Video_6_Convulsive behaviors of spontaneous recurrent seizures in a mouse model of extended hippocampal kindling.WMV

Growing studies indicate that vigilance states and circadian rhythms can influence seizure occurrence in patients with epilepsy and rodent models of epilepsy. Electrical kindling, referred to brief, repeated stimulations of a limbic structure, is a commonly used model of temporal lobe epilepsy. Kindling via the classic protocol lasting a few weeks does not generally induce spontaneous recurrent seizures (SRS), but extended kindling that applies over the course of a few months has shown to induce SRS in several animal species. Kindling-induced SRS in monkeys and cats were observed mainly during resting wakefulness or sleep, but the behavioral activities associated with SRS in rodent models of extended kindling remain unknown. We aimed to add information in this area using a mouse model of extended hippocampal kindling. Middle-aged C57 black mice experienced ≥80 hippocampal stimulations (delivered twice daily) and then underwent continuous 24 h electroencephalography (EEG)-video monitoring for SRS detection. SRS were recognized by EEG discharges and associated motor seizures. The five stages of the modified Racine scale for mice were used to score motor seizure severities. Seizure-preceding behaviors were assessed in a 3 min period prior to seizure onset and categorized as active and inactive. Three main observations emerged from the present analysis. (1) SRS were found to predominantly manifest as generalized (stage 3–5) motor seizures in association with tail erection or Straub tail. (2) SRS occurrences were not significantly altered by the light on/off cycle. (3) Generalized (stage 3–5) motor seizures were mainly preceded by inactive behaviors such as immobility, standing still, or apparent sleep without evident volitional movement. Considering deeper subcortical structures implicated in genesis of tail erection in other seizure models, we postulate that genesis of generalized motor seizures in extended kindled mice may involve deeper subcortical structures. Our present data together with previous findings from post-status epilepticus models support the notion that ambient cage behaviors are strong influencing factors of SRS occurrence in rodent models of temporal lobe epilepsy.</p

Characteristics of study population grouped in patients with and without MAU or mildly decreased GFR.

<p><b>Abbreviation</b>: MAU: microalbuminuria; GFR: glomerular filtration rate; UACR: uric albumin-to-creatinine ratio; cSBP: central systolic blood pressure; AIx: augmentation index; pSBP: peripheral systolic blood pressure; CAD: coronary artery disease; BMI: body mass index; WC: waist circumstance; HR: heart rate; FBG: fasting blood glucose; PBG: postprandial blood glucose; HDL-c: high-density lipoprotein-cholesterol; LDL-c: low-density lipoprotein-cholesterol; ACEI/ARB: angiotensin converting enzyme inhibitor/angiotensin receptor blocker.</p

Description of AIx and BP in subgroups based on the presence or absence of MAU and mildly decreased GFR.

<p><b>Abbreviation</b>: AIx: augmentation index; BP: blood pressure; MAU: microalbuminuria; GFR: glomerular filtration rate; UACR: uric albumin-to-creatinine ratio; cSBP: central systolic blood pressure; OR: odd ratio; CI: confidence interval; pSBP: peripheral systolic blood pressure.</p

AIx and BP of the study population categorized into 4 subgroups based on the presence or absence (normal GFR) of mildly decreased GFR and the presence or absence (normal ACR) of MAU.

<p>The difference between subgroups was highly significant (all p<0.001). <b>Abbreviation</b>: AIx: augmentation index; BP: blood pressure; GFR: glomerular filtration rate; ACR: albumin-to-creatinine ratio; MAU: microalbuminuria; SBP: systolic blood pressure.</p

Independent association of MAU and mildly decreased GFR with AIx and BP according to multivariate analysis.

<p><b>Note</b>: ^aFirst model: no adjusted; ^bSecond model: regression model adjusted by age and gender; ^cThird model: regression model adjusted by age, gender, smoking, coronary artery disease, type 2 diabetes, body mass index, waist circumstance, heart rate, fasting blood glucose, postprandial blood glucose, triglyceride, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, angiotensin converting enzyme inhibitor/angiotensin receptor blocker, and statins use.</p><p><b>Abbreviation</b>: MAU: microalbuminuria; GFR: glomerular filtration rate; AIx: augmentation index; BP: blood pressure; OR: odd ratio; CI: confidence interval; cSBP: central systolic blood pressure; pSBP: peripheral systolic blood pressure.</p

Maximized nanodrug-loaded mesenchymal stem cells by a dual drug-loaded mode for the systemic treatment of metastatic lung cancer

