Development and validation of machine learning models for diagnosis and prognosis of cancer by urinary proteomics, based on the FLEMENGHO cohort.

The current study aims to develop and validate machine learning (ML) models for the prediction of cancer status by the non-invasive urinary proteomic in a population-based cohort. In this retrospective study, urinary proteome profiles in 804 cases from the FLEMENGHO cohort were measured by mass spectrometry. After feature selection by LASSO on both clinical variables and urinary proteome profile, benchmark models by clinical variables were built with six different ML algorithms. Proteome-based models and combined models were built and compared with the benchmark models. The models' performance, i.e. area under the curve (AUC) was compared by Delong method. The 95% confidence interval was estimated by the bootstrapping method. The best-performing model was explained by Shapley Additive Explanations (SHAP) method. The predictive role of proteome biomarkers in longitudinal cancer diagnosis was also explored. A clinical model, based on age, blood sugar and blood lipid profile, yielded the best AUC of 0.75 (0.68-0.82), with 0.80 (0.72-0.91) for the proteome model based on 13 selected biomarkers and 0.83 (0.77-0.90) for the combined model (P=0.01 for comparison with clinical model). SHAP on the support vector machine in the combined setting showed that except for age, proteome biomarkers contribute to the final prediction of the model. After adjusting with clinical factors, three proteome biomarkers are independent risk factors for longitudinal cancer development. Urinary proteome profiling, together with fine-tuned machine learning algorithms, demonstrates the predictive potential for cancer diagnosis transparently.

A large sample-based case-control study of related risk factors of two types of lichenoid vulvar disease (LVD).

PURPOSE: The purpose of this study is to identify the associated factors of two types of lichenoid vulvar disease (LVD) and to compare the differences in related factors between the different pathological types of lichenoid vulvar disease (LVD). METHODS: The study conducted at the West China second Hospital of Sichuan University included a total of 1770 patients with biopsy-confirmed vulvar lichen simplex chronicus (VLSC)and vulvar lichen sclerosus(VLS), along with 1209 patients with normal vulvovagina as control. Further pathological subtype analysis was carried out on 163 cases of vulvar lichen simplex chronicus and 51 cases of vulvar lichen sclerosus. In addition, Univariate chi-square test and multivariate logistic regression were used to analyze the lichenoid vulvar disease group and vulvovaginal normal control group. RESULTS: Univariate analysis revealed that there were statistically significant differences (P < 0.05) in factors between the LVD group and the control group, except for living type, sleep habit, history of drinking, and allergic diseases. There was no significant difference in late sleep, spicy diet, and coffee intake in the factors of life and eating habits and the concomitant disease factors. Furthermore, univariate analysis showed that except for eating seafood, humid living environment, residence, caffeinated drinks, hypertension, and vaginitis, there were statistical differences in the related factors of LVSC. CONCLUSION: The incidence about lichenoid vulvar disease is influenced by various factors such as dietary habits, living environment, mental stress, concomitant diseases, hormone levels and so on, and there were no significant differences in these factors between VLS and VLSC except for income, work stress, systemic immune diseases, and menopause.

Non-overlapping epitopes on the gHgL-gp42 complex for the rational design of a triple-antibody cocktail against EBV infection.

Epstein-Barr virus (EBV) is closely associated with cancer, multiple sclerosis, and post-acute coronavirus disease 2019 (COVID-19) sequelae. There are currently no approved therapeutics or vaccines against EBV. It is noteworthy that combining multiple EBV glycoproteins can elicit potent neutralizing antibodies (nAbs) against viral infection, suggesting possible synergistic effects. Here, we characterize three nAbs (anti-gp42 5E3, anti-gHgL 6H2, and anti-gHgL 10E4) targeting different glycoproteins of the gHgL-gp42 complex. Two antibody cocktails synergistically neutralize infection in B cells (5E3+6H2+10E4) and epithelial cells (6H2+10E4) in vitro. Moreover, 5E3 alone and the 5E3+6H2+10E4 cocktail confer potent in vivo protection against lethal EBV challenge in humanized mice. The cryo-EM structure of a heptatomic gHgL-gp42 immune complex reveals non-overlapping epitopes of 5E3, 6H2, and 10E4 on the gHgL-gp42 complex. Structural and functional analyses highlight different neutralization mechanisms for each of the three nAbs. In summary, our results provide insight for the rational design of therapeutics or vaccines against EBV infection.

