Entropy-driven Denaturation for Sustainable Regeneration of Protein Waste.

Electrolytes are essential parts of the environment for all life forms, where proteins, water, and solutes interplay to support vital activities. However, a fundamental understanding of the effect of ionic solutes on proteins remains elusive for more than a century. Here we show how some ionic solutes can serve as potent denaturants despite the absence of direct protein-ion interactions. We demonstrate dramatic differences between denaturation potency of different ionic solutes with lithium bromide (LiBr) being the strongest denaturant and sodium bromide (NaBr) being the least potent. Experiments and simulations indicate the presence of certain ions disrupts the structure of water network, thereby induce protein denaturation indirectly via an entropy-driven mechanism. We further introduce a scalable strategy for protein waste revalorization, distinguished by the closed-loop recycling of denaturants, straightforward protein separation, and facile manufacturing, all enabled by the entropy-driven denaturation by LiBr. Through successful isolation and systematic study of indirect solute effects, our findings suggest a unified and generally applicable framework for decoding of the protein-water-solute nexus, where all current studies can be easily incorporated. Besides, our regeneration approach underscores the feasibility of repurposing protein waste into valuable biomaterials in a sustainable way with wide-reaching application potential.

[Binocular loupe assisted mini-lateral and medial incisions in lateral position for release of elbow stiffness].

Objective: To analyze the effectiveness of binocular loupe assisted mini-lateral and medial incisions in lateral position for the release of elbow stiffness. Methods: The clinical data of 16 patients with elbow stiffness treated with binocular loupe assisted mini-internal and external incisions in lateral position release between January 2021 and December 2022 were retrospectively analyzed. There were 9 males and 7 females, aged from 19 to 57 years, with a median age of 33.5 years. Etiologies included olecranon fracture in 6 cases, elbow dislocation in 4 cases, medial epicondyle fracture in 2 cases, radial head fracture in 4 cases, terrible triad of elbow joint in 2 cases, supracondylar fracture of humerus in 1 case, coronoid process fracture of ulna in 1 case, and humerus fracture in 1 case, with 5 cases presenting a combination of two etiologies. The duration of symptoms ranged from 5 to 60 months, with a median of 8 months. Preoperatively, 12 cases had concomitant ulnar nerve numbness, and 6 cases exhibited ectopic ossification. The preoperative range of motion for elbow flexion and extension was (58.63±22.30)°, the visual analogue scale (VAS) score was 4.3±1.6, and the Mayo score was 71.9±7.5. Incision lengths for both lateral and medial approaches were recorded, as well as the occurrence of complications. Clinical outcomes were evaluated using Mayo scores, VAS scores, and elbow range of motion both preoperatively and postoperatively. Results: The lateral incision lengths for all patients ranged from 3.0 to 4.8 cm, with an average of 4.1 cm. The medial incision lengths ranged from 2.4 to 4.2 cm, with an average of 3.0 cm. The follow-up duration ranged from 6 to 19 months and a mean of 9.2 months. At last follow-up, 1 patient reported moderate elbow joint pain, and 3 cases exhibited residual mild ulnar nerve numbness. The other patients had no complications such as new heterotopic ossification and ulnar nerve paralysis, which hindered the movement of elbow joint. At last follow-up, the elbow range of motion was (130.44±9.75)°, the VAS score was 1.1±1.0, and the Mayo score was 99.1±3.8, which significantly improved when compared to the preoperative ones ( t=-12.418, P<0.001; t=6.419, P<0.001; t=-13.330, P<0.001). Conclusion: The binocular loupe assisted mini-lateral and medial incisions in lateral position integrated the advantages of traditional open and arthroscopic technique, which demonstrated satisfying safety and effectivity for the release of elbow contracture, but it is not indicated for patients with posterior medial heterolateral heterotopic ossification.

The association between indoor air pollution from solid fuels and cognitive impairment: a systematic review and meta-analysis.

