) died, and 617 patients (27.77%) experienced a recurrence. Multivariate Cox model analysis showed that, compared to patients with highpre-highpost, those with highpre-lowpost (HR = 3.32, 95% CI: 1.60-6.51; HR = 2.54, 95% CI: 1.03-6.26; HR = 2.93, 95% CI: 1.19-7.19, all p < 0.05) had significantly worse RFS and OS (HR = 4.07, 95% CI: 1.55-10.69; HR = 4.78, 95% CI: 1.40-16.29; HR = 9.69, 95% CI: 2.53-37.05, all p < 0.05), at postoperative 6, 9 and 12 months, respectively. Patients with lowpre-lowpost were an independent prognostic factor for worse OS at postoperative 12 months (HR = 3.20, 95% CI: 1.06-9.71, p = 0.040). Patients with lowpre-highpost had similar risk of RFS compared to those with highpre-highpost at postoperative 3, 6 and 12 months (HR = 1.49, 95% CI: 0.75-2.98; HR = 1.05, 95% CI: 0.45-2.43; HR = 1.36, 95% CI: 0.31-6.06, all p > 0.05) and similar risk of OS at postoperative 3, 6, 9 and 12 months (all p > 0.05). CONCLUSIONS: Patients with a high preoperative SMI that decline postoperatively have poor RFS and OS. Consistently low SMI also correlates with worse OS. Patients with low SMI but increased after resection are not an indicator of better prognosis. Routine measurement of postoperative, rather than preoperative, SMI is warranted. Patients with low SMI are at an increased risk for recurrence and death, especially within the first year after surgery.

Bidirectional association between perioperative skeletal muscle and subcutaneous fat in colorectal cancer patients and their prognostic significance.

Introduction: Low skeletal muscle mass and high adipose tissue coexist across the body weight spectrum and independently predict the survival ratio of colorectal cancer (CRC) patients. This combination may lead to a mutually exacerbating vicious cycle. Tumor-associated metabolic conditions primarily affect subcutaneous adipose tissue, but the nature and direction of its relationship with skeletal muscle are unclear. This study aims to examine the bidirectional causal relationship between skeletal muscle index (SMI) and subcutaneous fat index (SFI) during the perioperative period in CRC patients; as well as to validate the association between perioperative SMI, SFI, and CRC prognosis. Methods: This population-based retrospective cohort study included patients with stage I-III colorectal cancer who underwent radical resection at the Third Affiliated Hospital of Kunming Medical University between September 2012 and February 2019. Based on inclusion and exclusion criteria, 1,448 patients were analyzed. Preoperative (P1), 2 months postoperative (P2), and 5 months postoperative (P3) CT scans were collected to evaluate the skeletal muscle index (SMI; muscle area at the third lumbar vertebra divided by height squared) and subcutaneous fat index (SFI; subcutaneous fat area at the third lumbar vertebra divided by height squared). A random intercept cross-lagged panel model (RI-CLPM) was used to examine the intra-individual relationship between SMI and SFI, and Cox regression was employed to assess the association between SMI, SFI, recurrence-free survival (RFS), and overall survival (OS). Results: The median age at diagnosis was 59.00 years (IQR: 51.00-66.00), and 587 patients (40.54%) were female. RI-CLPM analysis revealed a negative correlation between SFI and subsequent SMI at the individual level: P1-P2 (ß = -0.372, p = 0.038) and P2-P3 (ß = -0.363, p = 0.001). SMI and SFI showed a negative correlation during P1-P2 (ß = -0.363, p = 0.001) but a positive correlation during P2-P3 (ß = 0.357, p = 0.006). No significant correlation was found between the random intercepts of SFI and SMI at the between-person level (r = 0.157, p = 0.603). The Cox proportional hazards multivariate regression model identified that patients with elevated SFI had poorer recurrence-free survival (HR, 1.24; 95% CI: 1.00-1.55). Compared to patients with normal preoperative SMI and SFI, those with low SMI or high SFI had poorer recurrence-free survival (HR, 1.26; 95% CI: 1.03-1.55) and overall survival (HR, 1.39; 95% CI: 1.04-1.87). However, no significant association between SMI and SFI and the prognosis of colorectal cancer patients was observed postoperatively. Conclusion: In CRC patients, preoperative muscle loss leads to postoperative fat accumulation, exacerbating muscle loss in a feedback loop. Elevated preoperative SFI predicts poorer survival outcomes. Monitoring SMI and SFI is crucial as prognostic indicators, despite non-significant postoperative associations. Further research is needed to improve patient outcomes.

