Postoperative subphenotypes modified the hepatoma arterial-embolization prognostic score: A novel smHAP-II nomogram.

Background: Three subphenotypes were identified for unresectable hepatocellular carcinoma (uHCC) after frontline transarterial chemoembolization (TACE). This study aimed to develop an individual smHAP-Ⅱ nomogram for uHCC patients after TACE. Methods: Between January 2007 to December 2016, 1517 uHCC patients undergoing TACE were included from four hospitals in China (derivation cohort: 597 cases; validation cohort: 920 cases). Multivariable Cox proportion regression analysis was used to develop a nomogram, incorporating postoperative subphenotypes (Phenotype 1, 2, 3) and HAP score (Score 0 to 4). The model was validated by a 1000-time bootstrap resampling procedure. The performance of the model was compared with existing ones by Harrell's C-index and Area Under Curve (AUC). Results: Postoperative subphenotypes modified the HAP score (smHAP-Ⅱ nomogram) was developed and validated, with the Harrell's C-index of the nomogram was 0.679 (SD: 0.029) for the derivation cohort and 0.727(SD:0.029) for the external cohort. The area under curves of the nomogram for 1-, 3-, and 5-year OS were 0.750, 0.710, and 0.732 for the derivation cohort, respectively (0.789, 0.762, and 0.715 for the external cohort). In the calibration curves stratified by treatment after TACE, the lines for re-TACE and stop-TACE cross at 0.23, indicating that patients with a 3-year predicted survival >23% would not benefit from TACE. Conclusions: The addition of postoperative subphenotypes significantly improved the prognostic performance. The smHAP-Ⅱ nomogram can be used for accurate prognostication and selection of optimal candidates for TACE, with the value to guide sequential treatment strategy.

A Longitudinal Study of AFP Trajectories and Clinical Outcomes in Intermediate-Stage Hepatocellular Carcinoma After Hepatectomy.

Background: Previous studies have shown that the alpha-fetoprotein (AFP) response has been a key tumour marker in hepatocellular carcinoma (HCC), but its definition remains controversial. Recently, a new study has explored and defined the AFP serological response and used it to explain the subclass of intermediate-stage hepatocellular carcinoma (IM-HCC) with "sharp-falling" AFP change after transarterial chemoembolization (TACE). It may be a new and simple tool for assessing the prognosis of patients. This study aims to explore a simplified AFP trajectory and its impact on overall survival (OS) and disease-free survival (DFS) for IM-HCC after hepatectomy. Patients and Methods: Between January 2007 and May 2012, data from the Sun Yat-sen University Cancer Center was examined in this longitudinal, retrospective cohort study. A generalized additive model was applied to distinguish potential AFP dynamic trajectories. The Kaplan-Meier method was applied to analyze OS and DFS, and multivariate Cox models were used to calculate adjusted hazard ratios (aHRs) and 95% CIs for overall survival. Results: 144 patients who had IM-HCC with at least three AFP repeat measurements were included in the study. Three similar trajectories are displayed using the generalized additive model: low-stable (35.4%; n = 51), high-rising (36.1%; n = 52), and sharp-falling (28.5%; n = 41). Compared with the low-stable class, the aHRs for death were 2.84 (1.50, 5.41) and 0.59 (0.25, 1.40) for the high-rising and sharp-falling classes, adjusted by age and log AFP. Simplified AFP trajectory had higher relative importance than sex, intrahepatic tumor number, Child-Pugh class, and baseline AFP. Conclusion: The simplified AFP trajectory is a promising biomarker for IM-HCC patients undergoing hepatectomy. In the future, it should be verified by a larger population containing various stages of HCC.

Gamma Rhythm and Theta-gamma Coupling Alternation in Chronic Unpredictable Stress (CUS)-induced Depression Rats.