This study aimed to comprehensively and methodically evaluate the correlation between cognitive impairment and indoor air pollution from solid fuel used for cooking/heating. PubMed, Web of Science, EMBASE, and Cochrane Library databases were searched up to December January 2023. 13 studies from three countries with a total of 277,001 participants were enrolled. A negative correlation was discovered between solid fuel usage for cooking and total cognitive score (ß=-0.73, 95 % CI: -0.90 to -0.55) and episodic memory score (ß=-0.23, 95 % CI: -0.30 to -0.17). Household solid fuel usage for cooking was considerably associated with a raised risk of cognitive impairment (HR=1.31, 95 % CI: 1.09-1.57) and cognitive decline (HR=1.24, 95 % CI: 1.18-1.30). Compared to continuous solid fuel use for cooking, sustained use of clean fuel and switching from solid fuel to clean fuel were associated with a lower risk of cognitive decline (OR=0.55, 95 % CI: 0.42-0.73; OR=0.81, 95 % CI: 0.71-0.93). A negative association was found between solid fuel usage for heating and total cognitive score (ß=-0.43, 95 % CI: -0.59 to -0.26) and episodic memory score (ß=-0.22, 95 % CI: -0.34 to -0.10). Our research provided evidence that exposure to indoor air pollution from solid fuel is a potential cause of cognitive impairment and cognitive decline. Making the switch from solid fuels to cleaner fuels could be an important step in preventing cognitive impairment in the elderly.

C-C Motif Chemokine Ligand 5 (CCL5): A Potential Biomarker and Immunotherapy Target for Osteosarcoma.

BACKGROUND: Osteosarcoma (OS) is the most common primary malignant tumor of bone tissue, which has an insidious onset and is difficult to detect early, and few early diagnostic markers with high specificity and sensitivity. Therefore, this study aims to identify potential biomarkers that can help diagnose OS in its early stages and improve the prognosis of patients. METHODS: The data sets of GSE12789, GSE28424, GSE33382 and GSE36001 were combined and normalized to identify Differentially Expressed Genes (DEGs). The data were analyzed by Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genome (KEGG) and Disease Ontology (DO). The hub gene was selected based on the common DEG that was obtained by applying two regression methods: the Least Absolute Shrinkage and Selection Operator (LASSO) and Support vVector Machine (SVM). Then the diagnostic value of the hub gene was evaluated in the GSE42572 data set. Finally, the correlation between immunocyte infiltration and key genes was analyzed by CIBERSORT. RESULTS: The regression analysis results of LASSO and SVM are the following three DEGs: FK501 binding protein 51 (FKBP5), C-C motif chemokine ligand 5 (CCL5), complement component 1 Q subcomponent B chain (C1QB). We evaluated the diagnostic performance of three biomarkers (FKBP5, CCL5 and C1QB) for osteosarcoma using receiver operating characteristic (ROC) analysis. In the training group, the area under the curve (AUC) of FKBP5, CCL5 and C1QB was 0.907, 0.874 and 0.676, respectively. In the validation group, the AUC of FKBP5, CCL5 and C1QB was 0.618, 0.932 and 0.895, respectively. It is noteworthy that these genes were more expressed in tumor tissues than in normal tissues by various immune cell types, such as plasma cells, CD8+ T cells, T regulatory cells (Tregs), activated NK cells, activated dendritic cells and activated mast cells. These immune cell types are also associated with the expression levels of the three diagnostic genes that we identified. CONCLUSION: We found that CCL5 can be considered an early diagnostic gene of osteosarcoma, and CCL5 interacts with immune cells to influence tumor occurrence and development. These findings have important implications for the early detection of osteosarcoma and the identification of novel therapeutic targets.

Diversity, community structure, and quantity of eukaryotic phytoplankton revealed using 18S rRNA and plastid 16S rRNA genes and pigment markers: a case study of the Pearl River Estuary.