Amniotic fluid proteomic analysis identifies IL1RL1, APOE, and NECTIN4 as new biomarkers for preterm birth.

BACKGROUND: Despite extensive research, the identification of effective biomarkers for early prediction of preterm birth (PTB) continues to be a challenging endeavor. This study aims to identify amniotic fluid (AF) protein biomarkers useful for the early diagnosis of PTB. METHODS: We initially identified the protein expression profiles in the AF of women with PTB (n = 22) and full-term birth (FTB, n = 22), from the First People's Hospital of Yunnan Province who underwent amniocentesis from November 2019 to February 2020, using mass spectrometry employing the data-independent acquisition (DIA) technique, and then analyzed differentially expressed proteins (DEPs). Subsequently, the least absolute shrinkage and selection operator (LASSO) and random forest analysis were employed to further screen the key proteins for PTB biomarker identification. The receiver operating characteristic (ROC) analysis, calibration plots, and decision curve analyses (DCA) were utilized to assess the discrimination and calibration of the key biomarkers. RESULTS: A total of 25 DEPs were identified between the PTB and FTB groups, comprising 13 up-regulated and 12 down-regulated proteins. Three key protein biomarkers for early PTB diagnosis were identified: IL1RL1 (interleukin-1 receptor-like 1), APOE (apolipoprotein E), and NECTIN4 (nectin cell adhesion molecule 4). The results of the ROC analysis showed that the area under the curve (AUC) of the three proteins combined as a biomarker for early diagnosis of PTB was 0.913 (95% CI: 0.823-1.000), with a sensitivity of 0.864 and a specificity of 0.955, both superior to those of the individual biomarkers. Bootstrap internal validation revealed a concordance index (C-index) of 0.878, with a sensitivity of 0.812 and a specificity of 0.773, indicating the robust predictive performance of these biomarkers. CONCLUSIONS: We identified three previously unexplored yet potentially useful protein biomarkers in AF for early PTB diagnosis: IL1RL1, APOE, and NECTIN4.

Multidimensional influencing factors of postpartum depression based on the perspective of the entire reproductive cycle: evidence from western province of China.

OBJECTIVE: China has a serious burden of Postpartum depression (PPD). In order to improve the current situation of high burden of PPD, this study explores the factors affecting PPD from the multidimensional perspectives with physiology, family support and social support covering the full-time chain of pre-pregnancy-pregnancy-postpartum. METHODS: A follow-up survey was conducted in the Qujing First People's Hospital of Yunnan Province from 2020 to 2022, and a total of 4838 pregnant women who underwent antenatal checkups in the hospital were enrolled as study subjects. Mothers were assessed for PPD using the Edinburgh Postnatal Depression Scale (EPDS), and logistic regression was used to analyse the level of mothers' postnatal depression and identify vulnerability characteristics. RESULTS: The prevalence of mothers' PPD was 46.05%, with a higher prevalence among those who had poor pre-pregnancy health, had sleep problems during pregnancy, and only had a single female fetus. In the family support dimension, only family care (OR = 0.52, 95% CI 0.42-0.64) and only other people care(OR = 0.78, 95% CI 0.64-0.96) were the protective factors of PPD. The experience risk of PPD was higher among mothers who did not work or use internet. CONCLUSION: The PPD level in Yunnan Province was significantly higher than the global and Chinese average levels. Factors affecting mothers' PPD exist in all time stages throughout pregnancy, and the influence of family support and social support on PPD shouldn't be ignored. There is an urgent need to extend the time chain of PPD, move its prevention and treatment forward and broaden the dimensions of its intervention.

Trajectory patterns and cumulative burden of CEA during follow-up with non-small cell lung cancer outcomes: A retrospective longitudinal cohort study.

