Plasma ofCS-modified CD44 predicts the survival of patients with lung cancer.

Plasma levels of oncofetal chondroitin sulfate (ofCS)-modified CD44 have emerged as a promising biomarker for multi-cancer detection. Here, we explored its potential to predict the survival of patients with lung cancer. A prospective observational cohort was conducted involving 274 newly diagnosed patients with lung cancer at the Sun Yat-sen University Cancer Center from 2013 to 2015. The plasma levels of ofCS-modified CD44 were measured, and Cox regression analysis was performed to assess the association between plasma-modified CD44 levels and overall survival (OS) as well as other prognostic outcomes. Prognostic nomograms were constructed based on plasma ofCS-modified CD44 levels to predict survival outcomes for patients with lung cancer. Patients with high expression ofCS-modified CD44 exhibited significantly worse outcomes in terms of OS (HR = 1.61, 95%CI = 1.13-2.29, p = 0.009) and progression-free survival (PFS). These findings were consistent across various analyses. The concordance index of the prognostic nomogram for predicting OS in both the training set and validation set were 0.723 and 0.737, respectively. Additionally, time-dependent receiver operating characteristic (ROC) curves showed that the nomogram could serve as a useful tool for predicting OS in patients with lung cancer. Plasma ofCS-modified CD44 may serve as an independent prognosis marker for patients with lung cancer. Further validation of its predictive value could enhance prognostic assessment and guide personalized treatment strategies for patients with lung cancer.

Detection of Epstein‒Barr virus DNA methylation as tumor markers of nasopharyngeal carcinoma patients in saliva, oropharyngeal swab, oral swab, and mouthwash.

Saliva biopsy of nasopharyngeal carcinoma (NPC) has been developed in our latest study, indicating the application of oral sampling in NPC detection. Further exploration of the potential for self-sampling from the oral cavity is necessary. A total of 907 various samples from oral cavity, including saliva (n = 262), oropharyngeal swabs (n = 250), oral swabs (n = 210), and mouthwash (n = 185), were collected. Epstein‒Barr virus (EBV) DNA methylation at the 12,420 bp CpG site in EBV genome from the repeat-copy W promoter (Wp) region and at the 11,029 bp CpG site in the single-copy C promoter (Cp) region were simultaneously detected in these samples. A significant increase in EBV methylation, no matter at Wp or Cp region, was found in all types of samples from NPC patients. However, EBV DNA methylation in saliva and oropharyngeal swab showed a better diagnostic performance in detecting NPC. The combination of these two sample types and two markers could help to improve the detection of NPC. Our study further explored the optimal self-sampling methods and detection target in the detection of NPC and may facilitate the application of EBV DNA methylation detection in a home-based large-scale screening of NPC.

Efficacy and safety of navigation robot-assisted versus conventional oblique lateral lumbar interbody fusion with internal fixation in the treatment of lumbar degenerative diseases: A retrospective study.

Effective internal fixation with pedicle screw is a key factor in the success of lumbar fusion with internal fixation. Whether navigation robots can improve the efficacy and safety of screw placement is controversial. Thirty-eight patients who underwent oblique lateral lumbar interbody fusion internal fixation from March 2022 to May 2023 were retrospectively analyzed, 16 cases in the navigational robot group and 22 cases in the fluoroscopy group. Using visual analog score (VAS) for the low back and lower limbs, Oswestry Disability Index to compare the clinical efficacy of the 2 groups; using perioperative indexes such as the duration of surgery, intraoperative blood loss, intraoperative fluoroscopy times, and postoperative hospital stay to compare the safety of the 2 groups; and using accuracy of pedicle screws (APS) and the facet joint violation (FJV) to compare the accuracy of the 2 groups. Postoperative follow-up at least 6 months, there was no statistically significant difference between the 2 groups in the baseline data (P > .05). The navigational robot group's VAS-back was significantly lower than the fluoroscopy group at 3 days postoperatively (P < .05). However, the differences between the 2 groups in VAS-back at 3 and 6 months postoperatively, and in VAS-leg and Oswestry Disability Index at 3 days, 3 months, and 6 months postoperatively were not significant (P > .05). Although duration of surgery in the navigational robot group was significantly longer than in the fluoroscopy group (P > .05), the intraoperative blood loss and the intraoperative fluoroscopy times were significantly lower than in the fluoroscopy group (P < .05). The difference in the PHS between the 2 groups was not significant (P > .05). The APS in the navigation robot group was significantly higher than in the fluoroscopy group, and the rate of FJV was significantly lower than in the fluoroscopy group (P < .05). Compared with the traditional fluoroscopic technique, navigation robot-assisted lumbar interbody fusion with internal fixation provides less postoperative low back pain in the short term, with less trauma, less bleeding, and lower radiation exposure, as well as better APS and lower FJV, resulting in better clinical efficacy and safety.