Understanding consistencies and discrepancies in characterizing diversity and quantity of phytoplankton is essential for better modeling ecosystem change. In this study, eukaryotic phytoplankton in the Pearl River Estuary, South China Sea were investigated using nuclear 18S rRNA and plastid 16S or 23S rRNA genes and pigment analysis. It was found that 18S abundance poorly explained the variations in total chlorophyll a (Chl-a). However, the ratios of log-transformed 18S abundance to Chl-a in the major phytoplankton groups were generally environment dependent, suggesting that the ratio has potential as an indicator of the physiological state of phytoplankton. The richness of 18S-based operational taxonomic units was positively correlated with the richness of 16S-based amplicon sequence variants of the whole phytoplankton community, but insignificant or weak for individual phytoplankton groups. Overall, the 18S based, rather than the 16S based, community structure had a greater similarity to pigment-based estimations. Relative to the pigment data, the proportion of haptophytes in the 18S dataset, and diatoms and cryptophytes in the 16S dataset, were underestimated. This study highlights that 18S metabarcoding tends to reflect biomass-based community organization of eukaryotic phytoplankton. Because there were lower copy numbers of plastid 16S than 18S per genome, metabarcoding of 16S probably approximates cell abundance-based community organization. Changes in biomass organization of the pigment-based community were sensitive to environmental changes. Taken together, multiple methodologies are recommended to be applied to more accurately profile the diversity and community composition of phytoplankton in natural ecosystems. Supplementary Information: The online version contains supplementary material available at 10.1007/s42995-023-00186-x.

Different therapies of Chinese herbal medicine for diarrhea-predominant irritable bowel syndrome: A network meta-analysis of double-blinded, placebo-controlled trials.

ETHNOPHARMACOLOGICAL RELEVANCE: Shuganjianpi Therapy (SGJP), Jianpi Therapy (JP), Shugan Therapy (SG), Jianpiwenshen Therapy (JPWS), and Shuganjianpiwenshen Therapy (SGJPWS), consisting of formulas from Chinese herbal medicine (CHM), have been tremendously applied to irritable bowel syndrome (IBS). However, it remains uncertain when exploring the preferable option among different CHM therapies for diarrhea-predominant irritable bowel syndrome (IBS-D). AIM OF THE STUDY: To compare and rank the efficacy and safety of different CHM therapies for IBS-D. MATERIALS AND METHODS: We searched randomized, double-blinded, placebo-controlled trials through mainstream databases from their inception to October 31, 2022. Eligible randomized controlled trials (RCTs) applied one of the CHM therapies as the experimental group and placebo as the control group. Two authors independently extracted data into a form and evaluated the quality of the retrieved articles by the Cochrane Risk of Bias Tool. At least one of the following outcomes was assessed: Serotonin, Neuropeptide Y (NPY), Incidence of Adverse Events (AE), and Irritable Bowel Syndrome-Severity Scoring System (IBS-SSS) with its subscales of Severity of Abdominal Pain (SAP), Frequency of Abdominal Pain (FAP), Severity of Abdominal Distension (SAD), Dissatisfaction with Bowel Habits (DBH), and Interference with Quality of Life (IQOL). A Bayesian network meta-analysis on a random-effect model was conducted using R 4.2.2 software. RESULTS: 1367 records were retrieved from databases in an initial search. Fourteen studies involving six interventions with 2248 participants were identified. Provided pairwise comparisons, the surface under the cumulative ranking curve (SUCRA) ranking, and cluster analysis, JPWS was the best option for ameliorating clinical symptoms simultaneously, which included IBS-SSS, SAP, FAP, SAD, DBH, and IQOL. As for AE, JPWS contributed to fewer adverse events than others as well. In respect of serum indicators, we noticed the dominance of SGJP in regulating both serotonin and NPY. CONCLUSIONS: JPWS and SGJP were the most prominent CHM therapies for IBS-D in terms of clinical symptoms, including abdominal pain, distension, bowel habits, and improvement of quality of life. The effect of JP and SG for IBS-D required further investigation. As a potential candidate, SGJP may well treat IBS-D by mediating dysmotility, visceral hypersensitivity, and the gut-brain axis with an increase of NPY and a reduction of serotonin. For safety, JPWS was ideal for the fewest adverse events in the treatment of IBS-D. On account of a small sample size and possible geographical publication bias, more double-blinded and placebo-controlled trials with larger samples worldwide would be necessary for strengthening current evidence.