BACKGROUND: Previous studies of non-small cell lung cancer (NSCLC) focused on CEA measured at a single time point, ignoring serial CEA measurements. METHODS: This retrospective cohort included 2959 patients underwent surgery for stage I-III NSCLC. CEA trajectory patterns and long-term cumulative CEA burden were evaluated using the latent class growth mixture model. RESULTS: Four CEA trajectory groups were identified, named as low-stable, decreasing, early-rising and later-rising. Compared with the low-stable group, the adjusted hazard ratios associated with death were 1.27, 4.50, and 3.68 for the other groups. Cumulative CEA burden were positively associated with the risk of death in patients not belonging to the low-stable group. The 5-year overall survival (OS) rates decreased from 62.3% to 33.0% for the first and fourth quantile groups of cumulative CEA burden. Jointly, patients with decreasing CEA trajectory could be further divided into the decreasing & low and decreasing & high group, with 5-year OS rates to be 77.9% and 47.1%. Patients with rising CEA trajectory and high cumulative CEA were found to be more likely to develop bone metastasis. CONCLUSIONS: Longitudinal trajectory patterns and long-term cumulative burden of CEA were independent prognostic factors of NSCLC. We recommend CEA in postoperative surveillance of NSCLC.

ZNF326 as a potential prognostic and predictive biomarker in stage II colorectal cancer.

Background: Adjuvant chemotherapy is considered for stage II colorectal cancer (CRC) patients with poor prognostic risk factors. However, current stratification algorithms are still insufficient to identify high-risk patients. Methods: We conducted a screening strategy to define ZNF326 based on quantitative proteomics in 11 paired CRC patients selected by a nested case-control design, and tested the association between ZNF326 expression level with the prognosis of stage II CRC patients and the benefit from adjuvant chemotherapy in public datasets; further investigation was conducted through subgroup analyses. Results: We found that low ZNF326 expression was significantly associated with a lower 5-year overall survival (OS) rate among stage II patients in both the discovery [P=0.008; hazard ratio (HR): 3.13, 95% confidence interval (CI): 1.29-7.58] and validation (P=0.025; HR: 1.98, 95% CI: 1.08-3.65) cohorts. In the Cox multivariable analysis, low ZNF326 expression was both associated with shorter OS after adjustment for age, sex, and adjuvant chemotherapy in the discovery and validation data sets. Subgroup analyses yielded largely similar results. In a pooled database, the rate of 5-year OS was higher among stage II ZNF326-high tumors who were treated with adjuvant chemotherapy than it was among those who were not treated with adjuvant chemotherapy (P=0.011; HR: 0.28, 95% CI: 0.10-0.80). Conclusions: ZNF326 has the potential to be used in clinical practice for risk classification. ZNF326-low expression level identified a subgroup of patients with high-risk stage II CRC who appeared to less benefit from adjuvant chemotherapy.

Amniotic Fluid Proteomics Analysis and In Vitro Validation to Identify Potential Biomarkers of Preterm Birth.

This study aimed to investigate the regulation of amniotic fibroblast (AFC) function by vitamin K-dependent protein Z (PROZ) during preterm birth (PTB) and its potential role in adverse pregnancy outcomes. Proteomic samples were collected from amniotic fluid in the second trimester, and AFC were isolated from the amniotic membrane and cultured in vitro. The expression of extracellular and intracellular PROZ in AFC was modulated, and their biological properties and functions were evaluated. Clinical analysis revealed a significant upregulation of PROZ expression in amniotic fluid from preterm pregnant women. In vitro experiments demonstrated that PROZ stimulated AFC migration, enhanced their proliferative capacity, and reduced collagen secretion. Overexpression of PROZ further enhanced cell migration and proliferation, while knockdown of PROZ had the opposite effect. PROZ plays a crucial role in promoting the proliferation and migration of amniotic membrane fibroblasts. Increased PROZ expression in amniotic fluid is associated with the occurrence of PTB. These findings shed light on the potential involvement of PROZ in adverse pregnancy outcomes and provide a basis for further research on its regulatory mechanisms during PTB.

PDGF-BB accelerates TSCC via fibroblast lactates limiting miR-26a-5p and boosting mitophagy.

The tumor microenvironment and cancer-associated fibroblasts (CAFs) play crucial roles in tumor development, and their metabolic coupling remains unclear. Clinical data showed a positive correlation between PDGF-BB, CAFs, and glycolysis in the tumor microenvironment of oral tongue squamous cell carcinoma patients. In vitro, CAFs are derived from hOMF cells treated with PDGF-BB, which induces their formation and promotes aerobic glycolysis. Mitophagy increased the PDGF-BB-induced formation of CAF phenotypes and aerobic glycolysis, while autophagy inhibition blocked PDGF-BB-induced effects. Downregulation of miR-26a-5p was observed in CAFs; upregulation of miR-26a-5p inhibited the expression of mitophagy-related proteins ULKI, Parkin, PINK1, and LC3 and aerobic glycolysis in PDGF-BB-induced CAFs. PDGF-BB-induced CAFs promoted tumor cell proliferation, invasion, metastasis, NF-κB signaling pathway activation, and PDGF-BB secretion. Thus, PDGF-BB is associated with lactate-induced CAF formation and glucose metabolism reprogramming. These findings indicate potential therapeutic targets in oral tongue squamous cell carcinoma.

