Managing ecosystem services in oleaginous forests for bioenergy provision and climate change mitigation.

Oleaginous forests provide diverse ecosystem services, including timber, seed yield (a vital feedstock for biodiesel production), and substantial carbon savings. These carbon savings encompass carbon sequestration related to timber growth and carbon savings resulting from substituting fossil fuel with biodiesel. However, oleaginous forests are vulnerable to seed wasp attacks (disservice), which significantly threaten both seed yield and carbon savings. Using an integrated ecological-economic model that includes Faustmann's Land Expectation Value model and a pest damage control model, we aim to understand the intricate relationship among multiple ecosystem services and disservices of oleaginous forests. The results reveal four distinct phases contingent on varying pesticide application rates: the pesticide under-use phase, substitution phase, complementary phase, and over-use phase. Notably, a potential avenue to minimize pest damage is identified during the complementary phase by reducing the optimal rotation age at the expense of decreased carbon sequestration and bioenergy provision, posing a challenge to climate change mitigation. These findings have implications for formulating policies to manage conflicting ecosystem services of energy forests, offering valuable insights into the intersection of sustainable forest management and climate policy.

Analysis of Hemorrhagic Shock Following Percutaneous Nephrolithotomy Resulting from Diaphragm Injury: A Case Report.

BACKGROUND: Percutaneous nephrolithotomy (PCNL) is the first treatment for complex renal and/or ureteral calculi. This paper presents a case of hemorrhagic shock resulting from diaphragm injury due to PCNL, which has not been reported so far. CASE PRESENTATION: A 55-year-old Asian woman presented with a 2 × 2 cm calculus located in the upper calyx of the right kidney. After her uncomplicated PCNL operation, the patient's blood pressure decreased to less than 90/60 mmHg, and her hemoglobin level dropped from 128 g/L to 76 g/L. Physical examination and bedside ultrasound indicated a small amount of pleural effusion. Subsequently, a diagnostic puncture of the chest cavity was performed and revealed the presence of fresh blood. Therefore, thoracic closed drainage was conducted, and 950 mL of fresh blood was drained through a drainage tube. Intraoperatively, observation showed that the nephrostomy tube had penetrated the kidney through the diaphragm. The nephrostomy tube was subsequently removed, and the diaphragm was repaired. CONCLUSIONS: Hemorrhagic shock due to diaphragm injury is an unusual complication after PCNL. This complication should be considered if pleural effusion is present and if blood pressure progressively drops with no other obvious explanation. The recommended treatments include diagnostic thoracentesis and thoracic exploration.

Mouse KL2 is a unique MTSE involved in chromosome-based spindle organization and regulated by multiple kinases during female meiosis.

Microtubule-severing enzymes (MTSEs) play important roles in mitosis and meiosis of the primitive organisms. However, no studies have assessed their roles in mammalian meiosis of females, whose abnormality accounts for over 80% of the cases of gamete-originated human reproductive disease. In the current study, we reported that katanin-like 2 (KL2) was the only MTSE concentrating at chromosomes. Furthermore, the knockdown of KL2 significantly reduced chromosome-based increase in the microtubule (MT) polymer, increased aberrant kinetochore-MT (K-MT) attachment, delayed meiosis, and severely affected normal fertility. Importantly, we demonstrated that the inhibition of aurora B, a key kinase for correcting aberrant K-MT attachment, eliminated KL2 from chromosomes completely. KL2 also interacted with phosphorylated eukaryotic elongation factor-2 kinase; they competed for chromosome binding. We also observed that the phosphorylated KL2 was localized at spindle poles, and that KL2 phosphorylation was regulated by extracellular signal-regulated kinase 1/2. In summary, our study reveals a novel function of MTSEs in mammalian female meiosis and demonstrates that multiple kinases coordinate to regulate the levels of KL2 at chromosomes.

Extracellular volume-based scoring system for tracking tumor progression in pancreatic cancer patients receiving intraoperative radiotherapy.