Development and validation of machine learning models for nonalcoholic fatty liver disease.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) had become the most prevalent liver disease worldwide. Early diagnosis could effectively reduce NAFLD-related morbidity and mortality. This study aimed to combine the risk factors to develop and validate a novel model for predicting NAFLD. METHODS: We enrolled 578 participants completing abdominal ultrasound into the training set. The least absolute shrinkage and selection operator (LASSO) regression combined with random forest (RF) was conducted to screen significant predictors for NAFLD risk. Five machine learning models including logistic regression (LR), RF, extreme gradient boosting (XGBoost), gradient boosting machine (GBM), and support vector machine (SVM) were developed. To further improve model performance, we conducted hyperparameter tuning with train function in Python package 'sklearn'. We included 131 participants completing magnetic resonance imaging into the testing set for external validation. RESULTS: There were 329 participants with NAFLD and 249 without in the training set, while 96 with NAFLD and 35 without were in the testing set. Visceral adiposity index, abdominal circumference, body mass index, alanine aminotransferase (ALT), ALT/AST (aspartate aminotransferase), age, high-density lipoprotein cholesterol (HDL-C) and elevated triglyceride (TG) were important predictors for NAFLD risk. The area under curve (AUC) of LR, RF, XGBoost, GBM, SVM were 0.915 [95% confidence interval (CI): 0.886-0.937], 0.907 (95% CI: 0.856-0.938), 0.928 (95% CI: 0.873-0.944), 0.924 (95% CI: 0.875-0.939), and 0.900 (95% CI: 0.883-0.913), respectively. XGBoost model presented the best predictive performance, and its AUC was enhanced to 0.938 (95% CI: 0.870-0.950) with further parameter tuning. CONCLUSIONS: This study developed and validated five novel machine learning models for NAFLD prediction, among which XGBoost presented the best performance and was considered a reliable reference for early identification of high-risk patients with NAFLD in clinical practice.

Is the traction table necessary to treat femoral fractures with intramedullary nailing? A meta-analysis.

BACKGROUND: The traction table is generally used in femoral intramedullary nailing surgery. Recently, some published studies have shown that the same or better treatment effects can be gotten without a traction table. It remains no consensus on this issue. METHODS: The Preferred Reporting Items for Systematic Reviews and Meta-analyses guideline was applied in this study. We searched PubMed, Embase, Web of Science, and Cochrane Library databases for eligible studies. The random-effect model was used to calculate the standardized mean difference (SMD) and risk ratios with 95% CIs. Trial sequential analysis (TSA) was performed to verify the results. RESULTS: The pooled estimates of seven studies, including 266 cases each in the manual traction group and traction table group, indicated that manual traction could shorten operative time [SMD, - 0.77; 95% CI (- 0.98, - 0.55); P < 0.00001] and preoperative set-up time [SMD, - 2.37; 95% CI (- 3.90, - 0.84); P = 0.002], but it would not reduce intraoperative blood loss volume and fluoroscopy time. No statistical difference was found in their fracture healing time, postoperative Harris scores, and malunion rate. The use of a Traction repositor could reduce the set-up time [SMD, - 2.48; 95% CI (- 4.91, - 0.05); P < 0.00001]. CONCLUSIONS: Compared with manual traction, the traction table in femoral intramedullary nailing surgery lengthened operative time and preoperative set-up time. At the same time, it did not show significant advantages in reducing blood loss volume and fluoroscopy time, or improving prognosis. In clinical practice, the optimal surgical plan must be made on a case-by-case basis to avoid unnecessary traction table use.

Supramolecular salicylic acid ameliorates rosacea-like eruptions by suppressing NLRP3-mediated inflammasome activation in mice.