Preoperative splenic area as a prognostic biomarker of early-stage non-small cell lung cancer.

BACKGROUND: The correlation between the preoperative splenic area measured on CT scans and the overall survival (OS) of early-stage non-small cell lung cancer (NSCLC) patients remains unclear. METHODS: A retrospective discovery cohort and validation cohort consisting of consecutive NSCLC patients who underwent resection and preoperative CT scans were created. The patients were divided into two groups based on the measurement of their preoperative splenic area: normal and abnormal. The Cox proportional hazard model was used to analyse the correlation between splenic area and OS. RESULTS: The discovery and validation cohorts included 2532 patients (1374 (54.27%) males; median (IQR) age 59 (52-66) years) and 608 patients (403 (66.28%) males; age 69 (62-76) years), respectively. Patients with a normal splenic area had a 6% higher 5-year OS (n = 727 (80%)) than patients with an abnormal splenic area (n = 1805 (74%)) (p = 0.007) in the discovery cohort. A similar result was obtained in the validation cohort. In the univariable analysis, the OS hazard ratios (HRs) for the patients with abnormal splenic areas were 1.32 (95% confidence interval (CI): 1.08, 1.61) in the discovery cohort and 1.59 (95% CI: 1.01, 2.50) in the validation cohort. Multivariable analysis demonstrated that abnormal splenic area was independent of shorter OS in the discovery (HR: 1.32, 95% CI: 1.08, 1.63) and validation cohorts (HR: 1.84, 95% CI: 1.12, 3.02). CONCLUSION: Preoperative CT measurements of the splenic area serve as a prognostic indicator for early-stage NSCLC patients, offering a novel metric with potential implications for personalized therapeutic strategies in top-tier oncology research.

MiR-3529-3p from PDGF-BB-induced cancer-associated fibroblast-derived exosomes promotes the malignancy of oral squamous cell carcinoma.

AIMS: This study aims to explore the role of exosomes from cancer-associated fibroblasts (CAFs) induced by PDGF-BB in promoting the malignancy of oral squamous cell carcinoma (OSCC) and provide new insight into the mechanism of OSCC progression and its treatment. MAIN METHODS: Exosomes were extracted from human oral mucosa fibroblasts (hOMFs) and CAFs. Differentially expressed miRNAs of exosomes between hOMFs and CAFs were analysed using high-throughput sequencing and self-programmed R software. Cal-27, a human tongue squamous carcinoma cell line, was treated with exosomes. Differentially expressed miRNAs between clinical cancer tissues and adjacent tissues and between hOMF and CAF exosomes were verified by qRT‒PCR. The effect of miR-3529-3p on Cal-27 cells was clarified by overexpressing or knocking down miR-3529-3p in Cal-27 cells. Sample expression and differentially expressed miRNA expression were compared between cancer and paracarcinoma tissues. KEY FINDINGS: We found that exosomes from CAFs (CAF-Exos) were internalized by tongue squamous carcinoma cells and promoted their proliferation, migration, invasion, and antiapoptotic effects. MiR-3529-3p was a significant differentially expressed miRNA between CAF-Exos and exosomes from hOMFs (hOMF-Exos). The overexpression of miR-3529-3p promoted proliferation, migration, and invasion and inhibited apoptosis of Cal-27 cells. SIGNIFICANCE: This study explores the role of PDGF-BB-induced CAFs in promoting malignancy in OSCC. This study will provide new insight into the mechanism of OSCC progression and its treatment.

Analysis of mRNA-miRNA interaction network reveals the role of CAFs-derived exosomes in the immune regulation of oral squamous cell carcinoma.