OBJECTIVES: To investigate the value of extracellular volume (ECV) derived from portal-venous phase (PVP) in predicting prognosis in locally advanced pancreatic cancer (LAPC) patients receiving intraoperative radiotherapy (IORT) with initial stable disease (SD) and to construct a risk-scoring system based on ECV and clinical-radiological features. MATERIALS AND METHODS: One hundred and three patients with LAPC who received IORT demonstrating SD were enrolled and underwent multiphasic contrast-enhanced CT (CECT) before and after IORT. ECV maps were generated from unenhanced and PVP CT images. Clinical and CT imaging features were analyzed. The independent predictors of progression-free survival (PFS) determined by multivariate Cox regression model were used to construct the risk-scoring system. Time-dependent receiver operating characteristic (ROC) curve analysis and the Kaplan-Meier method were used to evaluate the predictive performance of the scoring system. RESULTS: Multivariable analysis revealed that ECV, rim-enhancement, peripancreatic fat infiltration, and carbohydrate antigen 19-9 (CA19-9) response were significant predictors of PFS (all p < 0.05). Time-dependent ROC of the risk-scoring system showed a satisfactory predictive performance for disease progression with area under the curve (AUC) all above 0.70. High-risk patients (risk score ≥ 2) progress significantly faster than low-risk patients (risk score < 2) (p < 0.001). CONCLUSION: ECV derived from PVP of conventional CECT was an independent predictor for progression in LAPC patients assessed as SD after IORT. The scoring system integrating ECV, radiological features, and CA19-9 response can be used as a practical tool for stratifying prognosis in these patients, assisting clinicians in developing an appropriate treatment approach. CRITICAL RELEVANCE STATEMENT: The scoring system integrating ECV fraction, radiological features, and CA19-9 response can track tumor progression in patients with LAPC receiving IORT, aiding clinicians in choosing individual treatment strategies and improving their prognosis. KEY POINTS: Predicting the progression of LAPC in patients receiving IORT is important. Our ECV-based scoring system can risk stratifying patients with initial SD. Appropriate prognostication can assist clinicians in developing appropriate treatment approaches.

A ZBP1 isoform blocks ZBP1-mediated cell death.

ZBP1 is an interferon (IFN)-induced nucleic acid (NA) sensor that senses unusual Z-form NA (Z-NA) to promote cell death and inflammation. However, the mechanisms that dampen ZBP1 activation to fine-tune inflammatory responses are unclear. Here, we characterize a short isoform of ZBP1 (referred to as ZBP1-S) as an intrinsic suppressor of the inflammatory signaling mediated by full-length ZBP1. Mechanistically, ZBP1-S depresses ZBP1-mediated cell death by competitive binding with Z-NA for Zα domains of ZBP1. Cells from mice (Ripk1D325A/D325A) with cleavage-resistant RIPK1-induced autoinflammatory (CRIA) syndrome are alive but sensitive to IFN-induced and ZBP1-dependent cell death. Intriguingly, Ripk1D325A/D325A cells die spontaneously when ZBP1-S is deleted, indicating that cell death driven by ZBP1 is under the control of ZBP1-S. Thus, our findings reveal that alternative splicing of Zbp1 represents autogenic inhibition for regulating ZBP1 signaling and indicate that uncoupling of Z-NA with ZBP1 could be an effective strategy against autoinflammations.

Prognostic performance of MRI LI-RADS version 2018 features and clinical-pathological factors in alpha-fetoprotein-negative hepatocellular carcinoma.

