NIR-activated electrospun nanodetonator dressing enhances infected diabetic wound healing with combined photothermal and nitric oxide-based gas therapy.

Diabetic wounds pose a challenge to healing due to increased bacterial susceptibility and poor vascularization. Effective healing requires simultaneous bacterial and biofilm elimination and angiogenesis stimulation. In this study, we incorporated polyaniline (PANI) and S-Nitrosoglutathione (GSNO) into a polyvinyl alcohol, chitosan, and hydroxypropyltrimethyl ammonium chloride chitosan (PVA/CS/HTCC) matrix, creating a versatile wound dressing membrane through electrospinning. The dressing combines the advantages of photothermal antibacterial therapy and nitric oxide gas therapy, exhibiting enduring and effective bactericidal activity and biofilm disruption against methicillin-sensitive Staphylococcus aureus, methicillin-resistant Staphylococcus aureus, and Escherichia coli. Furthermore, the membrane's PTT effect and NO release exhibit significant synergistic activation, enabling a nanodetonator-like burst release of NO through NIR irradiation to disintegrate biofilms. Importantly, the nanofiber sustained a uniform release of nitric oxide, thereby catalyzing angiogenesis and advancing cellular migration. Ultimately, the employment of this membrane dressing culminated in the efficacious amelioration of diabetic-infected wounds in Sprague-Dawley rats, achieving wound closure within a concise duration of 14 days. Upon applying NIR irradiation to the PVA-CS-HTCC-PANI-GSNO nanofiber membrane, it swiftly eradicates bacteria and biofilm within 5 min, enhancing its inherent antibacterial and anti-biofilm properties through the powerful synergistic action of PTT and NO therapy. It also promotes angiogenesis, exhibits excellent biocompatibility, and is easy to use, highlighting its potential in treating diabetic wounds.

Aberrant methylation and expression of TNXB promote chondrocyte apoptosis and extracullar matrix degradation in hemophilic arthropathy via AKT signaling.

Recurrent joint bleeding in hemophilia patients frequently causes hemophilic arthropathy (HA). Drastic degradation of cartilage is a major characteristic of HA, but its pathological mechanisms has not yet been clarified. In HA cartilages, we found server matrix degradation and increased expression of DNA methyltransferase proteins. We thus performed genome-wide DNA methylation analysis on human HA (N=5) and osteoarthritis (OA) (N=5) articular cartilages, and identified 1228 differentially methylated regions (DMRs) associated with HA. Functional enrichment analyses revealed the association between DMR genes (DMGs) and extracellular matrix (ECM) organization. Among these DMGs, Tenascin XB (TNXB) expression was down-regulated in human and mouse HA cartilages. The loss of Tnxb in F8-/- mouse cartilage provided a disease-promoting role in HA by augmenting cartilage degeneration and subchondral bone loss. Tnxb knockdown also promoted chondrocyte apoptosis and inhibited phosphorylation of AKT. Importantly, AKT agonist showed chondroprotective effects following Tnxb knockdown. Together, our findings indicate that exposure of cartilage to blood leads to alterations in DNA methylation, which is functionally related to ECM homeostasis, and further demonstrate a critical role of TNXB in HA cartilage degeneration by activating AKT signaling. These mechanistic insights allow development of potentially new strategies for HA cartilage protection.

NudCL2 is required for cytokinesis by stabilizing RCC2 with Hsp90 at the midbody.