The Role of Microvascular Variations in the Process of Intervertebral Disk Degeneration and Its Regulatory Mechanisms: A Literature Review.

Microvascular changes are considered key factors in the process of intervertebral disk degeneration (IDD). Microvascular invasion and growth into the nucleus pulposus (NP) and cartilaginous endplates are unfavorable factors that trigger IDD. In contrast, the rich distribution of microvessels in the bony endplates and outer layers of the annulus fibrosus is an important safeguard for the nutrient supply and metabolism of the intervertebral disk (IVD). In particular, the adequate supply of microvessels in the bony endplates is the main source of the nutritional supply for the entire IVD. Microvessels can affect the progression of IDD through a variety of pathways. Many studies have explored the effects of microvessel alterations in the NP, annulus fibrosus, cartilaginous endplates, and bony endplates on the local microenvironment through inflammation, apoptosis, and senescence. Studies also elucidated the important roles of microvessel alterations in the process of IDD, as well as conducted in-depth explorations of cytokines and biologics that can inhibit or promote the ingrowth of microvessels. Therefore, the present manuscript reviews the published literature on the effects of microvascular changes on IVD to summarize the roles of microvessels in IVD and elaborate on the mechanisms of action that promote or inhibit de novo microvessel formation in IVD.

PD-L2 Expression in Breast Cancer Promotes Tumor Development and Progression.

Background: This work focused on investigating the role of programmed death ligand 2 (PD-L2) in the progression of breast cancer by utilizing breast cancer specimens and cells. Materials and Methods: The serum levels of soluble PD-L2 (sPD-L2) in breast cancer patients and healthy individuals were analyzed by means of the enzyme-linked immunosorbent assay, and the PD-L2 levels within 416 resected breast cancer specimens were assessed through immunohistochemistry. Concurrently, in vitro cell experiments and in vivo animal experiments were carried out to analyze the relationship between PD-L2 and the invasion and migration of breast cancer. Results: The concentration of sPD-L2 in breast cancer patients significantly increased compared to that in the control groups. Additionally, breast cancer patients with high concentrations of sPD-L2 had higher Ki67 values (≥30%) and tumor grades. PD-L2 was expressed in 79.09% of the cancer samples, which exhibited a positive correlation with the progesterone receptor (PR) and the human epidermal growth factor receptor 2 (HER2). Furthermore, we discovered that knockdown of PD-L2 inhibited the migratory and invasive abilities of both MCF-7 and MDA-MB231 cells. Conclusion: Our findings demonstrated that knockdown of PD-L2 suppressed tumor growth, providing novel insights into important biological functions.

Structural equation model analysis of the effect of visceral fat on osteoporosis.

BACKGROUND: Osteoporosis is a considerable public health challenge in Moyu County, Xinjiang. Here, we evaluated the influencing factors of osteoporosis in this region. METHODS: We recruited 7,761 participants and randomized them into normal and osteoporotic populations based on T-score. The effects of general conditions, body composition, calcium sources and exercise, respiratory exposure, and daily diet on osteoporosis were analyzed. Furthermore, a structural equation model was constructed to uncover the direct and indirect influencing factors of osteoporosis. RESULTS: Among the participants, 1,803 (23.23%) had normal bone mass while 1,496 (19.28%) had osteoporosis. The univariate analysis showed significant differences in the general conditions, body composition, calcium sources and exercise, respiratory exposure, and daily diet. Stratification based on age (45 years) and body mass index (BMI) (18.5 kg/m2) showed variations in the body composition between the two groups; however, the visceral fat differed significantly. Logistic regression analysis affirmed the association of visceral fat index as it was included in all equations, except for age and female menopause. The structural equation exhibited that the general conditions, body composition, and, calcium sources, and exercise were direct factors of osteoporosis, while respiratory exposure and daily diet were indirect factors. The standardized path coefficient was highest in general conditions, followed by body composition, and lastly, calcium sources and exercise. CONCLUSION: Obesity, besides age and female menopause, is also an influencing factor of osteoporosis. The visceral fat index plays a vital role in osteoporosis. Our findings may provide experimental evidence for early prevention and treatment of osteoporosis.