Depression is a debilitating disease, which, in severe cases, can lead to suicide. However, objective and reliable biomarker for the diagnosis of depression is lack. In this preclinical study, we recorded resting local field potentials (LFPs) from chronic unpredictable stress (CUS)-induced depressed (n =20) and control (n = 20) rats and then compared their gamma activities in terms of single-band and cross-frequency coupling patterns. Both theta-gamma coupling and relative power in total gamma band revealed significant abnormalities in gamma rhythm in the right auditory cortex of depressed rats. These findings implied that resting-state gamma rhythms may be a promising objective diagnostic biomarker for depression. Furthermore, our research provided direct evidence from the perspective of source signals in deep brain sites, which might be useful for clinical applications.Clinical Relevance- This research showed that resting gamma in the auditory cortex is a promising biomarker for depression diagnosis.

Targeting Aspergillus allergen oryzin with a chemical probe at atomic precision.

We report the molecular basis of Aspergillus fumigatus oryzin, allergen Asp f 13, or alkaline proteinase ALP1, containing the sequence motif His-Asp-Ser of the subtilisin family, structure, and function at atomic detail. Given the resolution of the data (1.06 Å), we use fragment molecular replacement with ideal polyalanine α-helices to determine the first crystal structure of oryzin. We probe the catalytic serine through formation of an irreversible bond to a small molecule compound, specifically labeling it, describing the amino acid residues performing the catalytic function. Defined by a self-processed pro-peptide, the active site architecture shapes up pocket-like subsites that bind to and unveil the S1'-S4' substrate binding preferences. We use molecular modeling to dock a model of the pro-peptide in the S1-S4 region and to dock collagen along the active site cleft. Opposite to the face harboring the catalytic serine, the enzyme binds to a calcium ion in a binding site created by backbone flipping. We use thermal unfolding to show that this metal ion provides structural stability. With no known host inhibitor identified thus far, this structure may hasten the progress of developing new therapeutic agents for diseases caused by pathogenic fungi.

In situ forming hydrogel loaded with predatory bacteria treats drug-resistant corneal infection.

The development of potent bactericidal antibiotic alternatives is important to address the current antibiotic crisis. A representative example is the topical delivery of predatory Bdellovibrio bacteriovorus bacteria to treat ocular bacterial infection. However, the direct topical use of B. bacteriovorus suspensions has the problem of easy loss and inactivation. Here, a B. bacteriovorus in situ forming hydrogel (BIG) was constructed for the ocular delivery of B. bacteriovorus. BIGs, as a fluid in their primitive state, were temperature- and cation- dually sensitive, which was rapidly transformed into immobile gels in the ocular environment. BIGs not only kept the activity of B. bacteriovorus but also retained on the ocular surface for a long time. The biosafety of BIGs was good without HCEC cell toxicity and hemolysis. More importantly, BIGs highly inhibited the growth of drug-resistant Pseudomonas aeruginosa whether in vitro or in the infected rat eyes. The ocular infection was completely controlled by BIGs with no corneal ulcers and inflammations. This living bacteria gel is a promising medication for the local treatment of drug-resistant bacteria-induced ocular infection.

Prognosis of Patients with Hepatocellular Carcinoma Treated with Transarterial Chemoembolization(MC-hccAI 001): Development and Validation of the ALFP Score.

Background: Transarterial chemoembolization (TACE) is the recommended first-line treatment for intermediate-stage Hepatocellular carcinoma (HCC) patients. However, predicting the survival of HCC patients receiving TACE remains challenging. Methods: In this retrospective study, we analyzed a total of 1805 HCC patients who received TACE. The patients were randomly divided into a training set (n = 1264) and a validation set (n = 541). We examined various prognostic factors within the training set and developed a simple ALFP (ALBI grade, AFP, and Prothrombin time) score, which was subsequently validated using the independent validation set. Results: Our multivariate analysis revealed that baseline ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s were independent unfavorable prognostic factors for HCC patients receiving TACE (p < 0.05). Based on these findings, we constructed the ALFP score, which assigns 1 point each for ALBI grade 2 or 3, AFP ≥ 100 ng/mL, and PT > 13.1 s. The score has a range of 0 to 3, and higher scores are associated with poorer outcomes. The median overall survival (OS) varied significantly among different ALFP score groups, both in the training set and the validation set (p < 0.001). We further examined the ALFP score in subgroups based on tumor diameter and the number of intrahepatic lesions. In each subgroup, higher ALFP scores were consistently associated with lower OS (p < 0.05). Conclusion: Our study confirms the prognostic value of the ALFP score in predicting the survival of HCC patients undergoing TACE. The score incorporates easily obtainable baseline parameters and provides a simple and practical tool for risk stratification and treatment decision-making in HCC patients.