BACKGROUND: Rosacea is a chronic inflammatory skin disease with immunological dysfunction. Supramolecular salicylic acid (SSA) has the properties of keratolytic, antibacterial, and anti-inflammatory. However, the mechanism of SSA in the treatment of rosacea is still unclear. OBJECTIVE: To investigate the efficiencies and molecular mechanisms of SSA in rosacea. METHODS: Forty mice were randomly divided into four groups (10 in each group): control, LL-37, LL-37 + azelaic acid (AzA), and LL-37 + SSA. Forty µl LL-37 (320 µM) was administered intradermally into the dorsal skin of the mice in the latter 3 groups every 12 h and 4 times altogether (0 h, 12 h, 24 h, 36 h). Twenty % AzA was applied on the eruptions after the first and third LL-37 injection (0 h, 24 h) in LL-37 + AzA group, while 30 % SSA was applied after the first injection (0 h) in LL-37 + SSA group. The redness score and redness area were evaluated. The skin barrier function was measured by the transepidermal water loss (TEWL) and pH. The infiltration of inflammatory cells was evaluated by hematoxylin-eosin staining, and the inflammatory biomarkers were analyzed by RT-PCR and immunohistochemistry. RESULTS: SSA alleviated LL-37-induced rosacea-like inflammation. The increased TEWL and pH induced by LL-37 were also reversed by SSA. In addition, SSA reduced inflammatory cell infiltration and suppressed the production of Toll-like receptor 2, Matrix metallopeptidase 9, kallikrein 5, LL-37 associated with rosacea, and inhibited LL-37-induced NOD-like receptor family, pyrin domain containing 3 (NLRP3)-mediated inflammasome activation in mice. CONCLUSIONS: Our findings indicated that SSA ameliorated LL-37-induced rosacea-like lesions by suppressing NLRP3-mediated inflammasome activation in mice.

Mechanism of Sijunzi Decoction in the treatment of colorectal cancer based on network pharmacology and experimental validation.

ETHNOPHARMACOLOGICAL RELEVANCE: Sijunzi Decoction（SJZD）, as a famous classical prescription for the treatment of colorectal cancer(CRC) in the traditional Chinese medicine (TCM), has achieved good curative effects in clinical practice. However, its specific ingredients and molecular mechanisms is still unclear. AIM OF THE STUDY: To analyze the effective ingredients and molecular mechanisms of SJZD in the treatment of CRC through network pharmacology technology and experimental validation. MATERIALS AND METHODS: First, the TCM Systems Pharmacology database and analysis platform database were searched to screen the effective chemical components of SJZD. Swiss Target Prediction was used to predict corresponding potential target genes of compounds. After that, we constructed a components and corresponding target network by Cytoscape. Simultaneously, 5 disease databases were used to search and filter CRC targets, and then we constructed a drug-disease target protein-protein interaction (PPI) network. Cytoscape 3.7 was used for visualization and cluster analysis, and Metascape database was used for GO and KEGG enrichment analysis. We drew the main pathway-target network diagram. Autodock vina1.5.6 was applied to molecular docking for the main compounds and target proteins. Subsequently, the potential mechanism of SJZD on colon cancer predicted by network pharmacological analysis was experimentally studied and verified in vivo and in vitro. RESULTS: 144 effective active chemical components, 897 potential targets, and 2584 CRC target genes were screened out. The number of common targets between the SJZD and CRC was 414.3250 GO biological process items and 186 KEGG signal pathways were obtained after analysis. The main compounds and the target protein had a good binding ability in molecular docking. The results of cell and animal experiments showed that SJZD could promote apoptosis and autophagy of CRC cells through PI3K/Akt/mTOR pathway. CONCLUSIONS: SJZD can treat CRC through multiple components, multiple targets and multiple pathways. We initially revealed the effective components and molecular mechanisms of SJZD in the treatment of CRC, and we used molecular docking and experiment for preliminary verification.

Pam2 lipopeptides enhance the immunosuppressive activity of monocytic myeloid-derived suppressor cells by STAT3 signal in chronic inflammation.

Chronic inflammation develops when the immune system is unable to clear a persistent insult. Unresolved chronic inflammation leads to immunosuppression to maintain the internal homeostatic conditions, which is mediated primarily by myeloid-derived suppressor cells (MDSCs). Toll-like receptors 2 (TLR2) has an important role in chronic inflammation and can be activated by a vast number and diversity of TLR2 ligands, for example Pam2CSK4. However, the regulatory effect of TLR2 signaling on MDSCs in chronic inflammation remains controversial. This study demonstrated that heat-killed Mycobacterium bovis BCG-induced pathology-free chronic inflammation triggered suppressive monocytic MDSCs (M-MDSCs) that expressed TLR2. Activation of TLR2 signaling by Pam2CSK4 treatment enhanced immunosuppression of M-MDSCs by upregulating inducible nitric oxide synthase (iNOS) activity and nitric oxide (NO) production partly through signal transducer and activator of transcription 3 (STAT3) activation. Thus, TLR2 has a fundamental role in promoting the MDSC-mediated immunosuppressive environment during chronic inflammation and might represent a potentially therapeutic target in chronic inflammation disease.

