A capillary-aided microfiber Bragg grating pH sensor for hydrovoltaic technology.

Hydrovoltaic is an emerging technology that aims to harvest energy from water flow and evaporation, in which the plasmonic hydrogen ions are generated by the interaction between water and hydrovoltaic device. However, the volume of the water sample for the interaction is usually ultra-small due to the compact size of hydrovoltaic device, making the quantification and characterization of the hydrogen ions in such water sample an elusive goal. To address this issue, a miniature fiber-optic pH probe is proposed using a unilaterally tapered-microfiber Bragg grating. The microfiber Bragg grating has an intrinsic Bragg reflection signal with a narrow linewidth. The fiber probe is functionalized by coating the sodium alginate, which can respond to the variation of pH mediated by the alteration of the hydrophilicity. The rigidity and robustness of microfiber Bragg grating facilitates the encapsulation of the sensor into a sampling capillary, allowing for the detection of trace aqueous sample less than 2 µL. The pH sensitivity of the tapered-µFBG-based sensor is 62.8 p.m./pH (R2 = 0.995) with a limit resolution of 0.096 pH. The sensor performed a practical application in the monitoring and characterization of the hydrovoltaic microdevice, which can generate microcurrent as soaked in the water. This work demonstrates a promising technology in the fields of materials, energy, biology and medicine, in which the detection of the microsamples is inevitable.

Legumain-Triggered Macrocyclization of Radiofluorinated Tracer for Enhanced PET Imaging.

Enhancing the accumulation and retention of small-molecule probes in tumors is an important way to achieve accurate cancer diagnosis and therapy. Enzyme-stimulated macrocyclization of small molecules possesses great potential for enhanced positron emission tomography (PET) imaging of tumors. Herein, we reported an 18F-labeled radiotracer [18F]AlF-RSM for legumain detection in vivo. The tracer was prepared by a one-step aluminum-fluoride-restrained complexing agent ([18F]AlF-RESCA) method with high radiochemical yield (RCY) (88.35 ± 3.93%) and radiochemical purity (RCP) (>95%). More notably, the tracer can be transformed into a hydrophobic macrocyclic molecule under the joint action of legumain and reductant. Simultaneously, the tracer could target legumain-positive tumors and enhance accumulation and retention in tumors, resulting in the amplification of PET imaging signals. The enhancement of radioactivity enables PET imaging of legumain activity with high specificity. We envision that, by combining this highly efficient 18F-labeled strategy with our intramolecular macrocyclization reaction, a range of radiofluorinated tracers can be designed for tumor PET imaging and early cancer diagnosis in the future.

Reactive Oxygen Species Amplifier for Apoptosis-Ferroptosis Mediated High-Efficiency Radiosensitization of Tumors.

Insufficient reactive oxygen species (ROS) production and radioresistance have consistently contributed to the failure of radiotherapy (RT). The development of a biomaterial capable of activating ROS-induced apoptosis and ferroptosis is a potential strategy to enhance RT sensitivity. To achieve precision and high-efficiency RT, the theranostic nanoplatform Au/Cu nanodots (Au/CuNDs) were designed for dual-mode imaging, amplifying ROS generation, and inducing apoptosis-ferroptosis to sensitize RT. A large amount of ROS is derived from three aspects: (1) When exposed to ionizing radiation, Au/CuNDs effectively absorb photons and emit various electrons, which can interact with water to produce ROS. (2) Au/CuNDs act as a catalase-like to produce abundant ROS through Fenton reaction with hydrogen peroxide overexpressed of tumor cells. (3) Au/CuNDs deplete overexpressed glutathione, which causes the accumulation of ROS. Large amounts of ROS and ionizing radiation further lead to apoptosis by increasing DNA damage, and ferroptosis by enhancing lipid peroxidation, significantly improving the therapeutic efficiency of RT. Furthermore, Au/CuNDs serve as an excellent nanoprobe for high-resolution near-infrared fluorescence imaging and computed tomography of tumors. The promising dual-mode imaging performance shows their potential application in clinical cancer detection and imaging-guided precision RT, minimizing damage to adjacent normal tissues during RT. In summary, our developed theranostic nanoplatform integrates dual-mode imaging and sensitizes RT via ROS-activated apoptosis-ferroptosis, offering a promising prospect for clinical cancer diagnosis and treatment.

Low thermal contact resistance boron nitride nanosheets composites enabled by interfacial arc-like phonon bridge.

