DELFMUT: duplex sequencing-oriented depth estimation model for stable detection of low-frequency mutations.

Duplex sequencing technology has been widely used in the detection of low-frequency mutations in circulating tumor deoxyribonucleic acid (DNA), but how to determine the sequencing depth and other experimental parameters to ensure the stable detection of low-frequency mutations is still an urgent problem to be solved. The mutation detection rules of duplex sequencing constrain not only the number of mutated templates but also the number of mutation-supportive reads corresponding to each forward and reverse strand of the mutated templates. To tackle this problem, we proposed a Depth Estimation model for stable detection of Low-Frequency MUTations in duplex sequencing (DELFMUT), which models the identity correspondence and quantitative relationships between templates and reads using the zero-truncated negative binomial distribution without considering the sequences composed of bases. The results of DELFMUT were verified by real duplex sequencing data. In the case of known mutation frequency and mutation detection rule, DELFMUT can recommend the combinations of DNA input and sequencing depth to guarantee the stable detection of mutations, and it has a great application value in guiding the experimental parameter setting of duplex sequencing technology.

Deciphering the folate puzzle: Unraveling the impact of genetic variations and metabolites on cancer risk.

The C677T polymorphism in the MTHFR gene and its role in folate metabolism, impacting serum folate metabolites like THF and 5-MTHF, is a critical but underexplored area in cancer research. This nested case-control study utilized data from CHHRS, involving 87,492 hypertensive adults without prior cancer. During a median of 2.02 years, we identified 1332 cancer cases and matched controls based on age, sex, and residency. Serum levels of folate, THF, and 5-MTHF were measured, and the MTHFR C677T gene polymorphism was considered. Statistical analyses included restricted cubic spline regression and conditional logistic regression models. Serum THF levels were inversely associated with overall cancer risk (ORper SD = 0.90, 95% CI = 0.82-0.99), while 5-MTHF levels showed a negative association in the general cohort (ORQ3 vs. Q1 = 0.76, 95% CI = 0.60-0.96; ORQ4 vs. Q1 = 0.75, 95% CI = 0.58-0.98) and in individuals with MTHFR C677T (CC + CT) polymorphism (ORper SD = 0.87, 95% CI = 0.77-0.99; ORQ4 VS. Q1 = 0.79, 95% CI = 0.61-0.98), but a positive association in the MTHFR C677T (TT) subgroup (ORper SD = 1.89, 95% CI = 1.02-3.72; ORQ4 VS. Q1 = 2.17, 95% CI = 1.06-8.21). The impact of folate, THF, and 5-MTHF on cancer risk varied significantly across different cancer types and MTHFR C677T genotypes. This study provides novel insights into the variable effects of folate and its metabolites on cancer risk, influenced by genetic factors like the MTHFR C677T polymorphism and cancer type.

The association of metabolic syndrome score trajectory patterns with risk of all cancer types.

BACKGROUND: Metabolic syndrome (MetS) elevates cancer risk. However, a single MetS assessment does not fully reveal the long-term association with cancer. Inflammation, alongside MetS, could synergistically expedite both the onset and advancement of cancer. This study aims to investigate MetS score trajectories and cancer risk in a large, prospective cohort study. METHODS: The authors prospectively examined the relationship between MetS score trajectory patterns and new-onset cancer in 44,115 participants. Latent mixture modeling was used to identify the MetS score trajectories. Cox proportional hazards regression models were used to evaluate the association between MetS score trajectory patterns and the risk of overall and site-specific cancers. RESULTS: Four MetS score trajectory patterns were identified: low-stable (n = 4657), moderate-low (n = 18,018), moderate-high (n = 18,288), and elevated-increasing (n = 3152). Compared to participants with a low-stable trajectory pattern, the elevated-increasing trajectory pattern was associated with an elevated risk of overall (hazard ratio [HR], 1.27; 95% confidence interval [CI], 1.04-1.55), breast (HR, 2.11; 95% CI, 1.04-4.34), endometrial (HR, 3.33; 95% CI, 1.16-6.77), kidney (HR, 4.52; 95% CI, 1.17-10.48), colorectal (HR, 2.54; 95% CI, 1.27-5.09), and liver (HR, 1.61; 95% CI, 1.09-4.57) cancers. Among participants with chronic inflammation (C-reactive protein levels ≥3 mg/L), the elevated-increasing trajectory pattern was significantly associated with subsequent breast, endometrial, colorectal, and liver cancers. CONCLUSIONS: Trajectories of MetS scores are associated with the occurrence of cancers, especially breast, endometrial, kidney, colorectal, and liver cancers, emphasizing the importance of long-term monitoring and evaluation of MetS. PLAIN LANGUAGE SUMMARY: The association between long-term elevated metabolic syndrome (MetS) scores and a heightened risk of various cancers is a pivotal finding of our study. Our research further indicates that individuals with MetS, particularly when coupled with chronic inflammation, are at an increased risk of cancer. We propose that sustained monitoring and management of MetS could be beneficial in reducing cancer risk.