Associations of dietary inflammatory index scores and serum inflammatory factors with the risk of osteoporosis: a cross-sectional study from Xinjiang, China.

BACKGROUND: Previous studies have shown that the inflammatory potential of the diet is associated with a variety of chronic noncommunicable diseases characterized by a chronic low-grade inflammatory response. However, the relationships between dietary inflammatory potential and organismal inflammatory status and osteoporosis have been less studied. This study aimed to investigate the relationships among inflammatory diet, inflammatory state and osteoporosis in the Xinjiang multiethnic population. METHODS: The participants consisted of 4452 adults aged 35 to 74 years from Xinjiang, China. The dietary inflammatory index (DII) was calculated using dietary data collected with a semiquantitative food frequency questionnaire, and information about osteoporosis was derived from quantitative ultrasound measurements. The relationships of the DII score and inflammatory factors with the risk of osteoporosis were analysed using multivariate logistic regression, and the nonlinear associations between DII and osteoporosis were further analysed using restricted cubic splines. RESULTS: The results showed that proinflammatory diets were associated with a greater risk of osteoporosis (T3 vs. T1: OR = 1.87; 95% CI = 1.44, 2.45) and that there was no nonlinear relationship between the DII and the risk of osteoporosis. Increased concentrations of the inflammatory factors IL-6, IL-10, IL-12p70, IL-17, and IL-23 were associated with a greater risk of osteoporosis. CONCLUSIONS: The risk of osteoporosis can be reduced by increasing the consumption of an appropriate anti-inflammatory diet.

Multiplex assays reveal anti-EBV antibody profile and its implication in detection and diagnosis of nasopharyngeal carcinoma.

Epstein-Barr virus (EBV) is detected in nearly 100% of nonkeratinizing nasopharyngeal carcinoma (NPC) and EBV-based biomarkers are used for NPC screening in endemic regions. Immunoglobulin A (IgA) against EBV nuclear antigen 1 (EBNA1) and viral capsid antigen (VCA), and recently identified anti-BNLF2b antibodies have been shown to be the most effective screening tool; however, the screening efficacy still needs to be improved. This study developed a multiplex serological assay by testing IgA and immunoglobulin G (IgG) antibodies against representative EBV antigens that are highly transcribed in NPC and/or function crucially in viral reactivation, including BALFs, BNLF2a/b, LF1, LF2, and Zta (BZLF1). Among them, BNLF2b-IgG had the best performance distinguishing NPC patients from controls (area under the curve: 0.951, 95% confidence interval [CI]: 0.913-0.990). Antibodies to lytic antigens BALF2 and VCA were significantly higher in advanced-stage than in early-stage tumors; in contrast, antibodies to latent protein EBNA1 and early lytic antigen BNLF2b were not correlated with tumor progression. Accordingly, a novel strategy combining EBNA1-IgA and BNLF2b-IgG was proposed and validated improving the integrated discrimination by 15.8% (95% CI: 9.8%-21.7%, p < .0001) compared with the two-antibody method. Furthermore, we found EBV antibody profile in patients was more complicated compared with that in healthy carriers, in which stronger correlations between antibodies against different phases of antigens were observed. Overall, our serological assay indicated that aberrant latent infection of EBV in nasopharyngeal epithelial cells was probably a key step in NPC initiation, while more lytic protein expression might be involved in NPC progression.

Polygenic risk-stratified screening for nasopharyngeal carcinoma in high-risk endemic areas of China: a cost-effectiveness study.