Neutralizing antibodies against EBV gp42 show potent in vivo protection and define novel epitopes.

Epstein-Barr virus (EBV) is the first reported human oncogenic virus and infects more than 95% of the human population worldwide. EBV latent infection in B lymphocytes is essential for viral persistence. Glycoprotein gp42 is an indispensable member of the triggering complex for EBV entry into B cells. The C-type lectin domain (CTLD) of gp42 plays a key role in receptor binding and is the major target of neutralizing antibodies. Here, we isolated two rabbit antibodies, 1A7 and 6G7, targeting gp42 CTLD with potent neutralizing activity against B cell infection. Antibody 6G7 efficiently protects humanized mice from lethal EBV challenge and EBV-induced lymphoma. Neutralizing epitopes targeted by antibodies 1A7 and 6G7 are distinct and novel. Antibody 6G7 blocks gp42 binding to B cell surface and both 1A7 and 6G7 inhibit membrane fusion with B cells. Furthermore, 1A7- and 6G7-like antibodies in immunized sera are major contributors to B cell neutralization. This study demonstrates that anti-gp42 neutralizing antibodies are effective in inhibiting EBV infection and sheds light on the design of gp42-based vaccines and therapeutics.

The Active Fraction of Polyrhachis vicina Roger (AFPR) activates ERK to cause necroptosis in colorectal cancer.

ETHNOPHARMACOLOGICAL RELEVANCE: Polyrhachis vicina Roger (P. vicina), a traditional Chinese medicinal animal, has been used to treat rheumatoid arthritis, hepatitis, cancer, and other conditions. Due to its anti-inflammatory properties, our previous pharmacological investigations have demonstrated that it is effective against cancer, depression, and hyperuricemia. Nevertheless, the key active components and targets of P. vicina in cancers are still unexplored. AIM OF THE STUDY: The study aimed to evaluate the pharmacological treatment mechanism of the active fraction of P. vicina (AFPR) in treating colorectal cancer (CRC) and to further reveal its active ingredients and key targets. METHODS: To examine the inhibitory impact of AFPR on CRC growth, tumorigenesis assays, cck-8 assays, colony formation assays, and MMP detection were utilized. The primary components of AFPR were identified by GC-MS analysis. The network pharmacology, molecular docking, qRT-PCR, western blotting, CCK-8 assays, colony formation assay, Hoechst staining, Annexin V-FITC/PI double staining, and MMP detection were performed to pick out the active ingredients and potential key targets of AFPR. The function of Elaidic acid on necroptosis was investigated through siRNA interference and the utilization of inhibitors. Elaidic acid's effectiveness to suppress CRC growth in vivo was assessed using a tumorigenesis experiment. RESULTS: Studies confirmed that AFPR prevented CRC from growing and evoked cell death. Elaidic acid was the main bioactive ingredient in AFPR that targeted ERK. Elaidic acid greatly affected the ability of SW116 cells to form colonies, produce MMP, and undergo necroptosis. Additionally, Elaidic acid promoted necroptosis predominantly by activating ERK/RIPK1/RIPK3/MLKL. CONCLUSION: According to our findings, Elaidic acid is the main active component of AFPR, which induced necroptosis in CRC through the activation of ERK. It represents a promising alternative therapeutic option for CRC. This work provided experimental support for the therapeutic application of P. vicina Roger in the treatment of CRC.

A retrospective comparative cohort study of ultra-pulse CO2 lattice laser and glucocorticoids in the treatment of vulvar epithelial nonneoplastic lesions.