Sialic Acid as a Suitable Marker of Clinical Disease Activity in Patients with Crohn's Disease.

OBJECTIVE: Elevated serum levels of sialic acid (SA) have been verified in patients with various inflammatory conditions. The association between the Crohn's disease (CD) activity and serum SA has been insufficiently studied. MATERIALS AND METHODS: Serum SA concentrations were determined using an enzymatic colorimetric assay method, and the correlation of SA with the Harvey-Bradshaw Index (HBI) and other inflammation activity markers was evaluated using the Spearman correlation. The predictive value of SA in estimating CD disease activity was assessed using the receiver operating characteristic. RESULTS: The SA levels were positively correlated with HBI and C-reactive protein (CRP) levels. The correlation of SA with the HBI was superior to that of CRP with the HBI. The area under the curve for SA was higher than that for CRP, with an optimal cutoff value of 53.14 mg/dL for active CD. CONCLUSION: Serum SA correlates with the HBI score better and has better predictive value in monitoring CD disease activity than CRP or other inflammatory markers.

Efficacy and safety of underwater endoscopic mucosal resection for ≤20 mm superficial non-ampullary duodenal epithelial tumors: Systematic review and meta-analysis.

Background and aims: Superficial non-ampullary duodenal epithelial tumors (SNADETs) as a rare disease have gradually increased in recent years. Underwater endoscopic mucosal resection (UEMR) has emerged as a newly available option for the endoscopic resection of SNADETs. This study aimed to evaluate the efficacy and safety of UEMR for ≤20 mm SNADETs. Methods: A literature search was performed across multiple databases, including PubMed, Embase, Scopus, and Clinical trials for studies containing tumors ≤20 mm published from January 1, 2012, to August 8, 2022. Outcomes examined were the pooled rates of en bloc resection, R0 resection, adverse events, and recurrence. Subgroup analyses of the resection rate were conducted stratified by sample size and polyp size. Results: A total of 10 studies with UEMR performed in a total of 648 tumors were included for analysis. The pooled rate of en bloc resection and R0 resection was 88.2% (95% confidence interval (CI): 82.1-93.2) and 69.1% (95% CI: 62.2-76.1), respectively. The results showed pooled rate of intraoperative bleeding rate was 2.9% (95% CI: 0-9.0), delayed bleeding rate was 0.9% (95% CI: 0.1-2), recurrence rate was 1.5% (95% CI: 0-4.9). In the subgroup analysis, R0 and en-bloc resection rates were significantly higher in <10 mm than 10-20 mm SNADETs subgroups (R0 resection rate 83.1 vs. 48.6%; en bloc resection rate 100.0 vs. 84.0%, P < 0.05). Conclusion: Underwater endoscopic mucosal resection was an effective and safe technique for the optional treatment for ≤20 mm SNADETs, especially of <10 mm. Systematic review registration: https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022340578.

Pilot Study of the Effects of Polyphenols from Chestnut Involucre on Methane Production, Volatile Fatty Acids, and Ammonia Concentration during In Vitro Rumen Fermentation.