Background: Nasopharyngeal carcinoma (NPC) has an extremely high incidence rate in Southern China, resulting in a severe disease burden for the local population. Current EBV serologic screening is limited by false positives, and there is opportunity to integrate polygenic risk scores for personalized screening which may enhance cost-effectiveness and resource utilization. Methods: A Markov model was developed based on epidemiological and genetic data specific to endemic areas of China, and further compared polygenic risk-stratified screening [subjects with a 10-year absolute risk (AR) greater than a threshold risk underwent EBV serological screening] to age-based screening (EBV serological screening for all subjects). For each initial screening age (30-34, 35-39, 40-44, 45-49, 50-54, 55-59, 60-64, and 65-69 years), a modeled cohort of 100,000 participants was screened until age 69, and then followed until age 79. Results: Among subjects aged 30 to 54 years, polygenic risk-stratified screening strategies were more cost-effective than age-based screening strategies, and almost comprised the cost-effectiveness efficiency frontier. For men, screening strategies with a 1-year frequency and a 10-year absolute risk (AR) threshold of 0.7% or higher were cost-effective, with an incremental cost-effectiveness ratio (ICER) below the willingness to pay (¥203,810, twice the local per capita GDP). Specifically, the strategies with a 10-year AR threshold of 0.7% or 0.8% are the most cost-effective strategies, with an ICER ranging from ¥159,752 to ¥201,738 compared to lower-cost non-dominated strategies on the cost-effectiveness frontiers. The optimal strategies have a higher probability (29.4-35.8%) of being cost-effective compared to other strategies on the frontier. Additionally, they reduce the need for nasopharyngoscopies by 5.1-27.7% compared to optimal age-based strategies. Likewise, for women aged 30-54 years, the optimal strategy with a 0.3% threshold showed similar results. Among subjects aged 55 to 69 years, age-based screening strategies were more cost-effective for men, while no screening may be preferred for women. Conclusion: Our economic evaluation found that the polygenic risk-stratified screening could improve the cost-effectiveness among individuals aged 30-54, providing valuable guidance for NPC prevention and control policies in endemic areas of China.

FoxO3 Regulates Mouse Bone Mesenchymal Stem Cell Fate and Bone-Fat Balance During Skeletal Aging.

Age-related osteoporosis is characterized by an imbalance between osteogenic and adipogenic differentiation in bone mesenchymal stem cells (BMSCs). Forkhead box O 3 (FoxO3) transcription factor is involved in lifespan and cell differentiation. In this study, we explore whether FoxO3 regulates age-related bone loss and marrow fat accumulation. The expression levels of FoxO3 in BMSCs during aging were detected in vivo and in vitro. To explore the role of FoxO3 in osteogenic and adipogenic differentiation, primary BMSCs were isolated from young and aged mice. FoxO3 expression was modulated by adenoviral vector transfection. The role of FoxO3 in bone-fat balance was evaluated by alizarin red S staining, oil red O staining, quantitative reverse transcription-polymerase chain reaction, Western blot, and histological analysis. Age-related bone loss and fat deposit are associated with downregulation of FoxO3. Overexpression of FoxO3 alleviated age-related bone loss and marrow fat accumulation in aged mice. Mechanistically, FoxO3 reduced adipogenesis and enhanced osteogenesis of BMSCs via downregulation of PPAR-γ and Notch signaling, respectively. In conclusion, FoxO3 is an essential factor controlling the fate of BMSCs and is a potential target for the prevention of age-related osteoporosis.

Microbes translocation from oral cavity to nasopharyngeal carcinoma in patients.

The presence of oral microbes in extra-oral sites is linked to gastrointestinal cancers. However, their potential ectopically colonization in the nasopharynx and impact on local cancer development remains uncertain. Our study involving paired nasopharyngeal-oral microbial samples from nasopharyngeal carcinoma (NPC) patients and controls unveils an aberrant oral-to-nasopharyngeal microbial translocation associated with increased NPC risk (OR = 4.51, P = 0.012). Thirteen species are classified as oral-translocated and enriched in NPC patients. Among these, Fusobacterium nucleatum and Prevotella intermedia are validated through culturomics and clonal strain identification. Nasopharyngeal biopsy meta-transcriptomes confirm these microbes within tumors, influencing local microenvironment and cytokine response. These microbes correlate significantly with the Epstein-Barr virus (EBV) loads in the nasopharynx, exhibiting an increased dose-response relationship. Collectively, our study identifies oral microbes migrating to the nasopharynx, infiltrating tumors, impacting microenvironments and linking with EBV infection. These results enhance our understanding of abnormal microbial communication and their roles in carcinogenesis.