Background: A comparison of topical glucocorticoids with CO2 fractional laser treatment was conducted to investigate the differences in the efficacy of non-neoplastic vulvar epithelial lesion treatments in different pathological types and to provide a scientific basis for the management of these disorders. This paper was to study the difference of curative effect of different pathological types of non-tumor vulvar epithelial lesions and provide scientific basis for the treatment of these diseases. Methods: From November 2016 to July 2018, 178 cases of vulvar lichen simplex chronicus (LSC) or lichen sclerosus were confirmed with vulvar biopsy at our institute. Finally, 160 patients were enrolled in this trial. The patients were divided into 2 groups: a group treated with topical hormone and a group treated with CO2 lattice laser therapies. There were 80 cases in each group, including 40 with LSC and 40 with lichen sclerosus. Patients applied 1 gram of progesterone cream and betamethasone cream to the affected area in the morning and evening, respectively, once a day for 3 months. The efficacy was evaluated with the Patient Global Impression of Change (PGI-C) subjective symptom improvement scale and clinical efficacy evaluation scale. The formula was applied to calculate the curative effect index. Results: The PGI-C scores at 1, 3, and 6 months of treatment showed that the laser treatment group had remarkably superior outcomes to the glucocorticoid treatment group. The clinical efficacy score scale at 3- and 6-month treatments indicated a significantly greater curative effect in the laser than in the glucocorticoid treatment (P=0.006 and P=0.002 respectively). In the glucocorticoid group, the clinical effects of different pathological subtypes were significantly different following the 1- and 3-month treatments. The efficacy of treatment for LSC was better than that for lichen sclerosus. Following the 3- and 6-month treatments, the clinical effect for LSC was better than that of lichen sclerosus (3 months: 95% vs. 75%; 6 months: and 95% vs. 70%). Conclusions: Ultrapulse CO2 lattice laser was more effective than was glucocorticoid therapy in the treatment of vulvar epithelial non-tumor-like lesions.

Comparison of electrophysiology therapy and glucocorticoid therapy in the treatment of 2 subtypes of vulvar epithelial non-neoplastic lesions: a prospective cohort study.

Background: Lichen-like lesions with degeneration and pigmentation alterations can be divided into the following 2 types: (I) chronic simple lichen; and (II) sclerosing lichen. The etiology of the disease is unknown. This study sought to examine the therapeutic effects of electrophysiological smooth-muscle electrical stimulation in the treatment of lichen-like lesions of the vulva. Methods: A total of 80 outpatients, who had been confirmed to have vulvar lichen-like lesions by vulvar biopsy at our hospital from November 2016 to March 2018, were prospectively included in this study. The patients received electrophysiology or glucocorticoid therapy. After completing a treatment cycle according to the clinical treatment routine, the outpatients were monitored at 1-, 3- and 6-month intervals. Patients used an improvement scale (i.e., the patient global impression of change scale) to score their subjective perceptions and subjective symptoms. The clinical curative effect scale was used to calculate the curative effect index and grade the curative effect. Results: After 1 month of treatment, the active enhancement of simple lichen in the electrophysiological treatment group and glucocorticoid treatment group improved, while the active enhancement of simple lichen in the electrophysiological treatment group improved after 3 months of treatment. After 6 months of treatment, the subjective improvement score of the electrophysiological treatment group was better than that of lichen sclerosus. After 3 months of treatment, the effective rate of the electrophysiological therapy group was better than that of the glucocorticoid therapy group. After 6 months of treatment in the electrophysiological treatment group, the efficacy of simple lichen is also better than that of sclerotic lichen. Conclusions: Conventional hormone therapy is easier for patients to accept because of its convenience and low costs.

Prediction of coronary artery disease using urinary proteomics.

AIMS: Coronary artery disease (CAD) is multifactorial, caused by complex pathophysiology, and contributes to a high burden of mortality worldwide. Urinary proteomic analyses may help to identify predictive biomarkers and provide insights into the pathogenesis of CAD. METHODS AND RESULTS: Urinary proteome was analysed in 965 participants using capillary electrophoresis coupled with mass spectrometry. A proteomic classifier was developed in a discovery cohort with 36 individuals with CAD and 36 matched controls using the support vector machine. The classifier was tested in a validation cohort with 115 individuals who progressed to CAD and 778 controls and compared with two previously developed CAD-associated classifiers, CAD238 and ACSP75. The Framingham and SCORE2 risk scores were available in 737 participants. Bioinformatic analysis was performed based on the CAD-associated peptides. The novel proteomic classifier was comprised of 160 urinary peptides, mainly related to collagen turnover, lipid metabolism, and inflammation. In the validation cohort, the classifier provided an area under the receiver operating characteristic curve (AUC) of 0.82 [95% confidence interval (CI): 0.78-0.87] for the CAD prediction in 8 years, superior to CAD238 (AUC: 0.71, 95% CI: 0.66-0.77) and ACSP75 (AUC: 0.53 and 95% CI: 0.47-0.60). On top of CAD238 and ACSP75, the addition of the novel classifier improved the AUC to 0.84 (95% CI: 0.80-0.89). In a multivariable Cox model, a 1-SD increment in the novel classifier was associated with a higher risk of CAD (HR: 1.54, 95% CI: 1.26-1.89, P < 0.0001). The new classifier further improved the risk reclassification of CAD on top of the Framingham or SCORE2 risk scores (net reclassification index: 0.61, 95% CI: 0.25-0.95, P = 0.001; 0.64, 95% CI: 0.28-0.98, P = 0.001, correspondingly). CONCLUSION: A novel urinary proteomic classifier related to collagen metabolism, lipids, and inflammation showed potential for the risk prediction of CAD. Urinary proteome provides an alternative approach to personalized prevention.