PURPOSE: To evaluate the role of the magnetic resonance imaging (MRI) Liver Imaging Reporting and Data System (LI-RADS) version 2018 features and clinical-pathological factors for predicting the prognosis of alpha-fetoprotein (AFP)-negative (≤ 20 ng/ml) hepatocellular carcinoma (HCC) patients, and to compare with other traditional staging systems. METHODS: We retrospectively enrolled 169 patients with AFP-negative HCC who received preoperative MRI and hepatectomy between January 2015 and August 2020 (derivation dataset:validation dataset = 118:51). A prognostic model was constructed using the risk factors identified via Cox regression analysis. Predictive performance and discrimination capability were evaluated and compared with those of two traditional staging systems. RESULTS: Six risk factors, namely the LI-RADS category, blood products in mass, microvascular invasion, tumor size, cirrhosis, and albumin-bilirubin grade, were associated with recurrence-free survival. The prognostic model constructed using these factors achieved C-index of 0.705 and 0.674 in the derivation and validation datasets, respectively. Furthermore, the model performed better in predicting patient prognosis than traditional staging systems. The model effectively stratified patients with AFP-negative HCC into high- and low-risk groups with significantly different outcomes (p < 0.05). CONCLUSION: A prognostic model integrating the LI-RADS category, blood products in mass, microvascular invasion, tumor size, cirrhosis, and albumin-bilirubin grade may serve as a valuable tool for refining risk stratification in patients with AFP-negative HCC.

Islet-resident macrophage-derived miR-155 promotes ß cell decompensation via targeting PDX1.

Chronic inflammation is critical for the initiation and progression of type 2 diabetes mellitus via causing both insulin resistance and pancreatic ß cell dysfunction. miR-155, highly expressed in macrophages, is a master regulator of chronic inflammation. Here we show that blocking a macrophage-derived exosomal miR-155 (MDE-miR-155) mitigates the insulin resistances and glucose intolerances in high-fat-diet (HFD) feeding and type-2 diabetic db/db mice. Lentivirus-based miR-155 sponge decreases the level of miR-155 in the pancreas and improves glucose-stimulated insulin secretion (GSIS) ability of ß cells, thus leading to improvements of insulin sensitivities in the liver and adipose tissues. Mechanistically, miR-155 increases its expression in HFD and db/db islets and is released as exosomes by islet-resident macrophages under metabolic stressed conditions. MDE-miR-155 enters ß cells and causes defects in GSIS function and insulin biosynthesis via the miR-155-PDX1 axis. Our findings offer a treatment strategy for inflammation-associated diabetes via targeting miR-155.

Spin-orbital Jahn-Teller bipolarons.

Polarons and spin-orbit (SO) coupling are distinct quantum effects that play a critical role in charge transport and spin-orbitronics. Polarons originate from strong electron-phonon interaction and are ubiquitous in polarizable materials featuring electron localization, in particular 3d transition metal oxides (TMOs). On the other hand, the relativistic coupling between the spin and orbital angular momentum is notable in lattices with heavy atoms and develops in 5d TMOs, where electrons are spatially delocalized. Here we combine ab initio calculations and magnetic measurements to show that these two seemingly mutually exclusive interactions are entangled in the electron-doped SO-coupled Mott insulator Ba2Na1-xCaxOsO6 (0 < x < 1), unveiling the formation of spin-orbital bipolarons. Polaron charge trapping, favoured by the Jahn-Teller lattice activity, converts the Os 5d1 spin-orbital Jeff = 3/2 levels, characteristic of the parent compound Ba2NaOsO6 (BNOO), into a bipolaron 5d2 Jeff = 2 manifold, leading to the coexistence of different J-effective states in a single-phase material. The gradual increase of bipolarons with increasing doping creates robust in-gap states that prevents the transition to a metal phase even at ultrahigh doping, thus preserving the Mott gap across the entire doping range from d1 BNOO to d2 Ba2CaOsO6 (BCOO).

Preserved Ratio Impaired Spirometry (PRISm): A Global Epidemiological Overview, Radiographic Characteristics, Comorbid Associations, and Differentiation from Chronic Obstructive Pulmonary Disease.