<p>Mesenchymal stem cells (MSCs), exhibiting tumor-tropic and migratory potential, can serve as cellular carriers to improve the effectiveness of anticancer agents. However, several challenges, such as the safety issue, the limited drug loading, the conservation of stemness and migration of MSCs, still remain in the MSC-based delivery system. In the present study, a novel nano-engineered MSC delivery system was established by loading doxorubicin (DOX)–polymer conjugates for the systemic treatment of pulmonary metastasis of breast cancer. For the first time, a dual drug-loaded mode, endocytosis and membrane-bound, was adopted to achieve the maximum amount of DOX conjugates in MSCs. The <i>in vitro</i> studies revealed the loaded MSCs possessed multifunctional properties, including preservation of the stemness and migration of MSCs, excellent stability of drug loading, acid sensitive drug release and obvious cytotoxicity against 4T1 cells. The <i>in vivo</i> studies confirmed that the loaded MSCs mainly located and long stayed in the lung where the foci of metastatic tumor situated. Importantly, loaded MSCs can significantly inhibit the tumor growth and prolong the life span of tumor-bearing mice in contrast with DOX and DOX-conjugate. The present loaded MSCs system suggested a promising strategy to solve several issues existed in cell-based delivery systems. Especially for the problem of low drug loading, the strategy, simultaneously loading nanodrug in cells’ internal and membrane, might be the most desirable method so far and could be developed as a generalizable manner for cell-mediated tumor-targeted therapy.</p

DataSheet_1_Prognostic value of postoperative anti-thyroglobulin antibody in patients with differentiated thyroid cancer.xlsx

PurposePostoperative thyroglobulin (Tg) generally serves as a biomarker to monitor the recurrence or persistence of differentiated thyroid cancer (DTC), whereas it constrains to interference from anti-thyroglobulin antibody (TgAb). This study aimed to determine the value of postoperative TgAb as a surrogate for monitoring tumor status in DTCs with positive TgAb after successful radioactive iodine (RAI) remnant ablation.MethodsWe retrospectively enrolled DTC patients with positive (≥40 IU/mL, Roche) postoperative TgAb measurements. An index of TgAb change (ΔTgAb) was defined to describe the TgAb decrease rate. DTC status was defined as either no evidence of disease (NED) or persistent/recurrent disease (PRD). Univariate and multivariate binary logistic analyses were used to identify the independent risk factors of PRD. Receiver operating characteristic (ROC) curves were performed to determine the optimal cutoff values of each risk factor, and DeLong’s test was conducted to compare their predictive powers. Kaplan–Meier curves were used to assess the impact of different TgAb trends in the first year on progression-free survival.ResultsOf the 232 patients enrolled, the median diagnosis age was 34 years (range, 18–62 years), with a male-to-female ratio of 1:4.66 (41/191). Among them, after a median follow-up of 44 months (range, 4–128 months),183 (78.87%) patients were evaluated as NED, while the other 49 (21.12%) had either persistent (n = 25) or recurrent disease (n = 24). Multivariate regression showed that ΔTgAb (P 47.0% had longer progression-free survival than those with ΔTgAb ≤47.0% (not reached vs. 50 months, P 47.0% or negative conversion within the first year after RAI ablation had longer progression-free survival.ConclusionOur study suggested that ΔTgAb could serve as a valuable indicator of disease status in DTC patients with positive TgAb. A ΔTgAb of >47.0% is conducive to identify those with NED and may help to obviate their overtreatment. The decrease rate and negative conversion of TgAb in the first year were good predictors of disease-free survival in patients.</p

Data_Sheet_1_Non-targeted metabonomics and transcriptomics revealed the mechanism of mulberry branch extracts promoting the growth of Sanghuangporus vaninii mycelium.xlsx

Sanghuangprous vaninii is a wood-inhabiting fungus, and its mycelium and fruiting body show excellent medicinal values. Mulberry is one of the major hosts of S. vaninii, however, the mechanism of mulberry affecting the growth of S. vaninii has not been reported. In the present study, a mulberry-inhabiting strain of S. vaninii was selected to explore the effects of mulberry branch extracts (MBE) on the growth of the strain. Results showed that MBE could significantly promote the growth of S. vaninii mycelium at the concentration of 0.2 g/l. After 16 days of liquid culture, the dry weight of mycelium in 0.2 g/l MBE medium was higher by three times compared with that in the control. The non-targeted metabonomic analysis of the culture medium at different culture times and concentrations was conducted to find the key components in MBE that promoted the growth of S. vaninii mycelium. Under the different concentrations of MBE culture for 10 and 16 days, 22 shared differential metabolites were identified. Next, in accordance with the peak value trend of these metabolites, HPLC–MS and liquid culture validation, four components derived from MBE (i.e., scopoletin, kynurenic acid, 3,5-dihydroxybenzoic acid and 2,4-dihydroxybenzoic acid) could significantly increase the growth rate of mycelium at the concentration of 2 mg/l. Transcriptomic and qRT-PCR analyzes showed that MBE could upregulate hydrolase-related genes, such as serine–glycine–asparaginate–histidine (SGNH) hydrolase, alpha-amylase, poly-beta-hydroxybutyrate (PHB) depolymerase, glycosyl hydrolase family 61, cerato-platanin protein and Fet3, which might enhance the nutrient absorption ability of S. vaninii. Importantly, MBE could significantly increase the content of harmine, androstenedione and vesamicol, which have been reported to possess various medicinal effects. Results suggested that MBE could be an excellent additive for liquid culture of S. vaninii mycelium, and these hydrolase-related genes also provided candidate genes for improving the nutrient absorption capacity of S. vaninii.</p