Nutritional strategies can be employed to mitigate greenhouse emissions from ruminants. This article investigates the effects of polyphenols extracted from the involucres of Castanea mollissima Blume (PICB) on in vitro rumen fermentation. Three healthy Angus bulls (350 ± 50 kg), with permanent rumen fistula, were used as the donors of rumen fluids. A basic diet was supplemented with five doses of PICB (0%-0.5% dry matter (DM)), replicated thrice for each dose. Volatile fatty acids (VFAs), ammonia nitrogen concentration (NH3-N), and methane (CH4) yield were measured after 24 h of in vitro fermentation, and gas production was monitored for 96 h. The trial was carried out over three runs. The results showed that the addition of PICB significantly reduced NH3-N (p < 0.05) compared to control. The 0.1%-0.4% PICB significantly decreased acetic acid content (p < 0.05). Addition of 0.2% and 0.3% PICB significantly increased the propionic acid content (p < 0.05) and reduced the acetic acid/propionic acid ratio, CH4 content, and yield (p < 0.05). A highly significant quadratic response was shown, with increasing PICB levels for all the parameters abovementioned (p < 0.01). The increases in PICB concentration resulted in a highly significant linear and quadratic response by 96-h dynamic fermentation parameters (p < 0.01). Our results indicate that 0.2% PICB had the best effect on in-vitro rumen fermentation efficiency and reduced greenhouse gas production.

Design, Synthesis, and Structure-Activity Relationships of Novel Tetrahydroisoquinolino Benzodiazepine Dimer Antitumor Agents and Their Application in Antibody-Drug Conjugates.

A series of tetrahydroisoquinoline-based benzodiazepine dimers were synthesized and tested for in vitro cytotoxicity against a panel of cancer cell lines. Structure-activity relationship investigation of various spacers guided by molecular modeling studies helped to identify compounds with picomolar activity. Payload 17 was conjugated to anti-mesothelin and anti-fucosylated monosialotetrahexosylganglioside (FucGM1) antibodies using lysosome-cleavable valine-citrulline dipeptide linkers via heterogeneous lysine conjugation and bacterial transglutaminase-mediated site-specific conjugation. In vitro, these antibody drug conjugates (ADCs) exhibited significant cytotoxic and target-mediated selectivity on human cancer cell lines. The pharmacokinetics and efficacy of these ADCs were further evaluated in gastric and lung cancer xenograft models in mice. Consistent pharmacokinetic profiles, high target specificity, and robust antitumor activity were observed in these models after a single dose of the ADC-46 (0.02 µmol/kg).

Evaluation of Architect anti-HCV Signal to Cutoff Ratios for Predicting Hepatitis C Viremia Using COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test.

BACKGROUND: The aim of the study is to evaluate the significance of the Architect anti-HCV signal to cutoff (S/CO) ratios for predicting hepatitis C viremia and determine the optimal S/Co ratio value for Architect anti-HCV assay. METHODS: The results of patients who underwent HCV RNA quantitative assays because of positive anti-HCV from January 2015 to August 2019 were retrospectively analyzed, including S/Co ratio values, HCV RNA quantitative results, alanine aminotransferase (ALT), and aspartate transaminase (AST) values. Binary logistic regression and Spearman's correlation coefficient were used to analyze the collected data. Receiver-operating characteristics curve (ROC) was applied to analyze the predicting values of the indexes. RESULTS: In total, 811 patients were included in our study and HCV viremia was detected in 342 (42.1%) patients. There is no correlation between anti-HCV S/CO ratio and HCV RNA level. The samples with an S/Co ratio between 1 and 4 (271/271, 100%) were all HCV RNA negative. The area under the ROC curve of anti-HCV S/CO ratio was 0.8714 and the maximal Youden index was 0.681 at an optimal cutoff S/CO ratio value of 8.99. CONCLUSIONS: With the cutoff value of 1.0, the Architect anti-HCV assay showed excellent sensitivity but poor specificity in predicting HCV viremia. An S/Co ratio of 8.99 was optimal for further confirmation testing of HCV viremia.

Clinical performance of non-invasive prenatal testing for trisomies 21, 18 and 13 in twin pregnancies: A cohort study and a systematic meta-analysis.