Two-dimensional materials with ultrahigh in-plane thermal conductivity are ideal for heat spreader applications but cause significant thermal contact resistance in complex interfaces, limiting their use as thermal interface materials. In this study, we present an interfacial phonon bridge strategy to reduce the thermal contact resistance of boron nitride nanosheets-based composites. By using a low-molecular-weight polymer, we are able to manipulate the alignment of boron nitride nanosheets through sequential stacking and cutting, ultimately achieving flexible thin films with a layer of arc-like structure superimposed on perpendicularly aligned ones. Our results suggest that arc-like structure can act as a phonon bridge to lower the contact resistance by 70% through reducing phonon back-reflection and enhancing phonon coupling efficiency at the boundary. The resulting composites exhibit ultralow thermal contact resistance of 0.059 in2 KW-1, demonstrating effective cooling of fast-charging batteries at a thickness 2-5 times thinner than commercial products.

Prevalence of High-Risk Human Papillomavirus Infection, Associated Risk Factors, and Relationship With Cervical Precancerous Lesions in Perimenopausal and Older Women in an Area With High Cervical Cancer Incidence in China.

Purpose This study delves into the epidemiology of high-risk human papillomavirus (HR-HPV) infection and its link to precancerous lesions among perimenopausal (40-59 years) and elderly (60-65 years) women in a Chinese county with a notably high incidence of cervical cancer. By uniquely focusing on these age groups in underdeveloped regions, the research aims to offer novel strategies for the management and prevention of cervical cancer. It seeks to inform targeted interventions and public health policies that could significantly benefit women at heightened risk for HPV, addressing a critical gap in current prevention efforts in economically disadvantaged communities. Methods This observational study was conducted at the Maternal and Child Health and Family Planning Service Centre in Lueyang County, from September 2021 to January 2022. It assessed 2008 women aged 40-65 for HPV screening, with 342 undergoing further cytological examination. The study evaluated the prevalence of HPV infection across different age groups and risk categories. It utilized a questionnaire to collect participants' basic information, health behaviors, and other relevant data to analyze factors influencing HR-HPV infection. Statistical analyses comprised chi-square tests, trend analysis, logistic regression, and multiple imputation techniques to address missing data. Results The prevalence of HR-HPV infection among women aged 40-65 years in Lueyang County was 18.43%. Older women exhibited a higher incidence of HPV infection, abnormal ThinPrep Cytology Test (TCT) results (Shaanxi Fu'an Biotechnology Co. Ltd., Baoji City, China), and low/high-grade squamous intraepithelial lesions (LSIL/HSIL) (P<0.05). The most prevalent HR-HPV genotypes in the overall, perimenopausal, and elderly groups were HPV-52, -53, and -58; HPV-52, -53, and -16; and HPV-58, -52, and -53, respectively. The prevalent HR-HPV genotypes in the abnormal The Bethesda System (TBS) results were HPV-16, -52, -33, -58; -16, -52, -58; and-16, -33, and -52. HPV-16, -18, -33 prevalence increased with increasing lesion severity (P<0.05). In this study, factors affecting HR-HPV in the three age groups were found to be mainly related to sexual behavior and education level, including history of lower genital tract diseases, multiple pregnancies, contraceptive methods without tubal ligation, age at first marriage greater than 18 years, never washing the vulva after sex, abstinence from sex, education level of junior high school or above, and spouse's education level of high school or above. Conclusions These findings suggest that the elevated rate of abnormal TBS in the older age group may be attributed to the higher prevalence of persistent infection-prone HR-HPV genotypes (HPV-58, -52, and-53), multiple infections, and potent oncogenic HR-HPV genotypes (HPV-16 and -33). Additionally, the higher HR-HPV prevalence in older patients may be related to lower education attainment, reduced screening rate, and limited condom usage. Therefore, strategies targeting perimenopausal and older women should prioritize enhancing health awareness, increasing screening rates, and encouraging condom utilization.

Knowledge and Practices Regarding Human Papillomavirus and Cervical Cancer Screening Among Women in Low-Income Areas of China: A Cross-Sectional Study.

BACKGROUND: Persistent human papillomavirus (HPV) infection is the primary cause of cervical cancer. However, this can be prevented through vaccination and screening. This study aimed to clarify the relationship between behavior, knowledge, and attitude toward cervical cancer and regular screening and HPV infection among women in Lueyang County. METHODS: Women who underwent cervical cancer screening at the outpatient department of a maternal and child health center between September and December 2021 were invited to participate. In total, 2,303 women completed the questionnaire. Women who underwent regular or irregular screening were 1:1 matched for age. Differences in knowledge of HPV and attitudes toward HPV vaccination among different populations were assessed. Logistic regression analysis was performed to identify the factors influencing HPV infection. RESULTS:  In total, 417 pairs of women who underwent regular and irregular screening were successfully matched. Multivariate logistic regression results indicated that age is a risk factor for HPV infection (OR=1.056 95%CI: [1.031 1.082]), while regular screening acts as a protective factor against HPV infection (OR=0.174 95%CI: [0.117 0.259]). Additionally, regular screening was associated with a higher level of knowledge about HPV among women compared to those who did not undergo regular screening (p<0.001). CONCLUSIONS:  Women in Lueyang County have low levels of knowledge regarding HPV and cervical cancer. Regular screening is a protective factor against HPV infection. The regular screening group demonstrates a higher level of HPV knowledge compared with the irregular screening group. These findings highlight the importance of regular screening and the need to strengthen public health education.