Clonal expansion of shared T cell receptors reveals the existence of immune commonality among different lesions of synchronous multiple primary lung cancer.

The increase in the detection rate of synchronous multiple primary lung cancer (MPLC) has posed remarkable clinical challenges due to the limited understanding of its pathogenesis and molecular features. Here, comprehensive comparisons of genomic and immunologic features between MPLC and solitary lung cancer nodule (SN), as well as different lesions of the same patient, were performed. Compared with SN, MPLC displayed a lower rate of EGFR mutation but higher rates of BRAF, MAP2K1, and MTOR mutation, which function exactly in the upstream and downstream of the same signaling pathway. Considerable heterogeneity in T cell receptor (TCR) repertoire exists among not only different patients but also among different lesions of the same patient. Invasive lesions of MPLC exhibited significantly higher TCR diversity and lower TCR expansion than those of SN. Intriguingly, different lesions of the same patient always shared a certain proportion of TCR clonotypes. Significant clonal expansion could be observed in shared TCR clonotypes, particularly in those existing in all lesions of the same patient. In conclusion, this study provided evidences of the distinctive mutational landscape, activation of oncogenic signaling pathways, and TCR repertoire in MPLC as compared with SN. The significant clonal expansion of shared TCR clonotypes demonstrated the existence of immune commonality among different lesions of the same patient and shed new light on the individually tailored precision therapy for MPLC.

Genomic and transcriptomic profiling of combined small-cell lung cancer through microdissection: unveiling the transformational pathway of mixed subtype.

BACKGROUND: Combined small-cell lung carcinoma (cSCLC) represents a rare subtype of SCLC, the mechanisms governing the evolution of cancer genomes and their impact on the tumor immune microenvironment (TIME) within distinct components of cSCLC remain elusive. METHODS: Here, we conducted whole-exome and RNA sequencing on 32 samples from 16 cSCLC cases. RESULTS: We found striking similarities between two components of cSCLC-LCC/LCNEC (SCLC combined with large-cell carcinoma/neuroendocrine) in terms of tumor mutation burden (TMB), tumor neoantigen burden (TNB), clonality structure, chromosomal instability (CIN), and low levels of immune cell infiltration. In contrast, the two components of cSCLC-ADC/SCC (SCLC combined with adenocarcinoma/squamous-cell carcinoma) exhibited a high level of tumor heterogeneity. Our investigation revealed that cSCLC originated from a monoclonal source, with two potential transformation modes: from SCLC to SCC (mode 1) and from ADC to SCLC (mode 2). Therefore, cSCLC might represent an intermediate state, potentially evolving into another histological tumor morphology through interactions between tumor and TIME surrounding it. Intriguingly, RB1 inactivation emerged as a factor influencing TIME heterogeneity in cSCLC, possibly through neoantigen depletion. CONCLUSIONS: Together, these findings delved into the clonal origin and TIME heterogeneity of different components in cSCLC, shedding new light on the evolutionary processes underlying this enigmatic subtype.

Geriatric Nutritional Risk Index Combined with Calf Circumference Can be a Good Predictor of Prognosis in Patients Undergoing Surgery for Gastric or Colorectal Cancer.