EBV DNA methylation profiles and its application in distinguishing nasopharyngeal carcinoma and nasal NK/T-cell lymphoma.

BACKGROUND: As an oncovirus, EBV is associated with multiple cancers, including solid tumors and hematological malignancies. EBV methylation plays an important role in regulating tumor occurrence. However, the EBV methylation profiles in EBV-associated tumor tissues are poorly understood. RESULTS: In this study, EBV methylation capture sequencing was conducted in several different tumor tissue samples, including NPC, EBVaGC, lung LELC and parotid LELC. Besides, EBV capture sequencing and following qMSP were performed on nasopharyngeal brushing samples from NPC and nasal NKTCL patients. Our results showed that the EBV genome among different types of tumors displayed specific methylation patterns. Among the four types of tumors from epithelial origin (NPC, EBVaGC, lung LELC and parotid LELC), the most significant differences were found between EBVaGC and the others. For example, in EBVaGC, all CpG sites within 1,44,189-1,45,136 bp of the EBV genome sequence on gene RPMS1 were hyper-methylated compared to the others. Differently, significant differences of EBV CpG sites, particularly those located on gene BILF2, were observed between NPC and nasal NKTCL patients in nasopharyngeal brushing samples. Further, the methylated level of BILF2 was further detected using qMSP, and a diagnostic model distinguishing NPC and nasal NKTCL was established. The AUC of the model was 0.9801 (95% CI 0.9524-1.0000), with the sensitivity and specificity of 98.81% (95% CI 93.63-99.94%) and 76.92% (95% CI 49.74-91.82%), respectively. CONCLUSIONS: Our study reveals more clues for further understanding the pathogenesis of EBV, and provides a possibility for distinguishing EBV-related tumor by detecting specific EBV CpG sites.

A comprehensive predictive model for radiation-induced brain injury in risk stratification and personalized radiotherapy of nasopharyngeal carcinoma.

BACKGROUND AND PURPOSE: Radiation-induced brain injury (RBI) is a severe radiotoxicity for nasopharyngeal carcinoma (NPC) patients, greatly affecting their long-term life quality and survival. We aim to establish a comprehensive predictive model including clinical factors and newly developed genetic variants to improve the precision of RBI risk stratification. MATERIALS AND METHODS: By performing a large registry-based retrospective study with magnetic resonance imaging follow-up on RBI development, we conducted a genome-wide association study and developed a polygenic risk score (PRS) for RBI in 1189 NPC patients who underwent intensity-modulated radiotherapy. We proposed a tolerance dose scheme for temporal lobe radiation based on the risk predicted by PRS. Additionally, we established a nomogram by combining PRS and clinical factors for RBI risk prediction. RESULTS: The 38-SNP PRS could effectively identify high-risk individuals of RBI (P = 1.42 × 10-34). Based on genetic risk calculation, the recommended tolerance doses of temporal lobes should be 57.6 Gy for individuals in the top 10 % PRS subgroup and 68.1 Gy for individuals in the bottom 50 % PRS. Notably, individuals with high genetic risk (PRS > P50) and receiving high radiation dose in the temporal lobes (D0.5CC > 65 Gy) had an approximate 50-fold risk over individuals with low PRS and receiving low radiation dose (HR = 50.09, 95 %CI = 24.27-103.35), showing an additive joint effect (Pinteraction < 0.001). By combining PRS with clinical factors including age, tumor stage, and radiation dose of temporal lobes, the predictive accuracy was significantly improved with C-index increased from 0.78 to 0.85 (P = 1.63 × 10-2). CONCLUSIONS: The PRS, together with clinical factors, could improve RBI risk stratification and implies personalized radiotherapy.

The interaction and mediation effects between the host genetic factors and Epstein-Barr virus VCA-IgA in the risk of nasopharyngeal carcinoma.