Association between Serum Lactate Dehydrogenase Level and 30-day Mortality in Patients with Intracranial Hemorrhage with Acute Leukemia in the Induction Phase: A Cohort Study.

Objectives This study aimed to identify the association between lactate dehydrogenase (LDH) levels and 30-day mortality in patients with intracranial hemorrhage (ICH) with acute leukemia during the induction phase. Methods This cohort study included patients with acute leukemia with ICH during induction. We evaluated serum LDH levels upon admission. Multivariable Cox regression analyzed the LDH 30-day mortality association. Interaction and stratified analyses based on factors like age, sex, albumin, white blood cell count, hemoglobin level, and platelet count were conducted. Results We selected 91 patients diagnosed with acute leukemia and ICH. The overall 30-day mortality rate was 61.5%, with 56 of the 91 patients succumbing. Among those with LDH levels ≥ 570 U/L, the mortality rate was 74.4% (32 out of 43), which was higher than the 50% mortality rate of the LDH < 570 U/L group (24 out of 48) ( p = 0.017). In our multivariate regression models, the hazard ratios and their corresponding 95% confidence intervals for Log2 and twice the upper limit of normal LDH were 1.27 (1.01, 1.58) and 2.2 (1.05, 4.58), respectively. Interaction analysis revealed no significant interactive effect on the relationship between LDH levels and 30-day mortality. Conclusions Serum LDH level was associated with 30-day mortality, especially in patients with LDH ≥ 570 U/L.

Immunogenicity and safety of an ORF7-deficient skin-attenuated and neuro-attenuated live vaccine for varicella: a randomised, double-blind, controlled, phase 2a trial.

BACKGROUND: The Oka varicella vaccine strain remains neurovirulent and can establish lifelong latent infection, raising safety concerns about vaccine-related herpes zoster. In this study, we aimed to evaluate the immunogenicity and safety of a skin-attenuated and neuro-attenuated varicella vaccine candidate (v7D vaccine). METHODS: We did this randomised, double-blind, controlled, phase 2a clinical trial in Jiangsu, China. Healthy children aged 3-12 years with no history of varicella infection or vaccination were enrolled and randomly assigned (1:1:1:1) to receive a single subcutaneous injection of the v7D vaccine at 3·3 log10 plaque forming units (PFU; low-dose v7D group), 3·9 log10 PFU (medium-dose v7D group), and 4·2 log10 PFU (high-dose v7D group), or the positive control varicella vaccine (vOka vaccine group). All the participants, laboratory personnel, and investigators other than the vaccine preparation and management staff were masked to the vaccine allocation. The primary outcome was assessment of the geometric mean titres (GMTs) and seroconversion rates of anti-varicella zoster virus immunoglobulin G (IgG) induced by different dose groups of v7D vaccine at 0, 42, 60, and 90 days after vaccination in the per-protocol set for humoral immune response analysis. Safety was a secondary outcome, focusing on adverse events within 42 days post-vaccination, and serious adverse events within 6 months after vaccination. This study was registered on Chinese Clinical Trial Registry, ChiCTR2000034434. FINDINGS: On Aug 18-21, 2020, 842 eligible volunteers were enrolled and randomly assigned treatment. After three participants withdrew, 839 received a low dose (n=211), middle dose (n=210), or high dose (n=210) of v7D vaccine, or the vOka vaccine (n=208). In the per-protocol set for humoral immune response analysis, the anti-varicella zoster virus IgG antibody response was highest at day 90. At day 90, the seroconversion rates of the low-dose, medium-dose, and high-dose groups of v7D vaccine and the positive control vOka vaccine group were 100·0% (95% CI 95·8-100·0; 87 of 87 participants), 98·9% (93·8-100·0; 87 of 88 participants), 97·8% (92·4-99·7; 91 of 93 participants), and 96·4% (89·8-99·2; 80 of 83 participants), respectively; the GMTs corresponded to values of 30·8 (95% CI 26·2-36·0), 31·3 (26·7-36·6), 28·2 (23·9-33·2), and 38·5 (31·7-46·7). The v7D vaccine, at low dose and medium dose, elicited a humoral immune response similar to that of the vOka vaccine. However, the high-dose v7D vaccine induced a marginally lower GMT compared with the vOka vaccine at day 90 (p=0·027). In the per-protocol set, the three dose groups of the v7D vaccine induced a similar humoral immune response at each timepoint, with no statistically significant differences. The incidence of adverse reactions in the low-dose, medium-dose, and high-dose groups of v7D vaccine was significantly lower than that in the vOka vaccine group (17% [35 of 211 participants], 20% [41 of 210 participants], and 13% [27 of 210 participants] vs 24% [50 of 208 participants], respectively; p=0·025), especially local adverse reactions (10% [22 of 211 participants], 14% [30 of 210 participants] and 9% [18 of 210 participants] vs 18% [38 of 208 participants], respectively; p=0·016). None of the serious adverse events were vaccine related. INTERPRETATION: The three dose groups of the candidate v7D vaccine exhibit similar humoral immunogenicity to the vOka vaccine and are well tolerated. These findings encourage further investigations on two-dose vaccination schedules, efficacy, and the potential safety benefit of v7D vaccine in the future. FUNDING: The National Natural Science Foundation of China, CAMS Innovation Fund for Medical Sciences, the Fundamental Research Funds for the Central Universities, and Beijing Wantai. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