Cytokinesis is required for faithful division of cytoplasmic components and duplicated nuclei into two daughter cells. Midbody, a protein-dense organelle that forms at the intercellular bridge, is indispensable for successful cytokinesis. However, the regulatory mechanism of cytokinesis at the midbody still remains elusive. Here, we unveil a critical role for NudC-like protein 2 (NudCL2), a co-chaperone of heat shock protein 90 (Hsp90), in cytokinesis regulation by stabilizing regulator of chromosome condensation 2 (RCC2) at the midbody in mammalian cells. NudCL2 localizes at the midbody, and its downregulation results in cytokinesis failure, multinucleation and midbody disorganization. Using iTRAQ-based quantitative proteomic analysis, we find that RCC2 levels are decreased in NudCL2 knockout (KO) cells. Moreover, Hsp90 forms a complex with NudCL2 to stabilize RCC2, which is essential for cytokinesis. RCC2 depletion mirrors phenotypes observed in NudCL2-downregulated cells. Importantly, ectopic expression of RCC2 rescues the cytokinesis defects induced by NudCL2 deletion, but not vice versa. Together, our data reveal the significance of the NudCL2/Hsp90/RCC2 pathway in cytokinesis at the midbody.

Boosting the sensitivity of single photon ionization time-of-flight mass spectrometry using a segmented focus quadrupole-ion guide.

Single photon ionization time-of-flight mass spectrometry (SPI-TOF-MS) is a powerful analytical technique for real-time detection of trace VOCs. However, efficient ion transmission within the ionization chamber has always been a challenging issue in SPI-TOF-MS. In this study, a novel ion guide termed the Segmented Focus Quadrupole Ion Guide (SFQ-IG) was introduced for SPI-TOF-MS. The SFQ-IG device consists of 12 printed circuit boards (PCB), each containing four quarter-ring electrodes with inner diameters progressively decreasing from 26 to 4 mm. The simulation results demonstrated that SFQ-IG exhibited superior ion transmission efficiency than both ion funnel (IF) field and direct current-only (DC-only) field. By integrating into a SPI-TOF-MS, this ion guide was optimized in terms of the ionization source pressure, direct current gradient, and radio frequency amplitude. Further comparative experiments demonstrated that the SPI-TOF-MS with the SFQ-IG exhibited higher sensitivity than both the IF field (1.3-7.4 times) and DC-only field (3.5-8.8 times) for the test VOCs. The improvements in limit of detection (LOD) with the SFQ-IG ranged from 1.6 to 5.3 times compared to the DC-only field for the test VOCs. Fabricated using PCB technology, the SFQ-IG is characterized by its cost-effectiveness, compact size, and high transmission efficiency, facilitating its integration into other mass spectrometers.

Associations between immune cell phenotypes and lung cancer subtypes: insights from mendelian randomization analysis.

INTRODUCTION: Lung cancer is a common malignant tumor, and different types of immune cells may have different effects on the occurrence and development of lung cancer subtypes, including lung squamous cell carcinoma (LUSC) and lung adenocarcinoma (LUAD). However, the causal relationship between immune phenotype and lung cancer is still unclear. METHODS: This study utilized a comprehensive dataset containing 731 immune phenotypes from the European Bioinformatics Institute (EBI) to evaluate the potential causal relationship between immune phenotypes and LUSC and LUAD using the inverse variance weighted (IVW) method in Mendelian randomization (MR). Sensitivity analyses, including MR-Egger intercept, Cochran Q test, and others, were conducted for the robustness of the results. The study results were further validated through meta-analysis using data from the Transdisciplinary Research Into Cancer of the Lung (TRICL) data. Additionally, confounding factors were excluded to ensure the robustness of the findings. RESULTS: Among the final selection of 729 immune cell phenotypes, three immune phenotypes exhibited statistically significant effects with LUSC. CD28 expression on resting CD4 regulatory T cells (OR 1.0980, 95% CI: 1.0627-1.1344, p < 0.0001) and CD45RA + CD28- CD8 + T cell %T cell (OR 1.0011, 95% CI: 1.0007; 1.0015, p < 0.0001) were associated with increased susceptibility to LUSC. Conversely, CCR2 expression on monocytes (OR 0.9399, 95% CI: 0.9177-0.9625, p < 0.0001) was correlated with a decreased risk of LUSC. However, no significant causal relationships were established between any immune cell phenotypes and LUAD. CONCLUSION: This study demonstrates that specific immune cell types are associated with the risk of LUSC but not with LUAD. While these findings are derived solely from European populations, they still provide clues for a deeper understanding of the immunological mechanisms underlying lung cancer and may offer new directions for future therapeutic strategies and preventive measures.