BACKGROUND: Cancer-associated fibroblasts (CAFs) have significant tumor regulatory functions, and CAFs-derived exosomes (CAFs-Exo) released from CAFs play an important role in the progression of oral squamous cell carcinoma (OSCC). However, a lack of comprehensive molecular biological analysis leaves the regulatory mechanisms of CAFs-Exo in OSCC unclear. METHODS: We used platelet derived growth factor-BB (PDGF-BB) to induce the transformation of human oral mucosa fibroblast (hOMF) into CAFs, and extracted exosomes from the supernatant of CAFs and hOMF. We validated the effect of CAFs-Exo on tumor progression by exosomes co-culture with Cal-27 and tumor-forming in nude mice. The cellular and exosomal transcriptomes were sequenced, and immune regulatory genes were screened and validated using mRNA-miRNA interaction network analysis in combination with publicly available databases. RESULTS: The results showed that CAFs-Exo had a stronger ability to promote OSCC proliferation and was associated with immunosuppression. We discovered that the presence of immune-related genes in CAFs-Exo may regulate the expression of PIGR, CD81, UACA, and PTTG1IP in Cal-27 by analyzing CAFs-Exo sequencing data and publicly available TCGA data. This may account for the ability of CAFs-Exo to exert immunomodulation and promote OSCC proliferation. CONCLUSIONS: CAFs-Exo was found to be involved in tumor immune regulation through hsa-miR-139-5p, ACTR2 and EIF6, while PIGR, CD81, UACA and PTTG1IP may be potentially effective targets for the treatment of OSCC in the future.

Transcriptome-wide profile of 1α,25 dihydroxyvitamin D3 in HTR-8/SVneo cells.

AIM: Vitamin D3 has been implicated in multiple reproductive events, whereas the effect of its bioactive metabolite 1α, 25 dihydroxyvitamin D3 (1,25(OH) 2 D3 ) on transcriptome profile of the placenta is unclear. The aim of this article is to determine transcriptome-wide profile caused by 1,25(OH) 2 D3 in human placental trophoblast cells. METHODS: We performed RNA sequencing after stimulation of HTR-8/SVneo cells with 0.1, 1, 10, and 100 nM 1,25(OH)2 D3 for 24 h, identified differentially expressed genes by edgeR package (version 3.38.4), and analyzed Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways by webtool Metascape. Also, common genes and specific genes in different concentrations of 1,25(OH) 2 D3 were identified. RESULTS: There were 180, 158, 161, and 174 differentially expressed genes after 0.1, 1, 10, and 100 nM 1,25(OH) 2 D3 stimulation, respectively. KEGG pathway analysis displayed that "lipid and atherosclerosis" were significantly enriched at 0.1 and 1 nM 1,25(OH)2 D3 , while "cytokine-cytokine receptor interaction," "TGF-beta signaling pathway" and "hippo signaling pathway" were significantly enriched in 1, 10, and 100 nM 1,25(OH)2 D3 . CYP24A1 was a significantly expressed common gene. UCP3 was significantly expressed in low concentrations and might affect energy metabolism. TCF24, EIF3CL, ABCD2, EPHA7, CRLF1, and SECTM1 were specific genes at physiological concentration. Similarly, SPDYE1, IQUB, IL18R1, and ZNF713 were considered as specific genes at supraphysiological concentration. CONCLUSIONS: 1,25(OH)2 D3 mainly affected the expression of CYP24A1 gene in HTR-8/SVneo cells. Specific genes accounted for the majority of differentially expressed genes at different concentrations. However, their functions need to be further confirmed.

hsa-mir-(4328, 4422, 548z and -628-5p) in diabetic retinopathy: diagnosis, prediction and linking a new therapeutic target.

AIMS: Growing evidence suggests that microRNAs (miRNAs) are crucial in controlling how diabetic retinopathy (DR) develops. We intend to mine miRNAs with diagnostic and predictive value for DR and to investigate new drug therapeutic targets. METHODS: After performing a differential analysis on the miRNA and mRNA datasets for DR and neovascularization (NEO), miRNA-mRNA networks were created. Combine the results of enrichment analysis, Protein-Protein Interaction Networks (PPI), and Cytoscape to identify key miRNAs. DrugBank was used to find drugs that interacted with transcription factors (TF) predicted by TransmiR. Finally, whole blood and clinical data were collected from 58 patients with type 2 diabetes mellitus (T2DM), and RT-qPCR, logistic analysis, and ROC were used to verify the value of key miRNAs. RESULTS: Differential analysis indicated the presence of genes and miRNAs that co-regulate DR and NEO. Enrichment analysis showed that key genes are inextricably linked to neovascularization. Combining the results of PPI and Cytoscape identified four key miRNAs, namely hsa-mir-(4328, 4422, 548z and -628-5p). RT-qPCR, logistic, and ROC results showed that decreased expression levels of hsa-mir-(4328, 4422, 548z and -628-5p) signal the risk of evolution to DR in T2DM patients. Finally, we constructed a TF-miRNA network to find the 15 TFs and the 35 drugs that interact with these TFs. CONCLUSION: hsa-mir-(4328, 4422, 548z and -628-5p) in whole blood are protective factors for DR as novel biomarkers for diagnosis and prediction. In addition, our research provides new drug directions for the treatment of DR, such as Diosmin, Atorvastatin, and so on.