INTRODUCTION: The objective of this study was to report on the clinical performance of non-invasive prenatal testing (NIPT) for trisomies 21, 18 and 13 in twin pregnancies and to define the performance of NIPT by combining our cohort study results with published studies in a systematic meta-analysis. MATERIAL AND METHODS: A cohort study was carried out in the First Affiliated Hospital of Sun Yat-sen University and Kanghua Hospital. Meanwhile, searches of PubMed, EMBASE, The Cochrane Library and Web of Science for all relevant peer-reviewed articles were performed with a restriction to English language publication before 15 June 2019. Quality assessments were conducted with the Quality Assessment Tool for Diagnostic Accuracy Studies-2 checklist. Data analysis, heterogeneity, subgroup analysis and publication bias were carried out using META-DISC 1.4 and STATA 12.0. RESULTS: In all, 141 twin pregnancies included in our cohort study; confirmation revealed one true-positive case for trisomy 21 and 140 true-negative cases. The sensitivity and specificity for trisomy 21 by NIPT were both 100%. Twenty-two eligible studies were enrolled in this meta-analysis together with our study. There were 199 cases of trisomy 21, 58 cases of trisomy 18, 14 cases of trisomy 13 and 6347 cases of euploids in total. For trisomy 21, NIPT showed the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.99, 1.00, 145.81, 0.06 and 1714.09, respectively. For trisomy 18, the pooled sensitivity, specificity, positive likelihood ratio, negative likelihood ratio and diagnostic odds ratio were 0.88, 1.00, 200.98, 0.19 and 483.68, respectively. CONCLUSIONS: The performance of NIPT for trisomy 21 in twin pregnancy was excellent and it was similar to that reported in singleton pregnancy. However, due to publication bias (trisomy 18) and small number of cases (trisomy 13), accurate assessment of the predictive performance of NIPT for trisomies 18 and 13 could not be achieved.

Performance evaluation of the DAAN HCV assay for quantification of hepatitis C virus RNA and its comparison with COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test, v2.0.

BACKGROUND: The Daan HCV RNA quantitative assay was a recently developed kit with high sensitivity for the detection of HCV RNA. We aimed to evaluate the analytical performance of the Daan HCV RNA quantitative assay and compare it with the COBAS AmpliPrep/COBAS TaqMan HCV Quantitative Test, v2.0. METHOD: WHO HCV RNA standard, NIBSC 06/102 standard, and CLSI EP documents were used to evaluate the precision, accuracy, linearity, anti-interference ability, and cross-reactivity of the Daan HCV RNA quantitative assay. Overall 198 clinical serum specimens were used to make comparison between the Daan HCV RNA quantitative assay and the Roche Cobas test. RESULTS: The within-run precision (Swithin ), and total precision (Stotal ) for 6.11 log IU/mL, 4.22 log IU/mL, and 2.32 log IU/mL HCV RNA were 0.13 and 0.15, 0.07 and 0.09, and 0.11 and 0.10, respectively. The linear range was 20-108  IU/mL, and the limit of detection was 15 IU/mL. It did not display any interference with commonly encountered conditions and cross-reactivity with some common virus. A good agreement was observed between the Daan HCV RNA quantitative assay and the Roche Cobas test. CONCLUSION: The Daan HCV RNA quantitative assay has shown satisfactory performances and excellent agreement with COBAS HCV Quantitative Test on clinical specimens with lower cost, which provides an alternative choice for the diagnosis and monitoring of HCV infection in developing countries.

Ionic Highways from Covalent Assembly in Highly Conducting and Stable Anion Exchange Membrane Fuel Cells.

A major challenge in the development of anion exchange membranes for fuel cells is the design and synthesis of highly stable (chemically and mechanically) conducting membranes. Membranes that can endure highly alkaline environments while rapidly transporting hydroxides are desired. Herein, we present a design using cross-linked polymer membranes containing ionic highways along charge-delocalized pyrazolium cations and homoconjugated triptycenes. These ionic highway membranes show improved performance. Specifically, a conductivity of 111.6 mS cm-1 at 80 °C was obtained with a low 7.9% water uptake and 0.91 mmol g-1 ion exchange capacity. In contrast to existing materials, ionic highways produce higher conductivities at reduced hydration and ionic exchange capacities. The membranes retain more than 75% of their initial conductivity after 30 days of an alkaline stability test. The formation of ionic highways for ion transport is confirmed by density functional theory and Monte Carlo studies. A single cell with platinum metal catalysts at 80 °C showed a high peak density of 0.73 W cm-2 (0.45 W cm-2 from a silver-based cathode) and stable performance throughout 400 h tests.