Ursolic acid molecules dock MAPK1 to modulate gut microbiota diversity to reduce neuropathic pain.

To investigate the efficacy of Ursolic acid in alleviating neuropathic pain in rats with spinal nerve ligation (SNL), the SNL rat model was surgically induced. Different concentrations of Ursolic acid and manipulated target mitogen-activated protein kinase 1 (MAPK1) were administered to the SNL rats. Fecal samples were collected from each group of rats for 16S rDNA analysis to examine the impact of gut microbiota. Molecular docking experiments were conducted to assess the binding energy between Ursolic acid and MAPK1. In vivo studies were carried out to evaluate the expression of inflammatory factors and signaling pathways in spinal cord and colon tissues. Ursolic acid was found to have a beneficial effect on pain reduction in rats by increasing plantar withdrawal latency (PWL) and paw withdrawal threshold (PWT). Comparing the Ursolic acid group with the control group revealed notable differences in the distribution of Staphylococcus, Allobaculum, Clostridium, Blautia, Bifidobacterium, and Prevotella species. Network pharmacology analysis identified MAPK1 and intercellular adhesion molecule-1 (ICAM1) as common targets for Ursolic acid, SNL, and neuropathic pain. Binding sites between Ursolic acid and these targets were identified. Additionally, immunofluorescent staining showed a decrease in GFAP and IBA1 intensity in the spinal cord along with an increase in NeuN following Ursolic acid treatment. Overexpression of MAPK1 in SNL rats led to an increase in inflammatory factors and a decrease in PWL and PWT. Furthermore, MAPK1 counteracted the pain-relieving effects of Ursolic acid in SNL rats. Ursolic acid was found to alleviate neuropathic pain in SNL rats by targeting MAPK1 and influencing gut microbiota homeostasis.

SIVA-1 enhances acquired chemotherapeutic drug resistance of gastric cancer in vivo by regulating the ARF/MDM2/p53 pathway.

SIVA-1 has been shown to affect apoptotic processes in various different cell lines, and SIVA-1 significantly contributes to the decreased responsiveness of cancer cells to some chemotherapy agents. However, whether SIVA-1 has potential application in gastric cancer remains unknown. Therefore, the objective of this investigation was to clarify the distinct function of SIVA-1 in chemotherapeutic drug resistance within a living murine model with gastric malignancy, and initially elucidate the underlying mechanisms. In an established multidrug-resistant gastric cancer xenograft mouse model, lentivirus, named Lv-SIVA-1, was injected into xenograft tumors, and increased the mRNA and protein expression of endogenous SIVA-1 in tumors. Immunohistochemical assays of xenograft tumor showed that SIVA-1 was significantly upregulated, and the protein expression levels of SIVA-1 were highly increased, as detected by Western blotting. In addition, we detected the role of SIVA-1 in cell proliferation and cell apoptosis in gastric cancer cells by TUNEL and found that SIVA-1 decreased tumor cell apoptosis and promoted tumor growth in vivo. Using a TMT assay between tumor tissues of experimental and control groups, differentially expressed proteins were examined and three potential biomarkers of multidrug resistance (ARF, MDM2, and p53) were screened. We further investigated the molecular mechanism by which SIVA-1 played an efficient role against chemotherapies and found that overexpressed SIVA-1 leads to increased ARF and MDM2 expression and suppressed expression of p53 in tumor tissue. In conclusion, SIVA-1 plays a significant role in the multidrug resistance of gastric tumors. In addition, overexpressed SIVA-1 positively regulates cell proliferation, adjusts cycle progression, and reduces the response to drug treatment for gastric cancer in an ARF/MDM2/p53-dependent manner. This novel research provides a basis for chemical management of gastric cancer through regulation of SIVA-1 expression.