Previous studies have demonstrated strong associations between host genetic factors and Epstein-Barr virus (EBV) VCA-IgA with the risk of nasopharyngeal carcinoma (NPC). However, the specific interplay between host genetics and EBV VCA-IgA on NPC risk is not well understood. In this two-stage case-control study (N = 4804), we utilized interaction and mediation analysis to investigate the interplay between host genetics (genome-wide association study-derived polygenic risk score [PRS]) and EBV VCA-IgA antibody level in the NPC risk. We employed a four-way decomposition analysis to assess the extent to which the genetic effect on NPC risk is mediated by or interacts with EBV VCA-IgA. We consistently found a significant interaction between the PRS and EBV VCA-IgA on NPC risk (discovery population: synergy index [SI] = 2.39, 95% confidence interval [CI] = 1.85-3.10; replication population: SI = 3.10, 95% CI = 2.17-4.44; all pinteraction < 0.001). Moreover, the genetic variants included in the PRS demonstrated similar interactions with EBV VCA-IgA antibody. We also observed an obvious dose-response relationship between the PRS and EBV VCA-IgA antibody on NPC risk (all ptrend < 0.001). Furthermore, our decomposition analysis revealed that a substantial proportion (approximately 90%) of the genetic effects on NPC risk could be attributed to host genetic-EBV interaction, while the risk effects mediated by EBV VCA-IgA antibody were weak and statistically insignificant. Our study provides compelling evidence for an interaction between host genetics and EBV VCA-IgA antibody in the development of NPC. These findings emphasize the importance of implementing measures to control EBV infection as a crucial strategy for effectively preventing NPC, particularly in individuals at high genetic risk.

Clinical Outcomes of Combined Transcranial and Endoscopic Transnasal Approaches in the Management of Cranionasal Communicating Tumors.

BACKGROUND: Cranionasal communicating tumors often originate from the extra-axial intracranial tissue, nasal cavity, and sinuses, and mostly invade the anterior skull base, leading to communication between the cranial and nasal cavities. Cranionasal communicating tumors are clinically rare and thus have been rarely reported in the literature. OBJECTIVE: To investigate the clinical outcomes of combined transcranial and endoscopic transnasal approaches in the surgical management of cranionasal communicating tumors. METHODS: We retrospectively analyzed patients with cranionasal communicating tumors treated at the Department of Neurosurgery, Jinhua Hospital, affiliated with Zhejiang University, from July 2017 to March 2020. All patients were surgically treated using combined transcranial and endoscopic transnasal approaches or the cranionasal dual approach, and skull base reconstruction was performed simultaneously. The postoperative gross tumor resection rate, perioperative complications, and postoperative efficacy were evaluated. RESULTS: Eleven patients with 14-37 months of follow-up were included. Eight patients underwent total resection, two patients underwent subtotal resection, and one patient was treated with partial resection. Postoperative pathological diagnoses revealed four olfactory neuroblastomas, three atypical meningiomas, two recurrent papilloma malignancies, one recurrent invasive pituitary tumor, and one recurrent invasive pituitary adenocarcinoma. Among the 11 patients, severe cerebral edema was observed postoperatively in one patient, and decompression craniectomy was performed. Intracranial infection was observed in two patients, including one with transient cerebrospinal fluid leakage, which was cured after symptomatic treatment. Moreover, postoperative ocular dysmotility and worse olfactory sensation were observed in one and two patients, respectively. The mean follow-up time of the 11 patients was (24.4 ± 5.7) months. The one-year survival rate of the patients was 100%; 10 patients (90.9%) had a favorable outcome (Glasgow Outcome Scale score of 4-5), and only one patient (9.1%) had a Glasgow Outcome Scale score of 3. Furthermore, during the last follow-up, tumor recurrence occurred in two patients (18.2%). CONCLUSION: Surgical treatment of cranionasal communicating tumors using the cranionasal dual approach and simultaneous skull base reconstruction improves the gross tumor resection rate with fewer postoperative complications and good short-term efficacy.

Risk factors for pulmonary embolism in lung cancer patients with lower limb deep venous thrombosis: a case-control study.