A biomarker that can predict coronary artery disease (CAD) is urgently in need. We developed and validated a urinary proteomic classifier for the prediction of CAD. The proteomic classifier involved in atherosclerosis improved the risk reclassification on top of the clinical risk score.

Analyzing the Role of Septin9 Gene Methylation in the Diagnosis and Treatment of Primary Liver Cancer in the Elderly.

Context: Because the early symptoms of primary hepatocellular carcinoma (PHC) aren't significant, it's difficult to diagnose it by routine inspection clinically, and if the lesion's diameter is small, less than 2.0 cm, false negatives can occur in pathological examinations. Researchers need to actively search for more diagnostic methods. Objective: The study intended to detect and analyze the value of plasma Septin9 gene methylation for the diagnosis and therapeutic monitoring of PHC in older adults. Design: The research team performed a prospective controlled study. Setting: The study took place at the First Hospital of Qiqihar, an Affiliated Qiqihar Hospital at Southern Medical University in Qiqihar, China. Participants: Participants were 32 patients with PHC and 28 with cholangiocarcinoma (CCA) who had been admitted to the hospital between January 2021 and July 2022 and 40 healthy individuals. Groups: The research team divided participants into three groups: (1) patients with PHC, the PHC group; (2) patients with CCA, the CCA group; and (3) healthy individuals, the control group. Outcome Measures: The research team: (1) determined the positive expression rate of Septin9 gene methylation; (2) measured liver function indicators-alanine aminotransferase (ALT), aspartate aminotransferase (AST), serum total bilirubin (TBIL), direct bilirubin (DBIL), alkaline phosphatase (ALP), γ-glutamyl transpeptidase (GGT), albumin (ALB); and (3) measured tumor markers-alpha-fetoprotein (AFP), carbohydrate antigen (CA) 199, CA125, and CA153. The team also: (1) established a binary logistic regression model based on levels of GGT and plasma Septin9 gene methylation to analyze risk factors and diagnosis accuracy, (2) created a receiver operating characteristic (ROC) curve to analyze diagnostic values; and (3) during followup, analyzed the negative conversion rate of Septin9 gene methylation in participants. Results: The positive expression rate of Septin9 methylation in the PHC group was significantly lower than that that of the CCA group and significantly higher than that of the control group (P < .05). The PHC group's ALT, AST, TBIL, DBIL, ALP, and GGT were significantly higher than those of the control group but significantly lower than those of the CCA group (all P < .05). PHC group's ALB was significantly lower than that of the control group (P < .05). The PHC group's AFP, CA199, and CA125 were significantly higher than those of the control group, and the PHC group's CA199 and CA125 were significantly lower than those in the CCA group (all P < .05). The positive expression of Septin9 gene methylation and the high expression of GGT were risk factors for PHC (OR>1, P < .05). The AUC of the Septin9 gene methylation, the GGT level, and the combined detection of both variables (all AUC > 0.70), suggests that the variables have a diagnostic value in the detection of PHC, with the combined detection having the highest value. The negative conversion rate after surgery of Septin9 gene methylation was 87.10%, for 27 out of 31 participants in the PHC and CCA groups (χ2 = 29.405, P < .001). Conclusion: Plasma Septin9 gene methylation is a sensitive molecular marker for the diagnosis and therapeutic monitoring of older adults with PHC, and combined with the serum GGT level, has a high diagnostic efficiency, which may reflect the treatment status of patients.

Association between incense burning and prenatal depressive symptoms: evidence from the Born in Guangzhou Cohort Study.