Effects of uric acid-lowering therapy (ULT) on renal outcomes in CKD patients with asymptomatic hyperuricemia: a systematic review and meta-analysis.

BACKGROUND: It is well known that asymptomatic hyperuricemia and gout play an important role in patients with chronic kidney disease (CKD). However, the effect of uric acid-lowering therapy (ULT) on the prognosis of CKD patients with asymptomatic hyperuricemia remains controversial. Therefore, we aim to investigate the influence of ULT on renal outcomes in these patients. METHODS: Comprehensive searches were conducted in PubMed, EMBASE, China National Knowledge Internet (CNKI), and the Cochrane Library, up until January 2024. We included randomized controlled trials (RCTs) that evaluated the effects of ULT on renal outcomes in CKD patients with asymptomatic hyperuricemia. RESULTS: A total of 17 studies were included in the meta-analysis. Compared with placebo or no treatment, ULT preserved the loss of estimated glomerular filtrating rate (eGFR) (Weighted mean difference [WMD] and its 95% confidence intercal(CI): 2.07 [0.15,3.98] mL/min/1.73m2) at long-term subgroup. At the same time, short-term subgroup also proved the preserved loss of eGFR (WMD 5.74[2.09, 9.39] mL/min/1.73m2). Compared with placebo or no treatment, ULT also reduced the increase in serum creatinine (Scr) at short-term (WMD -44.48[-84.03,-4.92]µmol/L) subgroup and long-term (WMD -46.13[-65.64,-26.62]µmol/L) subgroup. ULT was associated with lower incidence of the events of doubling of Scr without dialysis (relative risk (RR) 0.32 [0.21, 0.49], p < 0.001). However, no difference was found for lower incidence of acute kidney injury (AKI) (p = 0.943). CONCLUSIONS: According to our study, ULT is beneficial for slowing CKD progression both in short to long-term follow-ups. Additionally, in patients younger than 60 years old, the protective effect of ULT on renal outcome is more pronounced. However, it showed no significant difference in the incidence of AKI. These findings underscore the importance of considering ULT in clinical strategies for CKD patients with asymptomatic hyperuricemia.

Liquiritin reduces chondrocyte apoptosis through P53/PUMA signaling pathway to alleviate osteoarthritis.

AIMS: The main pathological features of osteoarthritis (OA) include the degeneration of articular cartilage and a decrease in matrix synthesis. Chondrocytes, which contribute to matrix synthesis, play a crucial role in the development of OA. Liquiritin, an effective ingredient extracted from Glycyrrhiza uralensis Fisch., has been used for over 1000 years to treat OA. This study aims to investigate the impact of liquiritin on OA and its underlying mechanism. MATERIALS AND METHODS: Gait and hot plate tests assessed mouse behavior, while Micro-CT and ABH/OG staining observed joint morphological changes. The TUNEL kit detected chondrocyte apoptosis. Western blot and immunofluorescence techniques determined the expression levels of cartilage metabolism markers COL2 and MMP13, as well as apoptosis markers caspase3, bcl2, P53, and PUMA. KEGG analysis and molecular docking technology were used to verify the relationship between liquiritin and P53. KEY FINDINGS: Liquiritin alleviated pain sensitivity and improved gait impairment in OA mice. Additionally, we found that liquiritin could increase COL2 levels and decrease MMP13 levels both in vivo and in vitro. Importantly, liquiritin reduced chondrocyte apoptosis induced by OA, through decreased expression of caspase3 expression and increased expression of bcl2 expression. Molecular docking revealed a strong binding affinity between liquiritin and P53. Both in vivo and in vitro studies demonstrated that liquiritin suppressed the expression of P53 and PUMA in cartilage. SIGNIFICANCE: This indicated that liquiritin may alleviate OA progression by inhibiting the P53/PUMA signaling pathway, suggesting that liquiritin is a potential strategy for the treatment of OA.

The phase separation of extracellular matrix protein matrilin-3 from cancer-associated fibroblasts contributes to gastric cancer invasion.