Preserved Ratio Impaired Spirometry (PRISm) manifests notable epidemiological disparities across the globe, with its prevalence and influential factors showcasing pronounced diversities among various geographical territories and demographics. The prevalence of PRISm fluctuates considerably among regions such as Latin America, the United States, and Asian nations, potentially correlating with a myriad of determinants, including socioeconomic status, environmental factors, and lifestyle modalities. Concurrently, the link between PRISm and health risks and other disorders, especially its distinction and interrelation with chronic obstructive pulmonary disease (COPD), has become a pivotal subject of scientific enquiry. Radiographic anomalies, such as perturbations in the pulmonary parenchyma and structural alterations, are posited as salient characteristics of PRISm. Furthermore, PRISm unveils intricate associations with multiple comorbidities, inclusive of hypertension and type 2 diabetes, thereby amplifying the intricacy in comprehending and managing this condition. In this review, we aim to holistically elucidate the epidemiological peculiarities of PRISm, its potential aetiological contributors, its nexus with COPD, and its association with radiographic aberrations and other comorbidities. An integrative understanding of these dimensions will provide pivotal insights for the formulation of more precise and personalised preventative and therapeutic strategies.

The Value of LI-RADS and Radiomic Features from MRI for Predicting Microvascular Invasion in Hepatocellular Carcinoma within 5 cm.

RATIONALE AND OBJECTIVES: To explore and compare the performance of LI-RADS® and radiomics from multiparametric MRI in predicting microvascular invasion (MVI) preoperatively in patients with solitary hepatocellular carcinoma (HCC)< 5 cm. METHODS: We enrolled 143 patients with pathologically proven HCC and randomly stratified them into training (n = 100) and internal validation (n = 43) cohorts. Besides, 53 patients were enrolled to constitute an independent test cohort. Clinical factors and imaging features, including LI-RADS and three other features (non-smooth margin, incomplete capsule, and two-trait predictor of venous invasion), were reviewed and analyzed. Radiomic features from four MRI sequences were extracted. The independent clinic-imaging (clinical) and radiomics model for MVI-prediction were constructed by logistic regression and AdaBoost respectively. And the clinic-radiomics combined model was further constructed by logistic regression. We assessed the model discrimination, calibration, and clinical usefulness by using the area under the receiver operating characteristic curve (AUC), calibration curve, and decision-curve analysis respectively. RESULTS: Incomplete tumor capsule, corona enhancement, and radiomic features were related to MVI in solitary HCC＜5 cm. The clinical model achieved AUC of 0.694/0.661 (training/internal validation). The single-sequence-based radiomic model's AUCs were 0.753-0.843/0.698-0.767 (training/internal validation). The combination model exhibited superior diagnostic performance to the clinical model (AUC: 0.895/0.848 [training/ internal validation]) and yielded an AUC of 0.858 in an independent test cohort. CONCLUSION: Incomplete tumor capsule and corona enhancement on preoperative MRI were significantly related to MVI in solitary HCC＜5 cm. Multiple-sequence radiomic features potentially improve MVI-prediction-model performance, which could potentially help determining HCC's appropriate therapy.

What happens to the osteoporotic bone mesenchymal stem cells? Evidence from RNA sequencing.

Evidence presented that osteoporosis is closely related to the dysfunction of bone mesenchymal stem cells (BMSCs). But most studies are insufficient to reveal what actually happens to the osteoporotic BMSCs. In this study, BMSCs were harvested from ovariectomized and sham-operated rats. After checking the characteristics of rat models and stem cells, the BMSCs were carried out for RNA sequencing. Part of the findings were verified that seven mRNAs (Abi3bp, Aifm3, Ccl11, Cdkn1c, Chst10, Id2, Vcam1) were significantly up-regulated in osteoporotic BMSCs while seven mRNAs (Cep63, Fgfr3, Myc, Omd, Pou2f1, Smarcal1, Timm10b) were down-regulated. In addition, potential miRNA-mRNA and lncRNA-mRNA regulatory networks were illustrated. The changes in osteoporotic BMSCs covered a large set of biological processes, including cell viability, differentiation, immunoreaction, bone repairment and estrogen defect. This study enriched the pathophysiological mechanisms of BMSCs and osteporosis, as well as provided dozens of attractive RNA targets for further treatment.

Zinc oxide nanoparticles-induced testis damage at single-cell resolution: Depletion of spermatogonia reservoir and disorder of Sertoli cell homeostasis.