OBJECTIVES: To explore the effect of combined hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancer and to screen for the best prognostic indicators. INTRODUCTION: Gastric and colorectal cancer is a widespread health concern worldwide and one of the major contributors to cancer-related death. The hematological and physical measurement indicators have been shown to associate with the prognosis of patients undergoing surgery for gastric or colorectal cancer, respectively, but it is still unclear whether the combination of the two can reflect the prognosis more effectively. METHODS: Thirteen hematological indicators and 5 physical measurement indicators were selected in this study, and the most promising ones were screened using LASSO regression. Then, the best prognostic indicators were selected by time-ROC curves. Survival curves were constructed using the Kaplan-Meier method, and the effects of hematological and physical measurement indicators on the prognosis of patients undergoing surgery for gastric or colorectal cancers were evaluated by Cox proportional risk regression analysis. In addition, the relationship between hematological and physical measurement indicators on secondary outcomes, including length of stay, hospitalization costs, intensive care unit (ICU) admission, and patients' subjective global assessment scores (PGSGA), was explored. RESULTS: After initial screening, among the hematological indicators, the geriatric nutritional risk index (GNRI) showed the highest mean area under the curve (AUC) values. Among body measures, calf circumference (CC) showed the highest mean AUC value. Further analyses showed that the combination of combined nutritional prognostic index (GNRI) and calf circumference (CC) (GNRI-CC) had the best performance in predicting the prognosis of patients undergoing surgery for gastric or colorectal cancers. Low GNRI, low CC, and low GNRI-low CC increased the risk of death by 44%, 48%, and 104%, respectively. Sensitivity analyses showed the same trend. In addition, low GNRI-low CC increased the risk of malnutrition by 17%. CONCLUSION: This study emphasizes that a combination of blood measures and body measures is essential to accurately assess the prognosis of patients undergoing surgery for gastric or colorectal cancers. The GNRI-CC is a good prognostic indicator and can also assess the risk of possible malnutrition.

Cholesterol-modified prognostic nutritional index (CPNI) as an effective tool for assessing the nutrition status and predicting survival in patients with breast cancer.

BACKGROUND: Malnutrition is associated with poor overall survival (OS) in breast cancer patients; however, the most predictive nutritional indicators for the prognosis of patients with breast cancer are not well-established. This study aimed to compare the predictive effects of common nutritional indicators on OS and to refine existing nutritional indicators, thereby identifying a more effective nutritional evaluation indicator for predicting the prognosis in breast cancer patients. METHODS: This prospective study analyzed data from 776 breast cancer patients enrolled in the "Investigation on Nutritional Status and its Clinical Outcome of Common Cancers" (INSCOC) project, which was conducted in 40 hospitals in China. We used the time-dependent receiver operating characteristic curve (ROC), Kaplan-Meier survival curve, and Cox regression analysis to evaluate the predictive effects of several nutritional assessments. These assessments included the patient-generated subjective nutrition assessment (PGSGA), the global leadership initiative on malnutrition (GLIM), the controlling nutritional status (CONUT), the nutritional risk index (NRI), and the prognostic nutritional index (PNI). Utilizing machine learning, these nutritional indicators were screened through single-factor analysis, and relatively important variables were selected to modify the PNI. The modified PNI, termed the cholesterol-modified prognostic nutritional index (CPNI), was evaluated for its predictive effect on the prognosis of patients. RESULTS: Among the nutritional assessments (including PGSGA, GLIM, CONUT, NRI, and PNI), PNI showed the highest predictive ability for patient prognosis (time-dependent ROC = 0.58). CPNI, which evolved from PNI, emerged as the superior nutritional index for OS in breast cancer patients, with the time-dependent ROC of 0.65. It also acted as an independent risk factor for mortality (p < 0.05). Moreover, the risk of malnutrition and mortality was observed to increase gradually among both premenopausal and postmenopausal age women, as well as among women categorized as non-overweight, overweight, and obese. CONCLUSIONS: The CPNI proves to be an effective nutritional assessment tool for predicting the prognosis of patients with breast cancer.

Muscle distribution in relation to all-cause and cause-specific mortality in young and middle-aged adults.

BACKGROUND: The relationship between muscle and prognosis, especially that between muscle distribution across different body parts, and the related prognosis is not well established. OBJECTIVE: To investigate the relationship between muscle distribution and all-cause and cause-specific mortality and their potential modifiers. DESIGN: Longitudinal cohort study. C-index, IDI, and NRI were used to determine the best indicator of prognosis. COX regression analysis was performed to explore the relationship between variables and outcomes. Interaction and subgroup analyses were applied to identify the potential modifiers. PARTICIPANTS: A total of 5052 participants (weighted: 124,841,420) extracted from the NHANES 2003-2006 of median age 45 years and constituting 50.3% men were assessed. For validation, we included 3040 patients from the INSCOC cohort in China. MAIN MEASURES: Muscle mass and distribution. KEY RESULTS: COX regression analysis revealed that upper limbs (HR = 0.41, 95% CI 0.33-0.51), lower limbs (HR = 0.54, 95% CI 0.47-0.64), trunk (HR = 0.71, 95% CI, 0.59-0.85), gynoid (HR = 0.47, 95% CI 0.38-0.58), and total lean mass (HR = 0.55, 95% CI 0.45-0.66) were all associated with the better survival of participants (P trend < 0.001). The changes in the lean mass ratio of the upper and lower limbs and the lean mass ratio of the android and gynoid attenuated the protective effect of lean mass. Age and sex acted as potential modifiers, and the relationship between lean mass and the prognosis was more significant in men and middle-aged participants when compared to that in other age groups. Sensitive analyses depicted that despite lean mass having a long-term impact on prognosis (15 years), it has a more substantial effect on near-term survival (5 years). CONCLUSION: Muscle mass and its distribution affect the prognosis with a more significant impact on the near-term than that on the long-term prognosis. Age and sex acted as vital modifiers.