Gamma auditory steady-state response as a promising electrophysiological biomarker for depression: an in vivo study with chronic unpredictable mild stress (CUS)-induced rats.

Gamma oscillations play a functional role in brain cognitions. Recently, auditory steady-state response (ASSR) has been reported abnormally in depression clinically, particularly in the low-gamma band. However, clinical electroencephalography research has challenges obtaining pure signals straight from the source level, making information isolation and precise localization difficult. Besides, the ASSR deficits pattern remains unclear. Herein, we focused on the origin of ASSR-primary auditory cortex (A1), the central node in the auditory pathway. We assessed the evoked-power and phase-synchronization using local field potentials (LFP) in depression (n = 21) and control (n = 22) rats. Subsequent processing of the received auditory information was examined using event-related potentials (AEPs). Results showed that depressed rats exhibited significant gamma ASSR impairments in peak-to-peak amplitude, inter-trial phase coherence, and signal-to-noise ratio. These deficits were more pronounced during 40-Hz auditory stimuli in right-A1, indicating severe gamma network abnormalities in the right auditory pathway. Besides, increased N2 and P3 amplitudes in depression group were found, indicating excessive inhibitory control and contextual processing. Taken together, these ASSR abnormalities have a high specificity of more than 90% and high sensitivity of more than 80% to distinguish depression under 40-Hz auditory stimuli. Our findings provided an abnormal gamma network in the auditory pathway, as a promising diagnostic biomarker in the future.

A novel non-invasive brain stimulation technique: "Temporally interfering electrical stimulation".

For decades, neuromodulation technology has demonstrated tremendous potential in the treatment of neuropsychiatric disorders. However, challenges such as being less intrusive, more concentrated, using less energy, and better public acceptance, must be considered. Several novel and optimized methods are thus urgently desiderated to overcome these barriers. In specific, temporally interfering (TI) electrical stimulation was pioneered in 2017, which used a low-frequency envelope waveform, generated by the superposition of two high-frequency sinusoidal currents of slightly different frequency, to stimulate specific targets inside the brain. TI electrical stimulation holds the advantages of both spatial targeting and non-invasive character. The ability to activate deep pathogenic targets without surgery is intriguing, and it is expected to be employed to treat some neurological or psychiatric disorders. Recently, efforts have been undertaken to investigate the stimulation qualities and translation application of TI electrical stimulation via computational modeling and animal experiments. This review detailed the most recent scientific developments in the field of TI electrical stimulation, with the goal of serving as a reference for future research.

Clinical models to predict lymph nodes metastasis and distant metastasis in newly diagnosed early esophageal cancer patients: A population-based study.

BACKGROUND: Patients with early esophageal cancer (EC) receive individualized therapy based on their lymph node metastasis (LNM) and distant metastasis (DM) status; however, deficiencies in current clinical staging techniques and the issue of cost-effectiveness mean LNM and DM often go undetected preoperatively. We aimed to develop three clinical models to predict the likelihood of LNM, DM, and prognosis in patients with early EC. METHOD: The Surveillance, Epidemiology, and End Results database was queried for T1 EC patients from 2004 to 2015. Multivariable logistic regression and Cox proportional hazards models were used to recognize the risk factors of LNM and DM, predict overall survival (OS), and develop relevant nomograms. Receiver operating characteristic (ROC)/concordance index and calibration curves were used to evaluate the discrimination and accuracy of the three nomograms. Decision curve analyses (DCAs), clinical impact curves, and subgroups based on model scores were used to determine clinical practicability. RESULTS: The area under the curve of the LNM and DM nomograms were 0.668 and 0.807, respectively. The corresponding C-index of OS nomogram was 0.752. Calibration curves and DCA showed an effective predictive accuracy and clinical applicability. In patients with T1N0M0 EC, surgery alone (p < 0.01) proved a survival advantage. Chemotherapy and radiotherapy indicated a better prognosis in the subgroup analysis for T1 EC patients with LNM or DM. CONCLUSIONS: We created three nomograms to predict the likelihood of LNM, DM, and OS probability in patients with early EC using a generalizable dataset. These useful visual tools could help clinical physicians deliver appropriate perioperative care.