Background: There is growing evidence that misdiagnosis contributes to the high mortality rate in lung cancer patients complicated with pulmonary embolism (PE). This current study analyzed predictors of PE in lung cancer patients with lower extremity deep venous thrombosis (DVT) with the aim of personalizing the treatment and management of patients with PE. Methods: This retrospective case-control study included lung cancer patients with DVT at the emergency department of Shanghai Chest Hospital from January 2018 to December 2019. Patients were classified as having DVT with or without PE. The following characteristics were examined, including age, gender, smoking, hypertension, surgical trauma, hyperlipidemia, long-term bedridden status, calf swelling, coronary heart disease, chronic pulmonary disease, DVT location, DVT type, prothrombin time (PT), international normalized ratio (INR), activated partial thromboplastin time (APTT), thrombin time (TT), fibrinogen, and D-dimer, and univariate and multivariate analyses were performed. Results: A total of 90 patients with lung cancer and DVT were analyzed, of whom 60% (54/90) had PE. Those variables independently associated to PE were hypertension [odds ratio (OR): 7.883, 95% confidence interval (CI): 2.038-30.495, P=0.003], long-term bedridden status (OR: 4.166, 95% CI: 1.236-14.044, P=0.021), and D-dimer levels (OR: 2.123, 95% CI: 1.476-3.053, P=0.000) were identified as independent risk factors for PE. The cut-off value of the receiver operating characteristic (ROC) curve for predicting PE by presented scoring system according to the risk factors was 1.5 and the area under the curve (AUC) was 0.84 (P<0.001). Conclusions: Hypertension, being bedridden for an extended period, and elevated serum D-dimer levels were independent risk factors of PE in lung cancer patients with lower extremity DVT. Novel strategies for patient management should be developed to decrease the risk of PE.

Peptidome-wide association analysis of Epstein-Barr virus identifies epitope repertoires associated with nasopharyngeal carcinoma.

Human leukocyte antigen (HLA) molecules are essential for presenting Epstein-Barr virus (EBV) antigens and are closely related to nasopharyngeal carcinoma (NPC). This study aims to systematically investigate the association between HLA-bound EBV peptides and NPC risk through in silico HLA-peptide binding prediction. A total of 455 NPC patients and 463 healthy individuals in NPC endemic areas were recruited, and HLA-target sequencing was performed. HLA-peptide binding prediction for EBV, followed by peptidome-wide logistic regression and motif analysis, was applied. Binding affinity changes for EBV peptides carrying high-risk mutations were analyzed. We found that NPC-associated EBV peptides were significantly enriched in immunogenic proteins and core linkage disequilibrium (LD) proteins related to evolution, especially those binding HLA-A alleles (p = 3.10 × 10-4 for immunogenic proteins and p = 8.10 × 10-5 for core LD proteins related to evolution). These peptides were clustered and showed binding motifs of HLA supertypes, among which supertype A02 presented an NPC-risk effect (padj = 3.77 × 10-4 ) and supertype A03 presented an NPC-protective effect (padj = 4.89 × 10-4 ). Moreover, a decreased binding affinity toward risk HLA supertype A02 was observed for the peptide carrying the NPC-risk mutation BNRF1 V1222I (p = 0.0078), and an increased binding affinity toward protective HLA supertype A03 was observed for the peptide carrying the NPC-risk mutation BALF2 I613V (p = 0.022). This study revealed the distinct preference of EBV peptides for binding HLA supertypes, which may contribute to shaping EBV population structure and be involved in NPC development.

High-throughput identification of regulatory elements and functional assays to uncover susceptibility genes for nasopharyngeal carcinoma.