Image_1_Non-targeted metabonomics and transcriptomics revealed the mechanism of mulberry branch extracts promoting the growth of Sanghuangporus vaninii mycelium.TIF

Sanghuangprous vaninii is a wood-inhabiting fungus, and its mycelium and fruiting body show excellent medicinal values. Mulberry is one of the major hosts of S. vaninii, however, the mechanism of mulberry affecting the growth of S. vaninii has not been reported. In the present study, a mulberry-inhabiting strain of S. vaninii was selected to explore the effects of mulberry branch extracts (MBE) on the growth of the strain. Results showed that MBE could significantly promote the growth of S. vaninii mycelium at the concentration of 0.2 g/l. After 16 days of liquid culture, the dry weight of mycelium in 0.2 g/l MBE medium was higher by three times compared with that in the control. The non-targeted metabonomic analysis of the culture medium at different culture times and concentrations was conducted to find the key components in MBE that promoted the growth of S. vaninii mycelium. Under the different concentrations of MBE culture for 10 and 16 days, 22 shared differential metabolites were identified. Next, in accordance with the peak value trend of these metabolites, HPLC–MS and liquid culture validation, four components derived from MBE (i.e., scopoletin, kynurenic acid, 3,5-dihydroxybenzoic acid and 2,4-dihydroxybenzoic acid) could significantly increase the growth rate of mycelium at the concentration of 2 mg/l. Transcriptomic and qRT-PCR analyzes showed that MBE could upregulate hydrolase-related genes, such as serine–glycine–asparaginate–histidine (SGNH) hydrolase, alpha-amylase, poly-beta-hydroxybutyrate (PHB) depolymerase, glycosyl hydrolase family 61, cerato-platanin protein and Fet3, which might enhance the nutrient absorption ability of S. vaninii. Importantly, MBE could significantly increase the content of harmine, androstenedione and vesamicol, which have been reported to possess various medicinal effects. Results suggested that MBE could be an excellent additive for liquid culture of S. vaninii mycelium, and these hydrolase-related genes also provided candidate genes for improving the nutrient absorption capacity of S. vaninii.</p

Data_Sheet_2_Non-targeted metabonomics and transcriptomics revealed the mechanism of mulberry branch extracts promoting the growth of Sanghuangporus vaninii mycelium.docx

Sanghuangprous vaninii is a wood-inhabiting fungus, and its mycelium and fruiting body show excellent medicinal values. Mulberry is one of the major hosts of S. vaninii, however, the mechanism of mulberry affecting the growth of S. vaninii has not been reported. In the present study, a mulberry-inhabiting strain of S. vaninii was selected to explore the effects of mulberry branch extracts (MBE) on the growth of the strain. Results showed that MBE could significantly promote the growth of S. vaninii mycelium at the concentration of 0.2 g/l. After 16 days of liquid culture, the dry weight of mycelium in 0.2 g/l MBE medium was higher by three times compared with that in the control. The non-targeted metabonomic analysis of the culture medium at different culture times and concentrations was conducted to find the key components in MBE that promoted the growth of S. vaninii mycelium. Under the different concentrations of MBE culture for 10 and 16 days, 22 shared differential metabolites were identified. Next, in accordance with the peak value trend of these metabolites, HPLC–MS and liquid culture validation, four components derived from MBE (i.e., scopoletin, kynurenic acid, 3,5-dihydroxybenzoic acid and 2,4-dihydroxybenzoic acid) could significantly increase the growth rate of mycelium at the concentration of 2 mg/l. Transcriptomic and qRT-PCR analyzes showed that MBE could upregulate hydrolase-related genes, such as serine–glycine–asparaginate–histidine (SGNH) hydrolase, alpha-amylase, poly-beta-hydroxybutyrate (PHB) depolymerase, glycosyl hydrolase family 61, cerato-platanin protein and Fet3, which might enhance the nutrient absorption ability of S. vaninii. Importantly, MBE could significantly increase the content of harmine, androstenedione and vesamicol, which have been reported to possess various medicinal effects. Results suggested that MBE could be an excellent additive for liquid culture of S. vaninii mycelium, and these hydrolase-related genes also provided candidate genes for improving the nutrient absorption capacity of S. vaninii.</p