This study aimed to examine the association of incense burning alone, a source of indoor air pollution, and jointly with passive smoking, with prenatal depressive symptoms. Information on incense exposure and depressive symptoms were collected at both early and late pregnancy using questionnaires in the Born in Guangzhou Cohort Study. Mixed-effects logistic regression models were used to assess the associations of incense exposure separately, and together with passive smoking, with prenatal depressive symptoms. Compared to the non-users, pregnant women with household incense burning had higher odds of depressive symptoms (odds ratio (OR), 1.17, 95% CI, 1.06, 1.28). Compared with non-users, women who occasionally (OR, 1.22, 95% CI, 1.09, 1.36) and frequently (1.51, 95% CI, 1.26, 1.80) smelled incense had higher odds of prenatal depressive symptoms. Higher duration of incense smelling was associated with higher odds of prenatal depressive symptoms compared with non-users. There was no strong evidence for an interaction of frequency of incense smelling and passive smoking in prenatal depressive symptoms. Prenatal exposure to incense burning was associated with higher odds of having depressive symptoms during pregnancy, and there is no evidence for interaction with concurrent exposure to passive smoking.

Association Between Potentially Functional Variants in chr5q14 and the Risk of Cervical Cancer in a Chinese Population.

Cervical cancer is a complex polygenic disease, and the interaction between single-nucleotide polymorphisms (SNPs) may lead to differences in the incidence and susceptibility of cervical cancer. In this study, we explored whether three potentially functional SNPs-rs59661306, rs257847, and rs637442 with reference/alternative alleles A/G, C/T, and T/G, respectively-in chr5q14 were related to cervical cancer risk in a Chinese population. A total of 703 samples were collected, including 215 patients with cervical cancer and 488 normal controls. The SNP genotyping was determined by using polymerase chain reaction-restriction fragment length polymorphism. There was an association between the AG rs59661306 genotype or the GG rs59661306 genotype and cervical cancer risk, and the percentage of cancer patients with the A/G rs59661306 genotype plus the percentage of cancer patients with the G/G rs59661306 genotype (AG + GG) was significantly higher than the percentage of AG + GG healthy women in the control group. There was no association between either the rs257847 or the rs637442 and cervical cancer risk. Genotype analysis showed that the genotype CT of rs257847 in combination with the AG, GG, and AG + GG genotypes of rs59661306 were associated with a higher cervical cancer risk, and that the genotypes TG and TG + GG of rs637442 in combination with the AG and AG + GG genotypes of rs59661306 were also associated with a higher cervical cancer risk. These findings indicate that rs59661306, rs257847, and rs637442 may be susceptible loci for cervical cancer. Our study advances the understanding of SNPs that are responsible for cervical cancer susceptibility.

Identification of potential associated factors for stress urinary incontinence in women: a retrospective study.

Background: This study sought to analyze the potential associated factors for female stress urinary incontinence (SUI). Methods: A total of 5,013 women were screened for pelvic floor function at the West China Second Hospital of Sichuan University from January 2015 to January 2019. Of these, 410 patients were diagnosed with SUI. A single-factor Chi-square test and multi-factor logistic regression analysis were conducted to examine the relationship between pre-pregnancy urinary incontinence, vaginal delivery, menopause, and hormone therapy, chronic cough, and smoking, and postpartum SUI. Results: The postpartum SUI rate in patients with urinary incontinence during pregnancy was 19.33%, while that of patients without urinary incontinence was only 5.44%. The rates of urinary incontinence in patients experiencing vaginal delivery or cesarean delivery were 13.62% and 4.36%, respectively. The SUI incidences in patients with or without a family genetic history of SUI were 28.46% and 7.48%, respectively. The incidence rates of SUI in smoking and non-smoking patients were 18.92% and 8.39%. The rate of SUI in patients with chronic cough (16.46%) behaved significantly differently from those with non-chronic cough (8.21%). The occurrence of SUI was highly correlated with the following factors, including pre-pregnancy urinary incontinence (OR =5.256; 95% CI: 2.061-13.409; P<0.001), urological incontinence during the pregnancy period (OR =2.965; 95% CI: 2.111-4.163; P<0.001), vaginal delivery (OR =4.028; 95% CI: 2.909-5.577; P<0.001), and genetic history (OR =4.341; 95% CI: 2.8-6.73; P<0.001). Conclusions: The occurrence of SUI is highly related to a history of urinary incontinence, the delivery mode, chronic cough, smoking, and genetic history. Further, urinary incontinence before and during pregnancy, natural delivery, and genetic history are important independent high-associated factors for SUI. Our findings show the importance of screening for the above associated factors in association with SUI.

Urinary matrix Gla protein is associated with mortality risk in Flemish population: A prospective study.