Preoperative Exercise Training Decreases Complications of Minimally Invasive Lung Cancer Surgery- A Randomized Controlled Trial.

OBJECTIVE: Limited evidence exists regarding the efficacy of preoperative exercise (PE) in reducing short-term complications after minimally invasive surgery in patients with non-small cell lung cancer (NSCLC). This study aims to investigate the impact of PE on short-term complications following minimally invasive lung resection. METHODS: In this prospective, open-label, randomized (1:1) controlled trial at Xiangya Hospital, China (Sep 2020-Feb 2022), patients were randomly assigned to a PE group with 16-day alternate supervised exercise or a control. The primary outcome assessed was short-term postoperative complications, with a follow-up period of 30 days post-surgery. RESULTS: A total of 124 patients were recruited (PE group n=62; control n=62). Finally, 101 patients (PE group; n=51 and control; n=50) with a median age of 56 years (interquartile range, 50-62 years) completed the study. Compared with the control, the PE group showed fewer postoperative complications (PE:3/51 vs. Control 10/50; OR [95% CI], 0.17 [0.04 to 0.86], P=0.03) and shorter hospital stays (mean difference [95% CI], -2 [-3 to -1], P=0.01). PE significantly improved depression, stress, functional capacity, and quality of life (all P<0.05) before surgery. Furthermore, PE demonstrated a significantly lower minimum blood pressure during surgery, lower increases body temperature on day 2 after surgery, neutrophil-to-lymphocyte ratio, and neutrophil count after surgery (all P<0.05). Exploratory research on lung tissue RNA sequencing (5 in each group) showed downregulation of the tumor necrosis factor signaling pathway in the PE group compared with control. CONCLUSIONS: Preoperative exercise training decreased short-term postoperative complications in patients with NSCLC.

The oxytocin receptor is essential for the protective effect of pair housing on post-stroke depression in mice.

The beneficial effect of social interaction in mitigating the incidence of post-stroke depression (PSD) and ameliorating depressive symptoms has been consistently demonstrated through preclinical and clinical studies. However, the underlying relationship with oxytocin requires further investigation. In light of this, the present study aimed to explore the protective effect of pair housing on the development of PSD and the potential relationship with oxytocin receptors. The PSD model was induced by middle cerebral artery occlusion (MCAO) for 50 min, followed by 4-week isolated housing and restrained stress. Subsequently, each mouse in the pair-housing group (PH) was pair-housed with an isosexual healthy partner. Another group was continuously administrated fluoxetine (10 mg/Kg, i.p, once a day) for 3 weeks. To elucidate the potential role of oxytocin, we subjected pair-housed PSD mice to treatment with an oxytocin receptor (OXTR) antagonist (L368,889) (5 mg/Kg, i.p, once a day) for 3 weeks. At 31 to 32 days after MCAO, anxiety- and depressive-like behaviors were assessed using sucrose consumption, forced swim test, and tail-suspension test. The results showed that pair housing significantly improved post-stroke depression to an extent comparable to that of fluoxetine treatment. Furthermore, pair housing significantly decreased corticosterone in serum, increasing OXT mRNA expression in the hypothalamus. Treatment with L368,889 essentially reversed the effect of pair housing, with no discernible sex differences apart from changes in body weight. Pair housing increased hippocampal serotonin (5-HT), but treatment with L368,889 had no significant impact. Additionally, pair housing effectively reduced the number of reactive astrocytes and increased Nissl's body in the cortex and hippocampal CA3 regions. Correspondingly, treatment with L368,889 significantly reversed the changes in the Nissl's body and reactive astrocytes. Moreover, pair housing downregulated mRNA levels of TNF-α, IL-1ß, and IL-6 in the cortex caused by PSD, which was also reversed by treatment with L368,889. In conclusion, pair housing protects against the development of PSD depending on OXT and OXTR in the brain, with no significant divergence based on sex. These findings provide valuable insights into the potential of social interaction and oxytocin as therapeutic targets for PSD. Further research into the underlying mechanisms of these effects may contribute to the development of novel treatments for PSD.