The widespread application of zinc oxide nanoparticles (ZnO NPs) in our daily life has initiated an enhanced awareness of their biosafety concern. An incredible boom of evidence of organismal disorder has accumulated for ZnO NPs, yet there has been no relevant study at the single-cell level. Here, we profiled > 28,000 single-cell transcriptomes and assayed > 25,000 genes in testicular tissues from two healthy Sprague Dawley (SD) rats and two SD rats orally exposed to ZnO NPs. We identified 10 cell types in the rat testis. ZnO NPs had more deleterious effects on spermatogonia, Sertoli cells, and macrophages than on the other cell types. Cell-cell communication analysis indicated a sharp decrease of interaction intensity for all cell types except macrophages in the ZnO NPs group than in the control group. Interestingly, two distinct maturation states of spermatogonia were detected during pseudotime analysis, and ZnO NPs induced reservoir exhaustion of undifferentiated spermatogonia. Mechanically, ZnO NPs triggered fatty acid accumulation in GC-1 cells through protein kinase B (Akt)/mammalian target of rapamycin (mTOR) signaling and peroxisome proliferator-activated receptor alpha (PPARα)/acyl-CoA oxidase 1 (Acox1) axis, contributing to cell apoptosis. In terms of Sertoli cells, downregulated genes were highly enriched for tight junction. In vitro and in vivo experiments verified that ZnO NPs disrupted blood-testis barrier formation and growth factors synthesis, which subsequently inhibited the proliferation and induced the apoptosis of spermatogonia. As for the macrophages, ZnO NPs activated oxidative stress of Raw264.7 cells through nuclear factor erythroid 2-related factor 2 (Nrf2)/heme oxygenase-1 (HO-1) pathway and promoted cell apoptosis through extracellular signal-regulated kinase (ERK) 1/2 pathway. Collectively, our work reveals the cell type-specific and cellularly heterogenetic mechanism of ZnO NPs-induced testis damage and paves the path for identifying putative biomarkers and therapeutics against this disorder.

Development and validation of a prognostic nomogram model incorporating routine laboratory biomarkers for preoperative patients with endometrial cancer.

BACKGROUND: Some biomarkers collected from routine laboratory tests have shown important value in cancer prognosis. The study aimed to evaluate the prognostic significance of routine laboratory biomarkers in patients with endometrial cancer (EC) and to develop credible prognostic nomogram models for clinical application. METHODS: A total of 727 patients were randomly divided into a training set and a validation set. Cox proportional hazards models were used to evaluate each biomarker's prognostic value, and independent prognostic factors were used to generate overall survival (OS) and progression-free survival (PFS) nomgrams. The efficacy of the nomograms were evaluated by Harrell's concordance index (C-index), receiver operating characteristic (ROC) curves, decision curve analysis (DCA), calibration curves, X-tile analysis and Kaplan‒Meier curves. RESULTS: Ten significant biomarkers in multivariate Cox analysis were integrated to develop OS and PFS nomograms. The C-indices of the OS- nomogram in the training and validation sets were 0.885 (95% confidence interval (CI), 0.810-0.960) and 0.850 (95% CI, 0.761-0.939), respectively; those of the PFS- nomogram in the training and validation sets were 0.903 (95% CI, 0.866-0.940) and 0.825 (95% CI, 0.711-0.939), respectively. ROC, DCA and calibration curves showed better clinical application value for the nomograms incorporating routine laboratory biomarkers. X-tile analysis and Kaplan‒Meier curves showed that the nomograms were stable and credible in evaluating patients at different risks. CONCLUSIONS: Nomogram models incorporating routine laboratory biomarkers, including NLR, MLR, fibrinogen, albumin and AB blood type, were demonstrated to be simple, reliable and favourable in predicting the outcomes of patients with EC.

The Prevalence and Characteristics of Circulating IgA Anti-Glomerular Basement Membrane Autoantibodies in Anti-Glomerular Basement Membrane Disease.