Sensitive fluorometric determination of platelet-derived growth factor BB and avian influenza A virus DNA via dual signal amplification using the hybridization chain reaction and glucose oxidase assisted recycling.

A method is described for fluorometric determination of platelet-derived growth factor BB (PDGF-BB) and avian influenza A (H1N1) virus DNA. It is based on the use of the hybridization chain reaction (HCR) and of glucose oxidase (GOx) assisted dual-recycling amplification. A silver coated glass slide (SCGS) serves as an ideal material for separation. A signal DNA/initiator triggers the HCR and generates a cascade of hybridization to form a nicked double-helix polymer. Upon addition of the analytes (PDGF-BB or H1N1 DNA) and capture DNA immobilized on the SCGS, the nicked double-helix polymer binds on the surface of the SCGS through formation of a [capture DNA/analyte/signal DNA] sandwich structure. The GOx-biotin-streptavidin (SA) complexes were then attached to the nicked double-helix polymer through SA-biotin interaction. After cleavage by DNase I, the bound GOx is transferred into the buffer. Glucose is added and enzymatically oxidized to produce H2O2. The H2O2 formed oxidizes the substrate 3-(p-hydroxyphenyl)-propanoic acid to give a blue fluorescent product (with excitation/emission maxima at 320/416 nm) under the catalysis of horseradish peroxidase. Under optimal conditions, fluorescence increases linearly in the 0.5 to 70 pmol·L-1 PDGF-BB concentration range, and the detection limit is 191 fmol·L-1. For the H1N1 virus DNA, the respective data are 2.5 to 300 pmol·L-1 and 826 fmol·L-1. Graphical abstract Schematic presentation for detection of analytes (PDGF-BB or H1N1 virus DNA) based on the dual-signal amplification of Hybridization Chain Reaction (HCR) and glucose oxidase (GOx) using silver coated glass slide (SCGS) as separation material.

Estimation of Vertical Leaf Nitrogen Distribution Within a Rice Canopy Based on Hyperspectral Data.

Accurate estimations of the vertical leaf nitrogen (N) distribution within a rice canopy is helpful for understanding the nutrient supply and demand of various functional leaf layers of rice and for improving the predictions of rice productivity. A two-year field experiment using different rice varieties, N rates, and planting densities was performed to investigate the vertical distribution of the leaf nitrogen concentration (LNC, %) within the rice canopy, the relationship between the LNC in different leaf layers (LNCLi, i = 1, 2, 3, 4), and the relationship between the LNCLi and the LNC at the canopy level (LNCCanopy). A vertical distribution model of the LNC was constructed based on the relative canopy height. Furthermore, the relationship between different vegetation indices (VIs) and the LNCCanopy, the LNCLi, and the LNC vertical distribution model parameters were studied. We also compared the following three methods for estimating the LNC in different leaf layers in rice canopy: (1) estimating the LNCCanopy by VIs and then estimating the LNCLi based on the relationship between the LNCLi and LNCCanopy; (2) estimating the LNC in any leaf layer of the rice canopy by VIs, inputting the result into the LNC vertical distribution model to obtain the parameters of the model, and then estimating the LNCLi using the LNC vertical distribution model; (3) estimating the model parameters by using VIs directly and then estimating the LNCLi by the LNC vertical distribution model. The results showed that the LNC in the bottom of rice canopy was more susceptible to different N rates, and changes in the LNC with the relative canopy height could be simulated by an exponential model. Vegetation indices could estimate the LNC at the top of rice canopy. R705/(R717+R491) (R2 = 0.763) and the renormalized difference vegetation index (RDVI) (1340, 730) (R2 = 0.747) were able to estimate the parameter "a" of the LNC vertical distribution model in indica rice and japonica rice, respectively. In addition, method (2) was the best choice for estimating the LNCLi (R2 = 0.768, 0.700, 0.623, and 0.549 for LNCL1, LNCL2, LNCL3, and LNCL4, respectively). These results provide technical support for the rapid, accurate, and non-destructive identification of the vertical distribution of nitrogen in rice canopies.