Background: Vascular calcification is strongly related to the risk of mortality and cardiovascular (CV) diseases. In vascular calcification, matrix Gla protein (MGP), a small vitamin K-dependent protein, is an important mineralization inhibitor. Recent studies showed that circulating MGP is associated with mortality risk. However, the longitudinal association between urinary excretion of MGP and all-cause mortality was not established. Materials and methods: Urinary MGP was measured in 776 randomly recruited Flemish population (mean age: 51.2 years; 50.9% women) at baseline (during 2005-2010) using capillary electrophoresis coupled with mass spectrometry. Plasma inactive MGP [desphospho-uncarboxylated MGP (dp-ucMGP)] levels were quantified in 646 individuals by ELISA kits. Mortality status was ascertained through the Belgian Population Registry until 2016. The longitudinal association with mortality was determined by the multivariate-adjusted Cox proportional hazards regression models. The multivariate linear regression models were used to identify determinants of urinary MGP level. Results: Over the 9.2 years, 47 (6.06%) participants died, including 15 CV deaths. For a doubling of urinary MGP, the hazard ratios (HRs) were 1.31 (95% CI: 1.01-1.69, P = 0.040) for all-cause mortality and 2.05 (95% CI: 1.11-3.79, P = 0.023) for CV mortality with adjustment for covariates, including estimated glomerular filtration rate and urine microalbumin. The addition of urinary MGP to the basic models improved the reclassification as suggested by the increased net reclassification improvement [64.01% (95% CI: 32.64-98.63)] and integrated discrimination improvement [2.33% (95% CI: 0.24-4.71)]. Circulating inactive MGP, total cholesterol, urine microalbumin, and smoking were significantly associated with urinary MGP levels (P ≤ 0.041), independent of sex and age. Conclusion: Elevated urinary MGP was associated with an increased risk of all-cause mortality and CV mortality and improved the risk reclassification for all-cause mortality. These findings suggested that urinary MGP might be useful in mortality risk assessment in the general population. However, these observations need to be replicated in larger studies with a longer follow-up time.

Protective anti-gB neutralizing antibodies targeting two vulnerable sites for EBV-cell membrane fusion.

Epstein-Barr virus (EBV) infects more than 90% of the world's adult population and accounts for a significant cancer burden of epithelial and B cell origins. Glycoprotein B (gB) is the primary fusogen essential for EBV entry into host cells. Here, we isolated two EBV gB-specific neutralizing antibodies, 3A3 and 3A5; both effectively neutralized the dual-tropic EBV infection of B and epithelial cells. In humanized mice, both antibodies showed effective protection from EBV-induced lymphoproliferative disorders. Cryoelectron microscopy analyses identified that 3A3 and 3A5 bind to nonoverlapping sites on domains D-II and D-IV, respectively. Structure-based mutagenesis revealed that 3A3 and 3A5 inhibit membrane fusion through different mechanisms involving the interference with gB-cell interaction and gB activation. Importantly, the 3A3 and 3A5 epitopes are major targets of protective gB-specific neutralizing antibodies elicited by natural EBV infection in humans, providing potential targets for antiviral therapies and vaccines.

Glycoprotein B Antibodies Completely Neutralize EBV Infection of B Cells.

The Epstein-Barr virus (EBV) is the first reported oncogenic herpesvirus that establishes persistent infection in B lymphocytes in 95% of adults worldwide. Glycoprotein B (gB) plays a predominant role in the fusion of the viral envelope with the host cell membrane. Hence, it is of great significance to isolate gB-specific fusion-inhibiting neutralizing antibodies (NAbs). AMMO5 is the only gB NAb but fails to antagonize B-cell infection. It is essential to isolate potent NAbs that can completely block EBV infection of B cells. Using hybridoma technology and neutralization assay, we isolate two gB NAbs 8A9 and 8C12 that are capable of completely neutralizing B-cell infection in vitro. In addition, 8A9 shows cross-reactivity with rhesus lymphocryptovirus (rhLCV) gB. Competitive binding experiments demonstrate that 8A9 and 8C12 recognize novel epitopes that are different from the AMMO5 epitope. The epitopes of 8A9 and 8C12 are mapped to gB D-II, and the AMMO5 epitope is located precisely at gB aa 410-419. We find that 8A9 and 8C12 significantly inhibit gB-derived membrane fusion using a virus-free fusion assay. In summary, this study identifies two gB-specific NAbs that potently block EBV infection of B cells. Our work highlights the importance of gB D-II as a predominant neutralizing epitope, and aids in the rational design of therapeutics or vaccines based on gB.

Two-Year Responses of Renal Function to First Occupational Lead Exposure.