Additive value of [18F]PI-2620 perfusion imaging in progressive supranuclear palsy and corticobasal syndrome.

PURPOSE: Early after [18F]PI-2620 PET tracer administration, perfusion imaging has potential for regional assessment of neuronal injury in neurodegenerative diseases. This is while standard late-phase [18F]PI-2620 tau-PET is able to discriminate the 4-repeat tauopathies progressive supranuclear palsy and corticobasal syndrome (4RTs) from disease controls and healthy controls. Here, we investigated whether early-phase [18F]PI-2620 PET has an additive value for biomarker based evaluation of 4RTs. METHODS: Seventy-eight patients with 4RTs (71 ± 7 years, 39 female), 79 patients with other neurodegenerative diseases (67 ± 12 years, 35 female) and twelve age-matched controls (69 ± 8 years, 8 female) underwent dynamic (0-60 min) [18F]PI-2620 PET imaging. Regional perfusion (0.5-2.5 min p.i.) and tau load (20-40 min p.i.) were measured in 246 predefined brain regions [standardized-uptake-value ratios (SUVr), cerebellar reference]. Regional SUVr were compared between 4RTs and controls by an ANOVA including false-discovery-rate (FDR, p < 0.01) correction. Hypoperfusion in resulting 4RT target regions was evaluated at the patient level in all patients (mean value - 2SD threshold). Additionally, perfusion and tau pattern expression levels were explored regarding their potential discriminatory value of 4RTs against other neurodegenerative disorders, including validation in an independent external dataset (n = 37), and correlated with clinical severity in 4RTs (PSP rating scale, MoCA, activities of daily living). RESULTS: Patients with 4RTs had significant hypoperfusion in 21/246 brain regions, most dominant in thalamus, caudate nucleus, and anterior cingulate cortex, fitting to the topology of the 4RT disease spectrum. However, single region hypoperfusion was not specific regarding the discrimination of patients with 4RTs against patients with other neurodegenerative diseases. In contrast, perfusion pattern expression showed promise for discrimination of patients with 4RTs from other neurodegenerative diseases (AUC: 0.850). Discrimination by the combined perfusion-tau pattern expression (AUC: 0.903) exceeded that of the sole tau pattern expression (AUC: 0.864) and the discriminatory power of the combined perfusion-tau pattern expression was replicated in the external dataset (AUC: 0.917). Perfusion but not tau pattern expression was associated with PSP rating scale (R = 0.402; p = 0.0012) and activities of daily living (R = - 0.431; p = 0.0005). CONCLUSION: [18F]PI-2620 perfusion imaging mirrors known topology of regional hypoperfusion in 4RTs. Single region hypoperfusion is not specific for 4RTs, but perfusion pattern expression may provide an additive value for the discrimination of 4RTs from other neurodegenerative diseases and correlates closer with clinical severity than tau pattern expression.

Habitually Skipping Breakfast Is Associated with the Risk of Gastrointestinal Cancers: Evidence from the Kailuan Cohort Study.

BACKGROUND: Habitually skipping breakfast may promote the initiation and progression of gastrointestinal (GI) cancers, which have never been systematically explored in large-scale prospective studies. METHODS: We prospectively examined the effects of breakfast frequency on the occurrence of GI cancers among 62,746 participants. The hazard ratios (HRs) and 95% confidence intervals (95% CIs) of GI cancers were calculated by Cox regression. The CAUSALMED procedure was used to perform the mediation analyses. RESULTS: During a median follow-up of 5.61 (5.18 ~ 6.08) years, 369 incident GI cancer cases were identified. Participants who consumed 1-2 times breakfasts per week exhibited an increased risk of stomach (HR = 3.45, 95% CI: 1.06-11.20) and liver cancer (HR = 3.42, 95% CI: 1.22-9.53). Participants who did not eat breakfast had an elevated risk of esophageal (HR = 2.72, 95% CI: 1.05-7.03), colorectal (HR = 2.32, 95% CI: 1.34-4.01), liver (HR = 2.41, 95% CI: 1.23-4.71), gallbladder, and extrahepatic bile duct cancer (HR = 5.43, 95% CI: 1.34-21.93). In the mediation effect analyses, BMI, CRP, and TyG (fasting triglyceride-glucose) index did not mediate the association between breakfast frequency and the risk of GI cancer incidence (all P for mediation effect > 0.05). CONCLUSIONS: Habitually skipping breakfast was associated with a greater risk of GI cancers including esophageal, gastric, colorectal, liver, gallbladder, and extrahepatic bile duct cancer. TRIAL REGISTRATION: Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050.