Cancer-associated fibroblast (CAF) has emerged as a key contributor to the remodeling of tumor microenvironment through the expression and secretion of extracellular matrix (ECM) proteins, thereby promoting carcinogenesis. However, the precise contribution of ECM proteins from CAFs to gastric carcinogenesis remains poorly understood. In this study, we find that matrilin-3 (MATN3), an upregulated ECM protein associated with poorer prognosis in gastric cancer patients, originates from CAFs in gastric cancer tissues. Ectopic expression of MATN3 in CAFs significantly promotes the invasion of gastric cancer cells, which can be attenuated by neutralizing MATN3 with its antibody. Notably, a portion of MATN3 protein is found to form puncta in gastric cancer tissues ECM. MATN3 undergoes phase separation, which is mediated by its low complexity (LC) and coiled-coil (CC) domains. Moreover, overexpression of MATN3 deleted with either LC or CC in CAFs is unable to promote the invasion of gastric cancer cells, suggesting that LC or CC domain is required for the effect of CAF-secreted MATN3 in gastric cancer cell invasion. Additionally, orthotopic co-injection of gastric cancer cells and CAFs expressing MATN3, but not its ΔLC and ΔCC mutants, leads to enhanced gastric cancer cell invasion in mouse models. Collectively, our works suggest that MATN3 is secreted by CAFs and undergoes phase separation, which promotes gastric cancer invasion.

Surrogate-driven respiratory motion model for projection-resolved motion estimation and motion compensated cone-beam CT reconstruction from unsorted projection data.

Objective.As the most common solution to motion artefact for cone-beam CT (CBCT) in radiotherapy, 4DCBCT suffers from long acquisition time and phase sorting error. This issue could be addressed if the motion at each projection could be known, which is a severely ill-posed problem. This study aims to obtain the motion at each time point and motion-free image simultaneously from unsorted projection data of a standard 3DCBCT scan.Approach.Respiration surrogate signals were extracted by the Intensity Analysis method. A general framework was then deployed to fit a surrogate-driven motion model that characterized the relation between the motion and surrogate signals at each time point. Motion model fitting and motion compensated reconstruction were alternatively and iteratively performed. Stochastic subset gradient based method was used to significantly reduce the computation time. The performance of our method was comprehensively evaluated through digital phantom simulation and also validated on clinical scans from six patients.Results.For digital phantom experiments, motion models fitted with ground-truth or extracted surrogate signals both achieved a much lower motion estimation error and higher image quality, compared with non motion-compensated results.For the public SPARE Challenge datasets, more clear lung tissues and less blurry diaphragm could be seen in the motion compensated reconstruction, comparable to the benchmark 4DCBCT images but with a higher temporal resolution. Similar results were observed for two real clinical 3DCBCT scans.Significance.The motion compensated reconstructions and motion models produced by our method will have direct clinical benefit by providing more accurate estimates of the delivered dose and ultimately facilitating more accurate radiotherapy treatments for lung cancer patients.

In vivo characterization of the superior fitness of classical swine fever virus genotype 2.1 to genotype 3.4.

Classical swine fever (CSF), caused by classical swine fever virus (CSFV), is a highly contagious disease in pigs. In Taiwan, the emerging genotype 2.1 (G2.1) CSFV caused sporadic outbreaks in 1994 and replaced the previous G3.4 CSFV in the field. The shift of CSFV genotypes to G2 CSFV was also observed in several CSFV-affected countries. The present study aimed to explore the mechanism of the genotype shift of CSFV. Two groups of specific pathogen-free (SPF) pigs were first inoculated with either G2.1 or G3.4 CSFV (single-inoculated group) and housed together with naïve SPF pigs (cohabitating group). The results showed that peak viremia, viral loads in blood and tissues, and viral shedding of G2.1 were consistently higher than those of G3.4 CSFV in single-inoculated and cohabitating pigs. The phenomenon of superinfection exclusion (SIE), characterized by the prevention of secondary infection by a primary infection, was readily observed in CSFV single-inoculated pigs. Interestingly, coinfection of both genotypes of CSFV was observed in 3 out of 4 cohabitating pigs, while only one pig was infected with G2.1 CSFV alone. These findings suggest that the genetic shift in CSFV in the field may be in part the consequence of SIE.