Introduction: Whether in advanced countries lead exposure still contributes to renal impairment is debated, because blood lead (BL) level is declining toward preindustrial levels and because longitudinal studies correlating renal function and BL changes over time are scarce. Methods: The Study for Promotion of Health in Recycling Lead (SPHERL) evaluated the 2-year renal function responses in 251 workers (mean age, 29.7 years) transiting from environmental to occupational exposure. Main study end point was the estimated glomerular filtration rate (eGFR) derived from serum creatinine (eGFRcrt), cystatin C (eGFRcys), or both (eGFRcc). BL level was measured by inductively coupled plasma mass spectrometry (detection limit 0.5 µg/dl). Results: In the follow-up, mean baseline BL level of 4.13 µg/dl increased 3.30-fold. In fully adjusted mixed models, additionally accounting for the within-participant clustering of the 1- and 2-year follow-up data, a 3-fold BL level increment was not significantly correlated with changes in eGFR with estimates amounting to -0.86 (95% CI: -2.39 to 0.67), -1.58 (-3.34 to 0.18), and -1.32 (-2.66 to 0.03) ml/min per 1.73 m2 for eGFRcrt, eGFRcys, or eGFRcc, respectively. Baseline BL level and the cumulative lead burden did not materially modify these estimates, but baseline eGFR was a major determinant of eGFR changes showing regression to the mean during follow-up. Responses of serum osmolarity, urinary gravity, or the urinary albumin-to-creatinine ratio (ACR) were also unrelated to the BL level increment. The age-related decreases in eGFRcrt, eGFRcys, and eGFRcc were -1.41, -0.96, and -1.10 ml/min per 1.73 m2, respectively. Conclusion: In the current study, the 2-year changes in renal function were unrelated to the increase in BL level. However, given the CIs around the point estimates of the changes in eGFRcc and eGFRcys, a larger study with longer follow-up is being planned.

Diagnostic test of bioimpedance-based neural network algorithm in early cervical cancer.

Background: Colposcopy is a critical component of cervical cancer screening services, but the accuracy of colposcopy varies greatly due to the lack of standardized training for colposcopists and pathologists. Thus, to improve the accuracy of colposcopy in the detection of cervical lesions intelligently is urgent. Here, we explored the sensitivity and specificity of a bioimpedance-based neural network algorithm in distinguishing normal and precancerous cervical tissues. Methods: Bioimpedance data were collected using a bioimpedance analyzer (Mscan1.0B, Sealand Technology, Chengdu, China) from the cervices of 102 female patients with abnormal cervical cytology (≥atypical squamous cells of undetermined significance) who required further colposcopy. Finally, the data of 106 samples from 37 patients were included, among which 85were used as the training set and 21 as the validation set. Using the biopsy pathology at each locus as the gold standard, the sensitivity, specificity, predictive value, likelihood ratio, and false positive and false negative rates of the bioimpedance-based neural network in identifying the normal and precancerous cervical tissues were calculated. Results: The bioimpedance method had a sensitivity of 0.90 [95% confidence interval (CI): 0.54 to 0.99], specificity of 0.82 (95% CI: 0.48 to 0.97), positive predictive value of 0.82 (95% CI: 0.48 to 0.97), and a negative predictive value of 0.90 (95% CI: 0.54 to 0.99) in distinguishing normal and precancerous cervical tissues. The Kappa value was 0.72. Conclusions: The bioimpedance method was an intelligent method with relative good sensitivity and specificity in distinguishing benign cervical tissue and precancerous lesions and can therefore be used as an adjunctive test to colposcopy to improve the detection of cervical lesions.

A Neutralizing Antibody Targeting gH Provides Potent Protection against EBV Challenge In Vivo.