The value of CRP-albumin-lymphocyte index (CALLY index) as a prognostic biomarker in patients with non-small cell lung cancer.

OBJECTIVE: The C-reactive protein-albumin-lymphocyte (CALLY) index is a new index related to inflammation, immunity, and nutrition. We investigated whether it can predict the prognosis of patients with non-small cell lung cancer (NSCLC) and developed a prognostic model including CALLY index. RESEARCH METHODS AND PROCEDURES: Data from patients with NSCLC who were followed up in the INSCOC database from May 2013 to December 2018 were retrospectively analyzed. Simple random sampling by splitting these patients into training (n = 1307) and validation cohorts (n = 557) resulted in a sample size ratio of 7:3. Using the results of COX regression analysis of the training cohort, a nomogram model for predicting 3- and 5-year overall survival (OS) was established and validated internally. The calibration and clinical decision curve were used to evaluate the prediction accuracy and clinical application ability of the nomogram and compared with the TNM staging system for lung cancer. RESULTS: Sex, TNM stage, surgical treatment, BMI, CALLY, and HGS were independent risk factors for the prognosis of NSCLC patients. The OS of NSCLC patients with a low CALLY index score was significantly worse than that of patients with a high CALLY index (P < 0.001). The CALLY-based nomogram had a good predictive prognostic power, with a C-index of 0.697. Compared with the traditional TNM staging system, our prognostic nomogram had better resolution and accuracy in predicting the 3-year and 5-year OS. Decision curve analysis showed that this prognostic model has a clinical application value. CONCLUSIONS: The CALLY index is a valuable biomarker for evaluating the prognosis of patients with lung cancer. The nomogram based on the CALLY index is highly effective in predicting OS in patients with NSCLC. The results of this study provide a reference tool for clinicians to guide the personalized treatment of patients with lung cancer.

METTL3/YTHDC1-medicated m6A modification of circRNA3634 regulates the proliferation and differentiation of antler chondrocytes by miR-124486-5-MAPK1 axis.

BACKGROUND: The deer antler, a remarkable mammalian appendage, has a growth rate surpassing that of any other known osseous organ. Emerging evidence indicates that circRNA and MAPK1 play critical roles in chondrocytes. Thus, exploration of their functions in antler chondrocytes will help us to understand the mechanism regulating the rapid antler growth. METHODS: qRT-PCR, western blot, and immunohistochemistry were used to assess the expression of mRNAs and proteins. CCK-8, EdU, Cell migration, ALP activity detection, and ALP staining examined the effects of MAPK1 in antler chondrocytes. FISH, RIP, and luciferase assays were performed to evaluate the interactions among circRNA3634/MAPK1 and miR-124486-5. RIP and RAP assays proved the binding interaction between circRNA3634 and RBPs. Me-RIP was used to determine the m6A methylation modification of circRNA3634. RESULTS: This study revealed high MAPK1 expression in antler cartilage tissue. Overexpression of MAPK1 promoted the proliferation, migration, and differentiation of antler chondrocytes and increased the expression of MAPK3, RAF1, MEK1, RUNX2, and SOX9. The silencing of MAPK1 had the opposite effect. CircRNA3634 was found to act as a molecular sponge for miR-124486-5, leading to increased MAPK1 expression and enhanced proliferation and migration of antler chondrocytes through competitive miR-124486-5 binding. We discovered that METTL3 mediates m6A modification near the splicing site of circRNA3634 and is involved in the proliferation and differentiation of antler chondrocytes. The m6A reader YTHDC1 facilitated the nuclear export of circRNA3634 in an m6A-dependent manner. Our results indicate that m6A-modified circRNA3634 promotes the proliferation of antler chondrocytes by targeting MAPK1 and show that the nuclear export of circRNA3634 is related to the expression of YTHDC1, suggesting that circRNA3634 could represent a critical regeneration marker for the antler. CONCLUSIONS: Our results revealed a novel m6A-modified circRNA3634 promoted the proliferation and differentiation of antler chondrocytes by regulating MAPK1. The nuclear export of circRNA3634 was related to the expression of YTHDC1.