Plasma steroid profiling combined with machine learning for the differential diagnosis in mild autonomous cortisol secretion from nonfunctioning adenoma in patients with adrenal incidentalomas.

BACKGROUND: To assess the diagnostic value of combining plasma steroid profiling with machine learning (ML) in differentiating between mild autonomous cortisol secretion (MACS) and nonfunctioning adenoma (NFA) in patients with adrenal incidentalomas. METHODS: The plasma steroid profiles data in the laboratory information system were screened from January 2021 to December 2023. EXtreme Gradient Boosting (XGBoost) was applied to establish diagnostic models using plasma 24-steroid panels and/or clinical characteristics of the subjects. The SHapley Additive exPlanation (SHAP) method was used for explaining the model. RESULTS: 76 patients with MACS and 86 patients with NFA were included in the development and internal validation cohort while the external validation cohort consisted of 27 MACS and 21 NFA cases. Among five ML models evaluated, XGBoost demonstrated superior performance with an AUC of 0.77 using 24 steroid hormones. The SHAP method identified five steroids that exhibited optimal performance in distinguishing MACS from NFA, namely dehydroepiandrosterone (DHEA), 11-deoxycortisol, 11ß-hydroxytestosterone, testosterone, and dehydroepiandrosteronesulfate (DHEAS). Upon incorporating clinical features into the model, the AUC increased to 0.88, with a sensitivity of 0.77 and specificity of 0.82. Furthermore, the results obtained through SHAP revealed that lower levels of testosterone, DHEA, LDL-c, BMI, and ACTH along with higher level of 11-deoxycortisol significantly contributed to the identification of MACS in the model. CONCLUSIONS: We have elucidated the utilization of ML-based steroid profiling to discriminate between MACS and NFA in patients with adrenal incidentalomas. This approach holds promise for distinguishing these two entities through a single blood collection.

Remnant cholesterol trajectory and subclinical arteriosclerosis: a 10-year longitudinal study of Chinese adults.

We aimed to identify different trajectories of remnant cholesterol (RC) and investigate the association of RC trajectories with vascular endothelial function and atherosclerosis progression in a longitudinal cohort of the Chinese population. A total of 521 participants were included in the flow-mediated vasodilation (FMD) subcohort study, and 7775 participants were included in the brachial-ankle pulse wave velocity (baPWV) subcohort study. All participants had ≥ 3 medical examinations during the 10-year follow-up period. In the FMD subcohort study, three distinct RC trajectories were identified according to the RC range and changing pattern over time: "low" (57.58%), "moderate" (30.90%) and "high" (11.52%). The proportion of the three groups with vascular endothelial dysfunction (FMD < 7.0%) was 20.00%, 39.75% and 60.00% respectively. Taking the low group as a reference, participants in the moderate and high groups had over 1.88 and 2.94 times the odds of vascular endothelial dysfunction (P = 0.048). In the baPWV subcohort study, three distinct RC trajectories were also identified: "low" (54.29%), "moderate" (38.97%) and "high" (6.74%). The proportion of the three groups with atherosclerosis (baPWV > 1400 cm/s) was 38.79%, 51.26% and 59.01% respectively. Taking the low group as a reference, participants in the moderate and high groups had over 1.46 and 2.16 times the odds of atherosclerosis (P < 0.001). The findings indicated that distinct RC trajectories are significantly associated with vascular endothelial function and atherosclerosis. Regular monitoring to identify persistent increases in RC may be more helpful in identifying individuals with a high risk of cardiovascular disease.

Deep groundwater irrigation altered microbial community and increased anammox and methane oxidation in paddy wetlands of Sanjiang Plain, China.

The over-utilizing of nitrogen fertilizers in paddy wetlands potentially threatens to the surrounding waterbody, and a deep understanding of the community and function of microorganisms is crucial for paddy non-point source pollution control. In this study, top soil samples (0-15 cm) of paddy wetlands under groundwater's irrigation at different depths (H1: 6.8 m, H2: 13.7 m, H3: 14.8 m, H4: 15.6 m, H5: 17.0 m, and H6: 17.8 m) were collected to investigate microbial community and function differences and their interrelation with soil properties. Results suggested some soil factor differences for groundwater's irrigation at different depths. Deep-groundwater's irrigation (H2-H6) was beneficial to the accumulation of various electron acceptors. Nitrifying-bacteria Ellin6067 had high abundance under deep groundwater irrigation, which was consistent with its diverse metabolic capacity. Meanwhile, denitrifying bacteria had diverse distribution patterns. Iron-reducing bacteria Geobacter was abundant in H1, and Anaeromyxobacter was abundant under deep groundwater irrigation; both species could participate in Fe-anammox. Furthermore, Geobacter could perform dissimilatory nitrate reduction to ammonia using divalent iron and provide substrate supply for anammox. Intrasporangium and norank_f_Gemmatimonadacea had good chromium- and vanadium-reducting potentials and could promote the occurrence of anammox. Low abundances of methanotrophs Methylocystis and norank_f_Methyloligellaceae were associated with the relatively anoxic environment of paddy wetlands, and the presence of aerobic methane oxidation was favorable for in-situ methane abatement. Moisture, pH, and TP had crucial effects on microbial community under phylum- and genus-levels. Microorganisms under shallow groundwater irrigation were highly sensitive to environmental changes, and Fe-anammox, nitrification, and methane oxidation were favorable under deep groundwater irrigation. This study highlights the importance of comprehensively revealing the microbial community and function of paddy wetlands under groundwater's irrigation and reveals the underlying function of indigenous microorganisms in agricultural non-point pollution control and greenhouse gas abatement.