Identification of neutralizing epitopes on the D/A domain of the E2 glycoprotein of classical swine fever virus.

Classical swine fever virus (CSFV) shares high antigenic homology with other members of the genus Pestivirus. Because several pestivirus species can also infect swine, eliciting cross-reactive antibodies, it is important to define CSFV-specific epitopes for the differential diagnosis of classical swine fever (CSF) by serology. For this purpose, epitope mapping of seven monoclonal antibodies (mAbs), recognizing sites on the D/A domain of glycoprotein E2, was performed using recombinant expressed antigenic domains and mutants of E2, as well as an overlapping peptide library. Three CSFV-specific epitopes, i.e., 780-IEEMGDDFGFGLCPF-794, 810-NGSAFYLVCPIGWTG-824, and 846-REKPF-850, were identified within the D/A domain of E2. Site-directed mutagenesis further confirmed that residues 783-MGD-785, 789-FGLCPF-794, 813-AFYLVCPIGWTG-824, and 846-REK-848 were critical residues in these regions. In addition, a F789S difference within the epitope 780-IEEMGDDFGFGLCPF-794 was responsible for the absence of binding of two mAbs to the E2 protein of the live attenuated CSFV vaccine strain Riems. Structural modeling revealed that, the three epitopes are located near each other, suggesting that they may form a more complex conformational epitope on the D/A domain in vivo. Six of the mAbs neutralized viruses of diverse genotypes, indicating that the target epitopes are involved in virus interaction with cells. The binding of CSFV to cells was significantly reduced after pre-incubation with either truncated E2 proteins comprising the D/A domain or with the CSFV-specific mAbs targeting the domain D/A. These epitopes identified on the D/A domain are important targets for virus neutralization that might be involved in the early steps of CSFV infection. These findings reveal potential candidates for improving the differential diagnosis of pestiviruses by serology.

Construction and experimental validation of a macrophage cell senescence-related gene signature to evaluate the prognosis, immunotherapeutic sensitivity, and chemotherapy response in bladder cancer.

Tumor-associated macrophages (TAMs) are pivotal components of tumor microenvironment (TME), and senescent TAMs contribute to the alternation of the profiles of TME. However, the potential biological mechanisms and the prognosis value of senescent macrophages are largely unknown, especially in bladder cancer (BLCA). Based on the single-cell RNA sequencing of a primary BLCA sample, 23 macrophage-related genes were identified. Genomic difference analysis, LASSO, and Cox regression were used to develop the risk model. TCGA-BLCA cohort (n = 406) was utilized as the training cohort, and then, three independent cohorts (n = 90, n = 221, n = 165) from Gene Expression Omnibus, clinical samples from the local hospital (n = 27), and in vitro cell experiments were used for external validation. Aldo-keto reductase family 1 member B (AKR1B1), inhibitor of DNA binding 1 (ID1), and transforming growth factor beta 1 (TGFB1I1) were determined and included in the predictive model. The model serves as a promising tool to evaluate the prognosis in BLCA (pooled hazard ratio = 2.51, 95% confidence interval = [1.43; 4.39]). The model was also effective for the prediction of immunotherapeutic sensitivity and chemotherapy treatment outcomes, which were further confirmed by IMvigor210 cohort (P < 0.01) and GDSC dataset, respectively. Twenty-seven BLCA samples from the local hospital proved that the risk model was associated with the malignant degree (P < 0.05). At last, the human macrophage THP-1 and U937 cells were treated with H2O2 to mimic the senescent process in macrophage, and the expressions of these molecules in the model were detected (all P < 0.05).Overall, a macrophage cell senescence-related gene signature was constructed to predict the prognosis, immunotherapeutic response, and chemotherapy sensitivity in BLCA, which provides novel insights to uncover the underlying mechanisms of macrophage senescence.