Association between the Dietary Inflammatory Index and All-Cause Mortality in Adults with Obesity.

INTRODUCTION: The dietary inflammatory index (DII) is associated with numerous chronic noncommunicable diseases. Previous studies have shown that the pro-inflammatory DII categories are associated with abdominal and simple obesity. However, the association between DII and mortality in patients with abdominal obesity and simple overweight or obesity remains unclear. METHODS: We used data from the US National Health and Nutrition Examination Survey (NHANES) from 2007 to 2018. A DII >0 (positive DII) was defined as a pro-inflammatory diet. A restricted cubic spline curve was used to describe the trend between DII and all-cause mortality. We then examined the association between DII and all-cause mortality in different body types using a Cox regression analysis and investigated the differences between sexes. Finally, the mediating effects of systemic inflammation were explored. RESULTS: A pro-inflammatory diet increased all-cause mortality in adults with abdominal obesity (aHR: 1.31, 95% confidence interval [CI]: 1.11-1.54; p < 0.001) and with simple overweight or obesity (aHR: 1.30, 95% CI: 1.11-1.53; p < 0.001). In addition, the most pro-inflammatory DII increased the risk of mortality by 43% (hazard ratio [HR]: Q4 vs. Q1 = 1.43, 95% CI = 1.14-1.79; p = 0.002; p for trend = 0.003) and 39% (HR: Q4 vs. Q1 = 1.39, 95% CI = 1.13-1.74; p = 0.003; p for trend = 0.009) in participants with abdominal obesity and with simple overweight or obesity, respectively. However, this association was not present in normal-sized participants. Compared with men, women resisted the effects of a pro-inflammatory diet. Mediation analysis showed that white blood cell and neutrophil were mediators of the association between DII and all-cause mortality (p < 0.001). CONCLUSION: A pro-inflammatory diet is associated with all-cause mortality in adults with abdominal obesity and simple overweight or obesity, and this effect differs between men and women. Systemic inflammation may mediate the association between DII and all-cause mortality.

Research on the Influence of Geometric Structure Parameters of Eddy Current Testing Probe on Sensor Resolution.

To study the influence of the geometric structure of the probe coil on the electromagnetic characteristics of the eddy current probe in the process of eddy current testing, based on the principle of eddy current testing, different probe coil models were established using finite element software. These geometric structure parameters include the difference between the inner and outer radius, thickness, and equivalent radius. The magnetic field distribution around the probe is simulated and analyzed under different parameters, and the detection performance of the probe is judged in combination with the change rate of the magnetic field around the probe coil. The simulation results show that at a closer position, increasing the difference between the inner and outer radii, reducing the thickness, and reducing the equivalent radius are beneficial to improve the resolution of the probe coil. At a far position, reducing the difference between the inner and outer radii, increasing the thickness, and reducing the equivalent radius are beneficial to improve the resolution of the probe coil. At the same time, the accuracy of the simulation data is verified by comparing the theoretical values with the simulated values under different conditions. Therefore, the obtained conclusions can provide a reference and basis for the optimal design of the probe structure.

Whole-Transcriptome Sequencing of Antler Tissue Reveals That circRNA2829 Regulates Chondrocyte Proliferation and Differentiation via the miR-4286-R+1/FOXO4 Axis.

The antler is the unique mammalian organ found to be able to regenerate completely and periodically after loss, and the continuous proliferation and differentiation of mesenchymal cells and chondrocytes together complete the regeneration of the antler. Circular non-coding RNAs (circRNAs) are considered to be important non-coding RNAs that regulate body development and growth. However, there are no reports on circRNAs regulating the antler regeneration process. In this study, full-transcriptome high-throughput sequencing was performed on sika deer antler interstitial and cartilage tissues, and the sequencing results were verified and analyzed. The competing endogenous RNA (ceRNA) network related to antler growth and regeneration was further constructed, and the differentially expressed circRNA2829 was screened out from the network to study its effect on chondrocyte proliferation and differentiation. The results indicated that circRNA2829 promoted cell proliferation and increased the level of intracellular ALP. The analysis of RT-qPCR and Western blot demonstrated that the mRNA and protein expression levels of genes involved in differentiation rose. These data revealed that circRNAs play a crucial regulatory role in deer antler regeneration and development. CircRNA2829 might regulate the antler regeneration process through miR-4286-R+1/FOXO4.

Hepatitis B virus infection and the risk of gastrointestinal cancers among Chinese population: A prospective cohort study.