Prediction models of colorectal cancer prognosis incorporating perioperative longitudinal serum tumor markers: a retrospective longitudinal cohort study.

BACKGROUND: Current prognostic prediction models of colorectal cancer (CRC) include only the preoperative measurement of tumor markers, with their available repeated postoperative measurements underutilized. CRC prognostic prediction models were constructed in this study to clarify whether and to what extent the inclusion of perioperative longitudinal measurements of CEA, CA19-9, and CA125 can improve the model performance, and perform a dynamic prediction. METHODS: The training and validating cohort included 1453 and 444 CRC patients who underwent curative resection, with preoperative measurement and two or more measurements within 12 months after surgery, respectively. Prediction models to predict CRC overall survival were constructed with demographic and clinicopathological variables, by incorporating preoperative CEA, CA19-9, and CA125, as well as their perioperative longitudinal measurements. RESULTS: In internal validation, the model with preoperative CEA, CA19-9, and CA125 outperformed the model including CEA only, with the better area under the receiver operating characteristic curves (AUCs: 0.774 vs 0.716), brier scores (BSs: 0.057 vs 0.058), and net reclassification improvement (NRI = 33.5%, 95% CI: 12.3 ~ 54.8%) at 36 months after surgery. Furthermore, the prediction models, by incorporating longitudinal measurements of CEA, CA19-9, and CA125 within 12 months after surgery, had improved prediction accuracy, with higher AUC (0.849) and lower BS (0.049). Compared with preoperative models, the model incorporating longitudinal measurements of the three markers had significant NRI (40.8%, 95% CI: 19.6 to 62.1%) at 36 months after surgery. External validation showed similar results to internal validation. The proposed longitudinal prediction model can provide a personalized dynamic prediction for a new patient, with estimated survival probability updated when a new measurement is collected during 12 months after surgery. CONCLUSIONS: Prediction models including longitudinal measurements of CEA, CA19-9, and CA125 have improved accuracy in predicting the prognosis of CRC patients. We recommend repeated measurements of CEA, CA19-9, and CA125 in the surveillance of CRC prognosis.

Exercise Interventions Improved Sleep Quality through Regulating Intestinal Microbiota Composition.

(1) Background: Sleep quality is closely related to the physical and mental health of college students. The objectives of this study were to obtain data on the sleep quality of university students and to investigate the relationship between intestinal flora and the improvement in sleep quality through exercise intervention. (2) Methods: Here, 11 university students with a body mass index (BMI) ≤ 18 and Pittsburgh Sleep Quality Index (PSQI) ≥ 7 were selected as experimental subjects, and another 11 healthy people were recruited as control subjects. The experimental group and control group were each intervened with exercise for 8 weeks. We used 16SrDNA sequencing technology to analyze the variations of the intestinal flora and the relation of the variations and sleep quality improvement between the experimental group and the control group before and after the exercise intervention. (3) Results: The differences in gut flora composition between people with sleep disorders and healthy people were statistically significant (p < 0.05). Before and after the exercise intervention, the differences were also statistically significant (p < 0.05) in people with sleep disorders. The sleep-disordered population had a larger proportion compared with the healthy population (p < 0.05). Blautia and Eubacterium hallii were microbe markers in the sleep-disordered population before and after the exercise intervention, while there was no microbe marker found in the healthy population. (4) Conclusions: The increase in Blautia and Eubacterium hallii, and the decrease in Agathobacter are associated with healthy sleep. Gut flora may be related to sleep disorders. Exercise intervention can improve sleep quality while changing the diversity of the gut flora, and exercise intervention targeting the gut flora is a new concept for preventing and treating sleep disorders.