Large-scale genetic association studies have identified multiple susceptibility loci for nasopharyngeal carcinoma (NPC), but the underlying biological mechanisms remain to be explored. To gain insights into the genetic etiology of NPC, we conducted a follow-up study encompassing 6,907 cases and 10,472 controls and identified two additional NPC susceptibility loci, 9q22.33 (rs1867277; OR = 0.74, 95% CI = 0.68-0.81, p = 3.08 × 10-11) and 17q12 (rs226241; OR = 1.42, 95% CI = 1.26-1.60, p = 1.62 × 10-8). The two additional loci, together with two previously reported genome-wide significant loci, 5p15.33 and 9p21.3, were investigated by high-throughput sequencing for chromatin accessibility, histone modification, and promoter capture Hi-C (PCHi-C) profiling. Using luciferase reporter assays and CRISPR interference (CRISPRi) to validate the functional profiling, we identified PHF2 at locus 9q22.33 as a susceptibility gene. PHF2 encodes a histone demethylase and acts as a tumor suppressor. The risk alleles of the functional SNPs reduced the expression of the target gene PHF2 by inhibiting the enhancer activity of its long-range (4.3 Mb) cis-regulatory element, which promoted proliferation of NPC cells. In addition, we identified CDKN2B-AS1 as a susceptibility gene at locus 9p21.3, and the NPC risk allele of the functional SNP rs2069418 promoted the expression of CDKN2B-AS1 by increasing its enhancer activity. The overexpression of CDKN2B-AS1 facilitated proliferation of NPC cells. In summary, we identified functional SNPs and NPC susceptibility genes, which provides additional explanations for the genetic association signals and helps to uncover the underlying genetic etiology of NPC development.

Saliva biopsy: Detecting the difference of EBV DNA methylation in the diagnosis of nasopharyngeal carcinoma.

Saliva sampling is a non-invasive method, and could be performed by donors themselves. However, there are few studies reporting biomarkers in saliva in the diagnosis of NPC. A total of 987 salivary samples were used in this study. First, EBV DNA methylation was profiled by capture sequencing in the discovery cohort (n = 36). Second, a q-PCR based method was developed and five representative EBV DNA CpG sites (11 029 bp, 45 849 bp, 57 945 bp, 66 226 bp and 128 102 bp) were selected and quantified to obtain the methylated density in the validation cohort1 (n = 801). Third, a validation cohort2 (n = 108) was used to further verify the differences of EBV methylation in saliva. A significant increase of EBV methylation was found in NPC patients compared with controls. The methylated score of EBV genome obtained by capture sequencing could distinguish NPC from controls (sensitivity 90%, specificity 100%). Further, the methylated density of EBV DNA CpG sites revealed by q-PCR showed a good diagnostic performance. The sensitivity and specificity of detecting a single CpG site (11 029 bp) could reach 75.4% and 99.7% in the validation cohort1, and 78.2% and 100% in the validation cohort2. Besides, the methylated density of the CpG site was found to decrease below the COV in NPC patients after therapy, and increase above the COV after recurrence. Our study provides an appealing alternative for the non-invasive detection of NPC without clinical setting. It paves the way for conducting a home-based large-scale screening in the future.

Correlation between different endometrial preparation protocols and pregnancy outcome of frozen embryo transfer in patients with polycystic ovary syndrome: a retrospective study.

OBJECTIVE: We retrospectively analyzed the correlation between different endometrial preparation protocols and pregnancy outcomes in patients with polycystic ovary syndrome (PCOS) who underwent frozen embryo transfer (FET). METHODS: A total of 200 PCOS patients who underwent FET were divided into HRT group (n = 65), LE group (n = 65), GnRHa + HRT group (n = 70) according to different endometrial preparation protocols. The endometrial thickness on the day of endometrial transformation, the number of embryos transferred, and the number of high-quality embryos transferred were compared among the three groups. The pregnancy outcomes of FET in the three groups were compared and analyzed, and a further multivariate logistic regression model was used to analyze the factors influencing FET pregnancy outcomes in PCOS patients. RESULTS: Endometrial thickness on the day of endometrial transformation, clinical pregnancy rate and live birth rate in GnRHa + HRT group were higher than those in the HRT group and LE group. The results of multivariate regression analysis showed that the pregnancy outcome of PCOS patients undergoing FET was significantly associated with the patient's age, endometrial preparation protocols, number of embryos transferred, endometrial thickness, and duration of infertility. CONCLUSION: Compared with HRT or LE alone, GnRHa + HRT protocol results in higher levels of endometrial thickness on the day of endometrial transformation, clinical pregnancy rate, and live birth rate. Female age, endometrial preparation protocols, number of embryos transferred, endometrial thickness, and duration of infertility are determined as factors influencing pregnancy outcomes in PCOS patients undergoing FET.