Our study aims to explore the relationship between chronic hepatitis B virus (HBV) infection and the risk of gastrointestinal (GI) cancers including liver, gastric, gallbladder or extrahepatic bile duct, pancreatic, small intestine, esophageal and colorectal cancer in the Kailuan Cohort study. We prospectively examined the relationship between HBV infection and new-onset GI cancers among 93 402 participants. Cox proportional hazards regression models, subgroup analyses and competing risk analyses were used to evaluate the association between HBV infection and the risk of new-onset GI cancers. During a median follow-up of 13.02 years, 1791 incident GI cancer cases were diagnosed. Compared to HBsAg seronegative participants, a significant positive association between HBV infection and GI cancers was observed in the multivariate-adjusted models (HR 5.59, 95% CI: 4.84-6.45). In the site-specific analyses, participants with HBsAg seropositive exhibited an increased risk of liver cancer (HR = 21.56, 95% CI: 17.32-26.85), gallbladder or extrahepatic bile duct cancer (HR = 14.89, 95% CI: 10.36-21.41), colorectal cancer (HR = 1.75, 95% CI: 1.15-2.96) and pancreatic cancer (HR = 1.86, 95% CI: 1.10-3.99). After taking death as the competing risk event, the associations of HBV infection with the risk of these cancers were attenuated but remained significant both in the cause-specific hazards models, the subdistribution proportional hazards models and sensitivity analyses. Our study suggests that HBV infection is associated with the elevated risk of liver cancer and extrahepatic cancer including gallbladder or extrahepatic bile duct, pancreatic and colorectal cancer among adults in Northern China.

C-reactive protein trajectories and the risk of all cancer types: A prospective cohort study.

A single CRP measurement is insufficient to examine the association of long-term patterns of CRP concentration with cancer risk. We prospectively examined the relationship between CRP trajectory patterns and new-onset cancers among 52 276 participants. Latent mixture modeling was used to identify CRP trajectories. Cox proportional hazards regression models were used to evaluate the association between CRP trajectory patterns and the risk of overall and specific-site cancer. Four CRP trajectories patterns were identified: low-stable pattern (n = 43 258), moderate-increasing pattern (n = 2591), increasing-decreasing pattern (n = 2068) and elevated-decreasing pattern (n = 4359). Relative to the low-stable pattern, the moderate-increasing trajectory pattern was associated with an elevated risk of overall, lung, breast, leukemia, bladder, stomach, colorectal, liver, gallbladder or extrahepatic bile duct cancer and leukemia. Participants in the increasing-decreasing trajectory pattern were associated with an elevated risk of overall, lung, breast, bladder, pancreatic and liver cancer. The increasing-decreasing trajectory pattern was also associated with decreased risk of colorectal cancer in the multivariate analyses. Elevated-decreasing trajectory pattern was associated with increased risk of leukemia and decreased risk of esophageal and colorectal cancer. CRP trajectories play an important role in the occurrence of cancers, especially in the lung, breast, bladder, stomach, colorectal, liver, gallbladder and extrahepatic bile duct cancer and leukemia.

Fluoxetine inhibited the activation of A1 reactive astrocyte in a mouse model of major depressive disorder through astrocytic 5-HT2BR/ß-arrestin2 pathway.

BACKGROUND: Fluoxetine, a selective serotonin reuptake inhibitor, has been reported to directly bind with 5-HT2B receptor (5-HT2BR), but the precise mechanisms, whereby fluoxetine confers the anti-depressive actions via 5-HT2BR is not fully understood. Although neuroinflammation-induced A1 astrocytes are involved in neurodegenerative diseases, the role of A1 astrocyte in the pathogenesis and treatment of major depressive disorder (MDD) remains unclear. METHODS: Mice were subjected to chronic mild stress (CMS) for 6 weeks and subsequently treated with fluoxetine for 4 weeks. The depressive-like and anxiety-like behaviors and the activation of A1 reactive astrocyte in hippocampus and cortex of mice were measured. Primary astrocytes were stimulated with A1 cocktail (tumor necrosis factor (TNF)-α, interleukin (IL)-1α and C1q), activated (LPS) microglia-conditioned medium (MCM) or IL-6 for 24 h and the expression of A1-special and A2-special markers were determined using RT-qPCR and western blot. The role of 5-HT2BR in the effects of fluoxetine on A1 reactive astrocyte was measured using 5-HT2BR inhibitor and siRNA in vitro and AAVs in vivo. The functions of downstream signaling Gq protein and ß-arrestins in the effects of fluoxetine on the activation of A1 astrocyte were determined using pharmacological inhibitor and genetic knockout, respectively. RESULTS: In this study, we found that fluoxetine inhibited the activation of A1 reactive astrocyte and reduced the abnormal behaviors in CMS mice, as well as ameliorated A1 astrocyte reactivity under three different stimulators in primary astrocytes. We also showed that astrocytic 5-HT2BR was required in the inhibitory effects of fluoxetine on A1 reactive astrocyte in MDD in vivo and in vitro. We further found that the functions of fluoxetine in the activation of A1 astrocyte were independent of either Gq protein or ß-arrestin1 in vitro. ß-arrestin2 pathway was the downstream signaling of astrocytic 5-HT2BR mediated the inhibitory effects of fluoxetine on A1 astrocyte reactivity in primary astrocytes and CMS mice, as well as the improved roles of fluoxetine in behavioral impairments of CMS mice. CONCLUSIONS: These data demonstrate that fluoxetine restricts reactive A1 astrocyte via astrocytic 5-HT2BR/ß-arrestin2 pathway in a mouse model of MDD and provide a novel therapeutic avenue for MDD.