Artificial intelligence for quantifying immune infiltrates interacting with stroma in colorectal cancer.

BACKGROUND: We proposed an artificial intelligence-based immune index, Deep-immune score, quantifying the infiltration of immune cells interacting with the tumor stroma in hematoxylin and eosin-stained whole-slide images of colorectal cancer. METHODS: A total of 1010 colorectal cancer patients from three centers were enrolled in this retrospective study, divided into a primary (N = 544) and a validation cohort (N = 466). We proposed the Deep-immune score, which reflected both tumor stroma proportion and the infiltration of immune cells in the stroma region. We further analyzed the correlation between the score and CD3+ T cells density in the stroma region using immunohistochemistry-stained whole-slide images. Survival analysis was performed using the Cox proportional hazard model, and the endpoint of the event was the overall survival. RESULT: Patients were classified into 4-level score groups (score 1-4). A high Deep-immune score was associated with a high level of CD3+ T cells infiltration in the stroma region. In the primary cohort, survival analysis showed a significant difference in 5-year survival rates between score 4 and score 1 groups: 87.4% vs. 58.2% (Hazard ratio for score 4 vs. score 1 0.27, 95% confidence interval 0.15-0.48, P < 0.001). Similar trends were observed in the validation cohort (89.8% vs. 67.0%; 0.31, 0.15-0.62, < 0.001). Stratified analysis showed that the Deep-immune score could distinguish high-risk and low-risk patients in stage II colorectal cancer (P = 0.018). CONCLUSION: The proposed Deep-immune score quantified by artificial intelligence can reflect the immune status of patients with colorectal cancer and is associate with favorable survival. This digital pathology-based finding might advocate change in risk stratification and consequent precision medicine.

Immunogenicity, durability, and safety of an mRNA and three platform-based COVID-19 vaccines as a third dose following two doses of CoronaVac in China: A randomised, double-blinded, placebo-controlled, phase 2 trial.

Background: More effective vaccine candidates against variants of concern as a booster dose are needed in people primed with two-dose inactivated COVID-19 vaccines. Methods: This randomised, double-blinded, investigator-initiated phase 2 trial aims to evaluate immunogenicity, durability, and safety of an mRNA vaccine candidate (RQ3013) and three other platform vaccines (an adenovirus-vectored vaccine candidate [ChAdTS-S], a recombinant protein vaccine candidate [ZR202-CoV], and an inactivated vaccine [CoronaVac]) as a booster. 250 eligible volunteers, who had received a prime two-dose CoronaVac (3 to 5 weeks apart) vaccination 100-270 days before, were randomly assigned in a 1:1:1:1:1 ratio to receive a third dose of RQ3013 (30 µg mRNA per 0.15 mL), ChAdTS-S (5×1010 viral particles per 0.5 mL), ZR202-CoV (25 µg prefusion-stabilized Spike ectodomain trimer per 0.5 mL), CoronaVac (3 µg inactivated CN02 strain of SARS-CoV-2 per 0.5 mL) or placebo (0.5 mL of 0.9% sodium chloride solution) via intramuscular injection into the upper arm at a single clinical site in Kunming, China. Participants, investigators, and immunogenicity laboratory were masked to group assignment. The primary immunogenicity outcomes were geometric mean titres (GMTs) of neutralising antibodies against live SARS-CoV-2 (wild-type, delta and omicron) virus at day 0 (before vaccination), day 7, day 14 and day 28 after vaccination, as analysed in a modified intention-to-treat (mITT) population (all participants who completed their booster doses and had at least one post-dose immunogenicity data). Secondary outcomes include T cell responses against the wild-type and omicron SARS-CoV-2 Spike protein. The primary safety outcome was incidence of adverse events within 14 days after the booster vaccination. This trial is registered with ChiCTR.org.cn, ChiCTR2200057758. Findings: Between January 1, 2022, and February 28, 2022, 235 eligible participants were enrolled and vaccinated, and the primary analysis included 234 participants. At baseline, neutralising antibodies against wild-type virus, the delta, or omicron variants were low or undetectable in all groups. After the booster vaccination, GMTs of neutralising antibodies ranged from 75.4 (95% confidence interval [CI] 61.4-92.5) in CoronaVac to 950.1 (95% CI 785.4-1149.3) in RQ3013 against live wild-type SARS-CoV-2, and from 8.1 (95% CI: 6.1-10.7) in CoronaVac to 247.0 (95% CI 194.1-314.3) in RQ3013 against the omicron variant at day 14. Immunogenicities of all heterologous regimens were superior to that of homologous regimen in neutralisation against all tested SARS-CoV-2 strains, with RQ3013 showing the highest geometric mean ratios (GMRs) of 12.6, 14.7, and 31.3 against the wild-type, the delta variant and the omicron variant compared to CoronaVac at day 14 post-vaccination, respectively. Durability analysis at day 90 showed that >90% of participants in RQ3013 and ZR202-CoV were seropositive for the omicron variant while ZR202-CoV with adjuvants containing CpG showed a slightly better durability than RQ3013. T cell responses specific to the omicron variant were similar to that of the wild-type, with RQ3013 showing the highest boosting effect. Any solicited injection site or systemic adverse events reported within 14 days after vaccination were most commonly observed in RQ3013 (47/47, 100%), followed by ZR202-CoV (46/47, 97.9%) and ChAdTS-S (43/48, 89.6%), and then CoronaVac (37/46, 80.4%) and placebo (21/47, 44.7%). More than 90% of the adverse events were grade 1 (mild) or 2 (moderate) with a typical resolution time of 3 days. No grade 4 adverse events or serious adverse events were reported by study vaccines. Interpretation: Although all study vaccines boosted neutralising antibodies with no safety concerns, RQ3013 showed much stronger cross-neutralisation and cellular responses, adding more effective vaccine candidates against the omicron variant. Funding: Yunnan Provincial Science and Technology Department China (202102AA100051 and 202003AC100010), the Double First-class University funding to Yunnan University, National Natural Science Foundation of China (81960116, 82060368 and 82170711), Yunnan Natural Science Foundation (202001AT070085), High-level Health Technical Personnel Project of Yunnan Province (H-2018102) and Spring City Plan: The High-level Talent Promotion and Training Project of Kunming.