Introduction: In some cases, immunoglobulin (IgA)-mediated antiglomerular basement membrane (anti-GBM) disease has been reported. Whether circulating IgA anti-GBM antibodies affect the clinico-pathologic characteristics and outcome of typical anti-GBM disease deserves further study. Methods: Circulating IgA anti-α3(IV)NC1 antibodies were examined by enzyme-linked immunosorbent assay (ELISA) using recombinant human α3(IV)NC1 as solid phase antigens in 107 patients with anti-GBM disease and 115 controls. Clinical, pathological, and follow-up data of patients were retrospectively analyzed. Results: Circulating IgA anti-α3(IV)NC1 antibodies were found in 18.7% (20/107) of patients with anti-GBM disease but were not detected in healthy controls or in patients with other glomerular diseases. The positivity of circulating IgA anti-α3(IV)NC1 antibodies was not associated with whether the patient was with combined IgA nephropathy or other glomerulonephritis. Kidney immunofluorescence showed no statistical difference in IgA deposition between patients with circulating IgA anti-α3(IV)NC1 antibodies and patients without (30.0% vs. 40.4%, P = 0.725). The titers of circulating immunoglobulin G (IgG) anti-α3(IV)NC1 antibodies in patients with circulating IgA anti-α3(IV)NC1 antibodies were significantly higher than those without (200 [183.3, 200] vs. 161 [85.5, 200] U/ml, P = 0.005). There were no significant differences in kidney outcome and mortality between the 2 groups. Conclusion: Circulating IgA anti-α3(IV)NC1 antibodies occurred in 18.7% (20/107) of patients with anti-GBM in our center and were specific to anti-GBM disease. Patients with circulating IgA anti-α3(IV)NC1 antibodies showed a higher levels of serum IgG anti-α3(IV)NC1 antibodies than those without.

Microvascular invasion-negative hepatocellular carcinoma: Prognostic value of qualitative and quantitative Gd-EOB-DTPA MRI analysis.

OBJECTIVES: The purpose of this study was to establish a model for predicting the prognosis of patients with microvascular invasion (MVI)-negative hepatocellular carcinoma (HCC) based on qualitative and quantitative analyses of Gd-EOB-DTPA magnetic resonance imaging (MRI). MATERIALS AND METHODS: Consecutive patients with MVI-negative HCC who underwent preoperative Gd-EOB-DTPA MRI between January 2015 and December 2019 were retrospectively enrolled.In total, 122 patients were randomly assigned to the training and validation groups at a ratio of 7:3. Univariate and multivariate logistic regression analyses were performed to identify significant clinical parameters and MRI features, including quantitative and qualitative parameters associated with prognosis, which were incorporated into a predictive nomogram. The end-point of this study was recurrence-free survival. Outcomes were compared between groups using the Kaplan-Meier method with the log-rank test. RESULTS: During a median follow-up period of 58.86 months, 38 patients (31.15 %) experienced recurrence. Multivariate analysis revealed that lower relative enhancement ratio (RER), hepatobiliary phase hypointensity without arterial phase hyperenhancement, Liver Imaging Reporting and Data System category, mild-moderate T2 hyperintensity, and higher aspartate aminotransferase levels were risk factors associated with prognosis and then incorporated into the prognostic model. C-indices for training and validation groups were 0.732 and 0.692, respectively. The most appropriate cut-off value for RER was 1.197. Patients with RER ≤ 1.197 had significantly higher postoperative recurrence rates than those with RER > 1.197 (p = 0.004). CONCLUSION: The model integrating qualitative and quantitative imaging parameters and clinical parameters satisfactorily predicted the prognosis of patients with MVI-negative HCC.

Clinical and immunological characteristics of patients with combined anti-glomerular basement membrane disease and IgA nephropathy.