Molecular characterization and functional roles of circulating cell-free extrachromosomal circular DNA.

Circular DNA segments isolated from chromosomes are known as extrachromosomal circular DNA (eccDNA). Its distinct structure and characteristics, along with the variations observed in different disease states, makes it a promising biomarker. Recent studies have revealed the presence of eccDNAs in body fluids, indicating their involvement in various biological functions. This finding opens up avenues for utilizing eccDNAs as convenient and real-time biomarkers for disease diagnosis, treatment monitoring, and prognosis assessment through noninvasive analysis of body fluids. In this comprehensive review, we focused on elucidating the size profiles, potential mechanisms of formation and clearance, detection methods, and potential clinical applications of eccDNAs. We aimed to provide a valuable reference resource for future research in this field.

Asymptomatic elevation of parathyroid hormone levels by antibodies against reagent alkaline phosphatase.

CONTEXT: Although immunoassay interference is a well-known phenomenon, its detection in routine clinical practice remains challenging. Most immunoassay interference can be attributed to the presence of heterophilic or anti-hormone antibodies. However, reports on immunoassay interference specifically related to parathyroid hormone (PTH) are scarce. CASE DESCRIPTION: A 77-year-old woman with hypertension, nephrotic syndrome, and high PTH levels for one year was admitted to our Surgical Department for treatment. The patient had no specific symptoms and normal calcium and alkaline phosphatase (ALP) levels but markedly elevated PTH levels. PTH was 2172 pg/mL using the Beckman Coulter system, whereas the Roche, Abbot, and Siemens systems yielded normal results. PTH concentration decreased to 63.8 pg/mL after pretreatment with polyethylene glycol 6000 and did not decrease to normal levels following pretreatment with heterophilic blocking tube-50 (HBT-50), heterophilic blocking reagent (HBR)-21, or HBR-25. When the HBR-21 concentration was increased, serum PTH decreased to 99.0 pg/mL. After treatment with scavenger bovine alkaline phosphatase (inactive), the concentration of PTH decreased to a normal value (51.3 pg/mL). Additionally, PTH (1-84) concentration was 17.6 pg/mL using LC-MS/MS. CONCLUSION: PTH was falsely evaluated due to anti-bovine ALP antibodies (antibodies against reagent ALP). Anti-bovine ALP antibodies should be considered in assays that use ALP as a signal generator.

Lignin bioconversion based on genome mining for ligninolytic genes in Erwinia billingiae QL-Z3.

BACKGROUND: Bioconversion of plant biomass into biofuels and bio-products produces large amounts of lignin. The aromatic biopolymers need to be degraded before being converted into value-added bio-products. Microbes can be environment-friendly and efficiently degrade lignin. Compared to fungi, bacteria have some advantages in lignin degradation, including broad tolerance to pH, temperature, and oxygen and the toolkit for genetic manipulation. RESULTS: Our previous study isolated a novel ligninolytic bacterial strain Erwinia billingiae QL-Z3. Under optimized conditions, its rate of lignin degradation was 25.24% at 1.5 g/L lignin as the sole carbon source. Whole genome sequencing revealed 4556 genes in the genome of QL-Z3. Among 4428 protein-coding genes are 139 CAZyme genes, including 54 glycoside hydrolase (GH) and 16 auxiliary activity (AA) genes. In addition, 74 genes encoding extracellular enzymes are potentially involved in lignin degradation. Real-time PCR quantification demonstrated that the expression of potential ligninolytic genes were significantly induced by lignin. 8 knock-out mutants and complementary strains were constructed. Disruption of the gene for ELAC_205 (laccase) as well as EDYP_48 (Dyp-type peroxidase), ESOD_1236 (superoxide dismutase), EDIO_858 (dioxygenase), EMON_3330 (monooxygenase), or EMCAT_3587 (manganese catalase) significantly reduced the lignin-degrading activity of QL-Z3 by 47-69%. Heterologously expressed and purified enzymes further confirmed their role in lignin degradation. Fourier transform infrared spectroscopy (FTIR) results indicated that the lignin structure was damaged, the benzene ring structure and groups of macromolecules were opened, and the chemical bond was broken under the action of six enzymes encoded by genes. The abundant enzymatic metabolic products by EDYP_48, ELAC_205 and ESOD_1236 were systematically analyzed via liquid chromatography-mass spectrometry (LC-MS) analysis, and then provide a speculative pathway for lignin biodegradation. Finally, The activities of ligninolytic enzymes from fermentation supernatant, namely, LiP, MnP and Lac were 367.50 U/L, 839.50 U/L, and 219.00 U/L by orthogonal optimization. CONCLUSIONS: Our findings provide that QL-Z3 and its enzymes have the potential for industrial application and hold great promise for the bioconversion of lignin into bioproducts in lignin valorization.