Association between the TyG index and TG/HDL-C ratio as insulin resistance markers and the risk of colorectal cancer.

BACKGROUND: No previous prospective research has explored the association of the TyG (fasting triglyceride-glucose) index and TG/HDL-C ratio as insulin resistance markers with the risk of colorectal cancer (CRC) incidence in the Northern Chinese population. METHODS: In this prospective cohort study, we included 93,659 cancer-free participants with the measurements of TyG index and TG/HDL-C ratio. Participants were divided by the quartiles of the TyG index or TG/HDL-C ratio. The associations of TyG index, TG/HDL-C ratio, and their components with CRC risk were assessed using Cox proportional hazards regression models. RESULTS: During a median follow-up of 13.02 years, 593 incident CRC cases were identified. Compared with the lowest quartile of the TyG index (Q1), the risk of CRC was higher in persons in the third (Q3) and highest quartiles (Q4) of the TyG index, with corresponding multivariable-adjusted HRs (95% CI) of 1.36 (1.06, 1.76) and 1.50 (1.19, 1.91), respectively. The elevated risks of CRC incidence were observed in people in the second, third, and highest quartiles of the TG/HDL-C ratio groups, with corresponding multivariable-adjusted HRs (95% CI) of 1.33 (1.05, 1.70), 1.36 (1.07, 1.73) and 1.37 (1.07, 1.75), respectively. CONCLUSIONS: Elevated TyG index and TG/HDL-C ratio were associated with a higher risk of developing CRC among adults in Northern China.

Association between metabolic syndrome, C-reactive protein, and the risk of primary liver cancer: a large prospective study.

BACKGROUND AND AIMS: High-sensitivity C-reactive protein (hs-CRP) levels and metabolic syndrome (MetS) are known to be associated with an increased incidence of different cancers. We aimed to evaluate the effect of MetS combined with high hs-CRP levels on the risk of primary liver cancer (PLC). METHODS: Participants were recruited from the Kailuan cohort study and were classified into four groups according to the presence or absence of MetS and inflammation (hs-CRP ≥ 3 or < 3 mg/L). The associations of MetS and inflammation with the risk of PLC were assessed using Cox proportional hazards models. RESULTS: This study included 92,770 participants. The mean age was 51.4 years old. Over a median follow-up of 13.02 years, 395 participants were diagnosed as PLC. Compared to the control participants without inflammation (hs-CRP < 3 mg/L) and MetS (n = 69,413), participants with high hs-CRP levels combined with MetS (n = 2,269) had a higher risk of PLC [hazard ratios (HR) 2.91; 95% confidence interval (CI), 1.77-4.81], and participants with high hs-CRP levels and without MetS (n = 14,576) had the same trend (HR, 1.36; 95%CI, 1.05-1.75). However, participants with low hs-CRP levels and MetS (n = 6,512) had no significant association with an elevated risk of PLC (HR, 1.18; 95%CI, 0.76-1.82). After excluding participants who had cancer during the first year of follow-up, sensitivity analysis showed the same trend. In addition, co-occurrence of MetS and high hs-CRP levels had significant interactive effects on the risk of PLC between the sexes (P < 0.001) and the patients with HBV infection (P = 0.012). CONCLUSIONS: Participants with co-occurrence of MetS and high hs-CRP levels have an elevated risk of PLC. TRIAL REGISTRATION: Kailuan study, ChiCTR-TNRC-11001489. Registered 24 August, 2011-Retrospectively registered, http://www.chictr.org.cn/showprojen.aspx?proj=8050.