Epstein-Barr virus (EBV) is an oncogenic herpesvirus that is associated with 200,000 new cases of cancer and 140,000 deaths annually. To date, there are no available vaccines or therapeutics for clinical usage. Recently, the viral heterodimer glycoprotein gH/gL has become a promising target for the development of prophylactic vaccines against EBV. Here, we developed the anti-gH antibody 6H2 and its chimeric version C6H2, which had full neutralizing activity in epithelial cells and partial neutralizing activity in B cells. C6H2 exhibited potent protection against lethal EBV challenge in a humanized mouse model. The cryo-electron microscopy (cryo-EM) structure further revealed that 6H2 recognized a previously unidentified epitope on gH/gL D-IV that is critical for viral attachment and subsequent membrane fusion with epithelial cells. Our results suggest that C6H2 is a promising candidate in the prevention of EBV-induced lymphoproliferative diseases (LPDs) and may inform the design of an EBV vaccine. IMPORTANCE Epstein-Barr virus (EBV) is a ubiquitous gammaherpesvirus that establishes lifelong persistence and is related to multiple diseases, including cancers. Neutralizing antibodies (NAbs) have proven to be highly effective in preventing EBV infection and subsequent diseases. Here, we developed an anti-EBV-gH NAb, 6H2, which blocked EBV infection in vitro and in vivo. This 6H2 neutralizing epitope should be helpful to understand EBV infection mechanisms and guide the development of vaccines and therapeutics against EBV infection.

Dysbiosis of vaginal microbiota associated with persistent high-risk human papilloma virus infection.

BACKGROUND: The status of vaginal microbiota in persistent high-risk human papilloma virus (HR-HPV) infection is unclear. The present work aimed to identify the vaginal microbiota of persistent HPV infection and explore the possible underlying microbiota factors. METHODS: A total of 100 women were recruited in this study, of which 28 presented HR-HPV persistent infection (P group), 30 showed clearance of any subtype of HR-HPV (C group), and 42 had no history of any HR-HPV infection (NC group). The vaginal microbiota and the community structure of the three groups were compared based on the 16S rRNA sequencing of the V3-V4 region. The microbiota diversity and differential analysis were carried out to detect the potential factors associated with HR-HPV infection. RESULTS: P and C groups showed an increase of Firmicutes and Actinobacteriota but a decrease in Proteobacteria compared to the NC group. The Chao1 index indicated that the microbial richness of the NC group was greater than C group (P < 0.05).The principal co-ordinate analysis(PCoA) revealed differences between the NC and P/C groups.The linear discriminant analysis effect size (LEfSe) method indicated that Proteobacteria phylum was significantly different in the mean relative abundance in the NC group,but the P and C groups did not show such indicative taxa. The Wilcox rank-sum test indicated that the Bifidobacterium (P = 0.002) and Lactobacillus (P = 0.005) of the C group were in a high mean relative abundance compared to the NC group. CONCLUSIONS: The persistent HR-HPV infection is associated with dysbiosis of the vaginal microbiota. Microbiome regulation with Bifidobacteria and Lactobacillus may affect the clearance of HPV.

Effects of nutritional support combined with insulin therapy on serum proteins, inflammatory factors, pentraxin-3, and serum amylase levels in patients with diabetic ketoacidosis complicated with acute pancreatitis.

ABSTRACT: To explore the effects of nutritional support combined with insulin therapy on serum protein, procalcitonin (PCT), C-reactive protein (CRP), tumor necrosis factor-α (TNF-α), pentraxin-3 (PTX-3), and serum amylase (AMS) levels in patients with diabetic ketoacidosis complicated with acute pancreatitis.A total of 64 patients with diabetic ketoacidosis complicated with acute pancreatitis admitted to our hospital from January 2018 to February 2019 were enrolled in this prospective study. They were divided into the study group and the control group according to the random number table method, with 32 patients in each group. Patients in the study group were given nutritional support combined with insulin therapy, and patients in the control group were given insulin therapy.There were no significant differences in general data including age, gender, body mass index, course and type of diabetes, acute physiology and chronic health evaluation II, RANSON, CT grades between the 2 groups before treatment (all P > .05). After 7 days of treatment, the clinical efficacy of the study group was significantly higher than that of the control group (study group vs control group, 94.44% vs 75.00%, P < .05). After 7 days of treatment, the levels of prealbumin and albumin in the study group were significantly higher than those in the control group (P < .05). After 7 days of treatment, the levels of PCT, CRP, TNF-α, PTX-3, and AMS in the 2 groups were significantly lower than those before treatment (P < .05), and the levels of PCT, CRP, TNF-α, PTX-3, and AMS in the study group were significantly lower than those in the control group. After 7 days of treatment, the levels of IgG, IgM, and IgA in the 2 groups were significantly higher than those before treatment, and the levels of IgG, IgM, and IgA in the study group were significantly higher than those in the control group (P < .05).Nutritional support combined with insulin is obviously effective in the treatment of diabetic ketoacidosis complicated with acute pancreatitis, which can improve serum protein levels, reduce inflammatory response, improve immune function, and is worthy of clinical application.