Preoperative serum CA19-9 should be routinely measured in the colorectal patients with preoperative normal serum CEA: a multicenter retrospective cohort study.

OBJECTIVE: Whether preoperative serum carbohydrate antigen 19-9 (CA19-9) is an independent prognostic factor and there are interactions of serum CA19-9 with carcinoembryonic antigen (CEA) on the risk of recurrence in colorectal cancer (CRC) patients are still not clarified. METHODS: Consecutive patients with CRC who underwent curative resection for stage II-III colorectal adenocarcinoma at five hospitals were collected. Based on Cox models, associations of preoperative CA19-9 with recurrence-free survival (RFS) and overall survival (OS) were evaluated in patients with or without elevated CEA, and interactions between CEA and CA19-9 were also calculated. Restricted cubic spline (RCS) curves were used to evaluate the associations between preoperative CA19-9 and CRC outcomes on a continuous scale. RESULTS: A total of 5048 patients (3029 [60.0%] men; median [interquartile range, IQR] age, 61.0 [51.0, 68.0] years; median [IQR] follow-up duration 46.8 [36.5-62.4] months) were included. The risk of recurrence increased with the elevated level of preoperative CA19-9, with the slope steeper in patients with normal CEA than those with elevated CEA. Worse RFS was observed for elevated preoperative CA19-9 (> 37 U/mL) (n = 738) versus normal preoperative CA19-9 (≤ 37 U/mL) (n = 4310) (3-year RFS rate: 59.4% versus 78.0%; unadjusted hazard ratio [HR]: 2.02; 95% confidence interval [CI]:1.79 to 2.28), and significant interaction was found between CA19-9 and CEA (P for interaction = 0.001). Increased risk and interaction with CEA were also observed for OS. In the Cox multivariable analysis, elevated CA19-9 was associated with shorter RFS and OS regardless of preoperative CEA level, even after adjustment for other prognostic factors (HR: 2.08, 95% CI:1.75 to 2.47; HR: 2.25, 95% CI:1.80 to 2.81). Subgroup analyses and sensitivity analyses yielded largely similar results. These associations were maintained in patients with stage II disease (n = 2724). CONCLUSIONS: Preoperative CA19-9 is an independent prognostic factor in CRC patients. Preoperative CA19-9 can be clinically used as a routine biomarker for CRC patients, especially with preoperative normal serum CEA.