Accuracy of solid portion size measured on multiplanar volume rendering images for assessing invasiveness in lung adenocarcinoma manifesting as subsolid nodules.

Background: The solid component of subsolid nodules (SSNs) is closely associated with the invasiveness of lung adenocarcinoma, and its accurate assessment is crucial for selecting treatment method. Therefore, this study aimed to evaluate the accuracy of solid component size within SSNs measured on multiplanar volume rendering (MPVR) and compare it with the dimensions of invasive components on pathology. Methods: A pilot study was conducted using a chest phantom to determine the optimal MPVR threshold for the solid component within SSN, and then clinical validation was carried out by retrospective inclusion of patients with pathologically confirmed solitary SSN from October 2020 to October 2021. The radiological tumor size on MPVR and solid component size on MPVR (RSSm) and on lung window (RSSl) were measured. The size of the tumor and invasion were measured on the pathological section, and the invasion, fibrosis, and inflammation within SSNs were also recorded. The measurement difference between computed tomography (CT) and pathology, inter-observer and inter-measurement agreement were analyzed. Receiver operating characteristic (ROC) analysis and Bland-Altman plot were performed to evaluate the diagnostic efficiency of MPVR. Results: A total of 142 patients (mean age, 54±11 years, 39 men) were retrospectively enrolled in the clinical study, with 26 adenocarcinomas in situ, 92 minimally invasive adenocarcinomas (MIAs), and 24 invasive adenocarcinomas (IAs). The RSSl was significantly smaller than pathological invasion size with fair inter-measurement agreement [intraclass correlation coefficient (ICC) =0.562, P<0.001] and moderate interobserver agreement (ICC =0.761, P<0.001). The RSSm was significantly larger than pathological invasion size with the excellent inter-measurement agreement (ICC =0.829, P<0.001) and excellent (ICC =0.952, P<0.001) interobserver agreement. ROC analysis showed that the cutoff value of RSSm for differentiating adenocarcinoma in situ from MIA and MIA from IA was 1.85 and 6.45 mm (sensitivity: 93.8% and 95.5%, specificity: 85.7% and 88.2%, 95% confidence internal: 0.914-0.993 and 0.900-0.983), respectively. The positive predictive value-and negative predictive value of MPVR in predicting invasiveness were 92.8% and 100%, respectively. Conclusions: Using MPVR to predict the invasive degree of SSN had high accuracy and good inter-observer agreement, which is superior to lung window measurements and helpful for clinical decision-making.

Lysosome-targeting and legumain-triggered 68Ga-labeled probe for enhanced tumor PET imaging.

Legumain is overexpressed in diverse tumors, serving as a significant tumor biomarker. Our study aimed to develop a new positron emission tomography (PET) probe [68Ga]Ga-NOTA-SF-AANM for imaging the expression level of legumain in vivo. The radio-labeling of [68Ga]Ga-NOTA-SF-AANM was accomplished within 15 min. The probe has good stability in vitro. NOTA-SF-AANM exhibited rapid response to recombinant human legumain enzyme, enabling intramolecular condensation cyclization. Cellular uptake and lysosomal co-localization experiments demonstrated that the probe was able to differentiate specifically between MDA-MB-468 and PC-3 cancer cells with varying degrees of legumain expression. PET imaging displayed a significant and persistent signal (3.59 ± 0.30 %ID/mL at 60 min) in MDA-MB-468 tumors, while PC-3 tumors exhibited lower radioactivity (1.08 ± 0.35 %ID/mL at 60 min), further validating the specific targeting of [68Ga]Ga-NOTA-SF-AANM towards legumain. [68Ga]Ga-NOTA-SF-AANM is a promising tool for precise diagnosis of legumain-related diseases due to its advantages in radio-labeling and accurate monitoring of legumain expression levels.