Online study of the plasma-accelerated aging process and toxicity of polyethylene terephthalate.

Plastic aging occurs in all environmental media and affects their environmental behavior and toxicity. In this study, non-thermal plasma was applied to simulate the aging process of plastics, with polyethylene terephthalate (PET-film) being used as a model. The surface morphology, mass defects, toxicity of aged PET-film and the generation of airborne fine particles were comprehensively characterized. The surface of PET films began to become rough and then gradually became uneven, generating pores, protrusions and cracks. The toxicity of aged PET films was assessed in Caenorhabditis elegans which significantly reduced head thrashing, body bending and brood size. A single particle aerosol mass spectrometry instrument was used to characterize the size distribution and chemical composition of airborne fine particles in real-time. Few particles were observed during the first 90 min, while the generation of particles accelerated significantly after aging time beyond 90 min. For two pieces of PET film with surface area of 5 cm2, during the 180 min, at least 15113 ± 153 fine particles were generated, having a unimodal size distribution with a peak of 0.4 µm. The main components of these particles included metals, inorganic non-metals, and organic components. The results provide useful information on plastic aging and are beneficial in assessing the potential environmental risks.

Cross-reactivities and cross-neutralization of different envelope glycoproteins E2 antibodies against different genotypes of classical swine fever virus.

Classical swine fever (CSF) is a highly contagious swine disease caused by the classical swine fever virus (CSFV), wreaking havoc on global swine production. The virus is divided into three genotypes, each comprising 4-7 sub-genotypes. The major envelope glycoprotein E2 of CSFV plays an essential role in cell attachment, eliciting immune responses, and vaccine development. In this study, to study the cross-reaction and cross-neutralizing activities of antibodies against different genotypes (G) of E2 glycoproteins, ectodomains of G1.1, G2.1, G2.1d, and G3.4 CSFV E2 glycoproteins from a mammalian cell expression system were generated. The cross-reactivities of a panel of immunofluorescence assay-characterized serum derived from pigs with/without a commercial live attenuated G1.1 vaccination against different genotypes of E2 glycoproteins were detected by ELISA. Our result showed that serum against the LPCV cross-reacted with all genotypes of E2 glycoproteins. To evaluate cross-neutralizing activities, hyperimmune serum from different CSFV E2 glycoprotein-immunized mice was also generated. The result showed that mice anti-E2 hyperimmune serum exhibited better neutralizing abilities against homologous CSFV than heterogeneous viruses. In conclusion, the results provide information on the cross-reactivity of antibodies against different genogroups of CSFV E2 glycoproteins and suggest the importance of developing multi-covalent subunit vaccines for the complete protection of CSF.

Comprehensive prognostic modeling of locoregional recurrence after radiotherapy for patients with locoregionally advanced hypopharyngeal squamous cell carcinoma.

Purpose: To propose and evaluate a comprehensive modeling approach combing radiomics, dosiomics and clinical components, for more accurate prediction of locoregional recurrence risk after radiotherapy for patients with locoregionally advanced HPSCC. Materials and methods: Clinical data of 77 HPSCC patients were retrospectively investigated, whose median follow-up duration was 23.27 (4.83-81.40) months. From the planning CT and dose distribution, 1321 radiomics and dosiomics features were extracted respectively from planning gross tumor volume (PGTV) region each patient. After stability test, feature dimension was further reduced by Principal Component Analysis (PCA), yielding Radiomic and Dosiomic Principal Components (RPCs and DPCs) respectively. Multiple Cox regression models were constructed using various combinations of RPC, DPC and clinical variables as the predictors. Akaike information criterion (AIC) and C-index were used to evaluate the performance of Cox regression models. Results: PCA was performed on 338 radiomic and 873 dosiomic features that were tested as stable (ICC1 > 0.7 and ICC2 > 0.95), yielding 5 RPCs and DPCs respectively. Three comprehensive features (RPC0, P<0.01, DPC0, P<0.01 and DPC3, P<0.05) were found to be significant in the individual Radiomic or Dosiomic Cox regression models. The model combining the above features and clinical variable (total stage IVB) provided best risk stratification of locoregional recurrence (C-index, 0.815; 95%CI, 0.770-0.859) and prevailing balance between predictive accuracy and complexity (AIC, 143.65) than any other investigated models using either single factors or two combined components. Conclusion: This study provided quantitative tools and additional evidence for the personalized treatment selection and protocol optimization for HPSCC, a relatively rare cancer. By combining complementary information from radiomics, dosiomics, and clinical variables, the proposed comprehensive model provided more accurate prediction of locoregional recurrence risk after radiotherapy.