Background: The combination of anti-glomerular basement membrane (GBM) disease and immunoglobulin A nephropathy (IgAN) has been well documented in sporadic cases, but lacks overall assessment in large collections. Herein, we investigated the clinical and immunological characteristics and outcome of this entity. Methods: Seventy-five consecutive patients with biopsy-proven anti-GBM disease from March 2012 to March 2020 were screened. Among them, patients with concurrent IgAN were identified and enrolled. The control group included biopsied classical anti-GBM patients during the same period, excluding patients with IgAN, other glomerular diseases or tumors, or patients with unavailable blood samples and missing data. Serum IgG and IgA autoantibodies against GBM were detected by enzyme-linked immunosorbent assay, as were circulating IgG subclasses against GBM. Results: Fifteen patients with combined anti-GBM disease and IgAN were identified, accounting for 20% (15/75) of all patients. Among them, nine were male and six were female, with an average (± standard deviation) age of 46.7 ± 17.3 years. Thirty patients with classical anti-GBM disease were enrolled as controls, with 10 males and 20 females at an average age of 45.4 ± 15.3 years. Patients with combined anti-GBM disease and IgAN had restricted kidney involvement without pulmonary hemorrhage. Compared with classical patients, anti-GBM patients with IgAN presented with significantly lower levels of serum creatinine on diagnosis (6.2 ± 2.9 vs 9.5 ± 5.4 mg/dL, P = .03) and less occurrence of oliguria/anuria (20%, 3/15 vs 57%, 17/30, P = .02), but more urine protein excretion [2.37 (1.48, 5.63) vs 1.11 (0.63, 3.90) g/24 h, P = .01]. They showed better kidney outcome during follow-up (ESKD: 47%, 7/15 vs 80%, 24/30, P = .03). The autoantigen and epitope spectrum were comparable between the two groups, but the prevalence of circulating anti-α3(IV)NC1 IgG1 (67% vs 97%, P = .01) and IgG3 (67% vs 97%, P = .01) were lower in patients with IgAN. Conclusions: Concurrent IgAN was not rare in anti-GBM disease. Patients showed milder kidney lesions and better recovery after immunosuppressive therapies. This might be partly explained by lower prevalence of anti-GBM IgG1 and IgG3 in these patients.

An ultrasensitive method for detecting mutations from short and rare cell-free DNA.

Circulating tumor DNA (ctDNA) was short and rare, making the detection performance of the current targeted sequencing methods unsatisfying. We developed the One-PrimER Amplification (OPERA) system and examined its performance in detecting mutations of low variant allelic frequency (VAF) in various samples with short-sized DNA fragments. In cell line-derived samples containing sonication-sheared DNA fragments with 50-150 bp, OPERA was capable of detecting mutations as low as 0.0025% VAF, while CAPP-Seq only detected mutations of >0.03% VAF. Both single nucleotide variant and insertion/deletion can be detected by OPERA. In synthetic fragments as short as 80 bp with low VAF (0.03%-0.1%), the detection sensitivity of OPERA was significantly higher compared to that of droplet digital polymerase chain reaction. The error rate was 5.9×10-5 errors per base after de-duplication in plasma samples collected from healthy volunteers. By suppressing "single-strand errors", the error rate can be further lowered by >5 folds in EGFR T790M hotspot. In plasma samples collected from lung cancer patients, OPERA detected mutations in 57.1% stage I patients with 100% specificity and achieved a sensitivity of 30.0% in patients with tumor volume of less than 1 cm3. OPERA can effectively detect mutations in rare and highly-fragmented DNA.

Autoantibodies against laminin-521 are pathogenic in anti-glomerular basement membrane disease.

Anti-glomerular basement membrane (anti-GBM) disease is an organ-specific autoimmune disorder characterized by autoantibodies against GBM components. Evidence from human inherited kidney diseases and animal models suggests that the α, ß, and γ chains of laminin-521 are all essential for maintaining the glomerular filtration barrier. We previously demonstrated that laminin-521 is a novel autoantigen within the GBM and that autoantibodies to laminin-521 are present in about one-third of patients. In the present study, we investigated the pathogenicity of autoantibodies against laminin-521 with clinical and animal studies. Herein, a rare case of anti-GBM disease was reported with circulating autoantibodies binding to laminin-521 but not to the NC1 domains of α1-α5(IV) collagen. Immunoblot identified circulating IgG from this patient bound laminin α5 and γ1 chains. A decrease in antibody levels was associated with improved clinical presentation after plasmapheresis and immunosuppressive treatments. Furthermore, immunization with laminin-521 in female Wistar-Kyoto rats induced crescentic glomerulonephritis with linear IgG deposits along the GBM, complement activation along with infiltration of T cells and macrophages. Lung hemorrhage occurred in 75.0% of the rats and was identified by the presence of erythrocyte infiltrates and hemosiderin-laden macrophages in the lung tissue. Sera and kidney-eluted antibodies from rats immunized with laminin-521 demonstrated specific IgG binding to laminin-521 but not to human α3(IV)NC1, while the opposite was observed in human α3(IV)NC1-immunized rats. Thus, our patient data and animal studies imply a possible independent pathogenic role of autoantibodies against laminin-521 in the development of anti-GBM disease.