Preclinical evaluation of 68 Ga-labeled peptide CK2 for PET imaging of NRP-1 expression in vivo.

PURPOSE: Neuropilin-1 (NRP-1) is a multifunctional protein involved in a variety of biological processes such as angiogenesis, tumorigenesis and immunomodulation. It was usually overexpressed in many cancer cell lines and correlated with poor prognosis of breast cancer. Positron emission tomography (PET) is an advanced imaging technique for detecting the function and metabolism of tumor-associated molecules in real time, dynamically, quantitatively and noninvasively. To improve the level of early diagnosis and evaluate the prognosis of breast cancer, an NRP-1 targeting peptide-based tracer [68 Ga]Ga-NOTA-PEG4-CK2 was designed to sensitively and specifically detect the NRP-1 expression in vivo via PET imaging. METHODS: In silico modeling and microscale thermophoresis (MST) assay were carried out to design the NRP-1 targeting peptide NOTA-PEG4-CK2, and it was further radiolabeled with 68 Ga to prepare the tracer [68 Ga]Ga-NOTA-PEG4-CK2. The radiochemical yield (RCY), radiochemical purity (RCP), molar activity (Am), lipid-water partition coefficient (Log P) and stability of [68 Ga]Ga-NOTA-PEG4-CK2 were assessed. The targeting specificity of the tracer for NRP-1 was investigated by in vitro cellular uptake assay and in vivo PET imaging as well as blocking studies. The sensitivity of the tracer in monitoring the dynamic changes of NRP-1 expression induced by chemical drug was also investigated in vitro and in vivo. Ex vivo biodistribution, autoradiography, western blot, and immunofluorescence staining were also performed to study the specificity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1. RESULTS: [68 Ga]Ga-NOTA-PEG4-CK2 was designed and synthesized with high RCY (> 98%), high stability (RCP > 95%) and high affinity to NRP-1 (KD = 25.39 ± 1.65 nM). In vitro cellular uptake assay showed that the tracer [68 Ga]Ga-NOTA-PEG4-CK2 can specifically bind to NRP-1 positive cancer cells MDA-MB-231 (1.04 ± 0.04% at 2 h) rather than NRP-1 negative cancer cells NCI-H1299 (0.43 ± 0.05%). In vivo PET imaging showed the maximum tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 in MDA-MB-231 xenografts (4.16 ± 0.67%ID/mL) was significantly higher than that in NCI-H1299 xenografts (1.03 ± 0.19%ID/mL) at 10 min post injection, and the former exhibited higher tumor-to-muscle uptake ratio (5.22 ± 0.18) than the latter (1.07 ± 0.27) at 60 min post injection. MDA-MB-231 xenografts pretreated with nonradioactive precursor NOTA-PEG4-CK2 showed little tumor uptake of [68 Ga]Ga-NOTA-PEG4-CK2 (1.67 ± 0.38%ID/mL at 10 min post injection). Both cellular uptake assay and PET imaging revealed that NRP-1 expression in breast cancer MDA-MB-231 could be effectively suppressed by SB-203580 treatment and can be sensitively detected by [68 Ga]Ga-NOTA-PEG4-CK2. Ex vivo analysis also proved the high specificity and sensitivity of [68 Ga]Ga-NOTA-PEG4-CK2 for NRP-1 expression in MDA-MB-231 xenografts. CONCLUSION: A promising NRP-1 targeting PET tracer [68 Ga]Ga-NOTA-PEG4-CK2 was successfully prepared. It showed remarkable specificity and sensitivity in monitoring the dynamic changes of NRP-1 expression. Hence, it could provide valuable information for early diagnosis of NRP-1 relevant cancers and evaluating the prognosis of cancer patients.

Cathepsin B-Activated PET Tracer for In Vivo Tumor Imaging.

Cathepsin B, a lysosomal protease, is considered as a crucial biomarker for tumor diagnosis and treatment as it is overexpressed in numerous cancers. A stimulus-responsive SF scaffold has been reported to detect the activity of a variety of tumor-associated enzymes. In this work, a small-molecule PET tracer ([68Ga]NOTA-SF-CV) was developed by combining an SF scaffold with a cathepsin B-specific recognition substrate Cit-Val. Upon activation by cathepsin B, [68Ga]NOTA-SF-CV could form the cyclization product in a reduction environment, resulting in reduced hydrophilicity. This unique property could effectively prevent exocytosis of the tracer in cathepsin B-overexpressing tumor cells, leading to prolonged retention and amplified PET imaging signal. Moreover, [68Ga]NOTA-SF-CV had great targeting specificity to cathepsin B. In vivo microPET imaging results showed that [68Ga]NOTA-SF-CV was able to effectively visualize the expression level of cathepsin B in various tumors. Hence, [68Ga]NOTA-SF-CV may be served as a potential tracer for diagnosing cathepsin B-related diseases.