Transmission of Classical Swine Fever Virus in Cohabitating Piglets with Various Immune Statuses Following Attenuated Live Vaccine.

Classical swine fever (CSF) is a systemic hemorrhagic disease affecting domestic pigs and wild boars. The modified live vaccine (MLV) induces quick and solid protection against CSF virus (CSFV) infection. Maternally derived antibodies (MDAs) via colostrum could interfere with the MLV's efficacy, leading to incomplete protection against CSFV infection for pigs. This study investigated CSFV transmission among experimental piglets with various post-MLV immune statuses. Nineteen piglets, 18 with MDAs and 1 specific-pathogen-free piglet infected with CSFV that served as the CSFV donor, were cohabited with piglets that had or had not been administered the MLV. Five-sixths of the piglets with MDAs that had been administered one dose of MLV were fully protected from contact transmission from the CSFV donor and did not transmit CSFV to the piglets secondarily exposed through cohabitation. Cell-mediated immunity, represented by the anti-CSFV-specific interferon-γ-secreting cells, was key to viral clearance and recovery. After cohabitation with a CSFV donor, the unvaccinated piglets with low MDA levels exhibited CSFV infection and spread CSFV to other piglets through contact; those with high MDA levels recovered but acted as asymptomatic carriers. In conclusion, MLV still induces solid immunity in commercial herds under MDA interference and blocks CSFV transmission within these herds.

OpenKBP-Opt: an international and reproducible evaluation of 76 knowledge-based planning pipelines.

Objective.To establish an open framework for developing plan optimization models for knowledge-based planning (KBP).Approach.Our framework includes radiotherapy treatment data (i.e. reference plans) for 100 patients with head-and-neck cancer who were treated with intensity-modulated radiotherapy. That data also includes high-quality dose predictions from 19 KBP models that were developed by different research groups using out-of-sample data during the OpenKBP Grand Challenge. The dose predictions were input to four fluence-based dose mimicking models to form 76 unique KBP pipelines that generated 7600 plans (76 pipelines × 100 patients). The predictions and KBP-generated plans were compared to the reference plans via: the dose score, which is the average mean absolute voxel-by-voxel difference in dose; the deviation in dose-volume histogram (DVH) points; and the frequency of clinical planning criteria satisfaction. We also performed a theoretical investigation to justify our dose mimicking models.Main results.The range in rank order correlation of the dose score between predictions and their KBP pipelines was 0.50-0.62, which indicates that the quality of the predictions was generally positively correlated with the quality of the plans. Additionally, compared to the input predictions, the KBP-generated plans performed significantly better (P< 0.05; one-sided Wilcoxon test) on 18 of 23 DVH points. Similarly, each optimization model generated plans that satisfied a higher percentage of criteria than the reference plans, which satisfied 3.5% more criteria than the set of all dose predictions. Lastly, our theoretical investigation demonstrated that the dose mimicking models generated plans that are also optimal for an inverse planning model.Significance.This was the largest international effort to date for evaluating the combination of KBP prediction and optimization models. We found that the best performing models significantly outperformed the reference dose and dose predictions. In the interest of reproducibility, our data and code is freely available.