Determination of prognostic predictors in patients with solitary hepatocellular carcinoma: histogram analysis of multiparametric MRI.

PURPOSE: To evaluate the histogram parameters of preoperative multiparametric magnetic resonance imaging (MRI) and clinical-radiological (CR) characteristics as prognostic predictors in patients with solitary hepatocellular carcinoma ≤ 5 cm and to determine the optimal time window for histogram analysis. METHODS: We retrospectively included 151 patients who underwent preoperative MRI between January 2012 and December 2017. All patients were randomly separated into training and validation cohorts (n = 105 and 46). Eight whole-lesion histogram parameters were extracted from T2-weighted images, apparent diffusion coefficient maps, and dynamic contrast-enhanced images. Univariate and multivariate logistic regression analyses were performed to evaluate these histogram parameters and CR variables related to early recurrence (ER) and recurrence-free survival. A nomogram was derived from the clinical-radiological-histogram (CRH) model that incorporated these risk factors. Kaplan-Meier survival analysis was performed to evaluate the prognostic performance of the CRH model. RESULTS: In total, 151 patients (male: female, 130: 21; median age, 54.46 ± 9.09 years) were evaluated. Multivariate logistic regression analysis revealed that the significant risk factors of ER were Mean Absolute Deviation and Minimum in the histogram analysis of the delayed phase images, as well as three important CR variables: albumin-bilirubin grade, microvascular invasion, and tumor size. The nomogram built by incorporating these risk factors showed satisfactory predictive ability in the training and validation cohorts with AUC values of 0.747 and 0.765, respectively. Furthermore, the prognostic nomogram can effectively classify patients into high- and low-risk groups (p < 0.05). CONCLUSION: Multiparametric MRI-derived histogram parameters provide additional value in predicting patient prognosis. The CRH model may be a useful and noninvasive method for achieving prognostic stratification and personalized disease management.

Combined CT and serum CA19-9 for stratifying risk for progression in patients with locally advanced pancreatic cancer receiving intraoperative radiotherapy.

Background and purpose: The aim of this study was to evaluate the significance of baseline computed tomography (CT) imaging features and carbohydrate antigen 19-9 (CA19-9) in predicting prognosis of locally advanced pancreatic cancer (LAPC) receiving intraoperative radiotherapy (IORT) and to establish a progression risk nomogram that helps to identify the potential beneficiary of IORT. Methods: A total of 88 LAPC patients with IORT as their initial treatment were enrolled retrospectively. Clinical data and CT imaging features were analyzed. Cox regression analyses were performed to identify the independent risk factors for progression-free survival (PFS) and to establish a nomogram. A risk-score was calculated by the coefficients of the regression model to stratify the risk of progression. Results: Multivariate analyses revealed that relative enhanced value in portal-venous phase (REV-PVP), peripancreatic fat infiltration, necrosis, and CA19-9 were significantly associated with PFS (all p < 0.05). The nomogram was constructed according to the above variables and showed a good performance in predicting the risk of progression with a concordance index (C-index) of 0.779. Our nomogram stratified patients with LAPC into low- and high-risk groups with distinct differences in progression after IORT (p < 0.001). Conclusion: The integrated nomogram would help clinicians to identify appropriate patients who might benefit from IORT before treatment and to adapt an individualized treatment strategy.