Family of hNQO1 Activatable Near-Infrared Fluoro-Photoacoustic Probes for Diagnosis of Wound Infection and Ulcerative Colitis.

Bacterial infections can easily occur when patients mishandle wounds or eat moldy food. The prompt diagnosis of a bacterial infection could effectively reduce the risk of possible anatomical damage. However, non-invasive early detection of bacterial infections is difficult to achieve due to the lack of favorable tools. Here, we designed two hNQO1 fluorescent probes (RX2 and RX3) to visualize bacterial infection after deep learning on the pathogenesis of bacterial infection. RX2 and RX3 enable early detection of bacterial infection and are verified to be, respectively, suitable for fluorescence imaging (FLI) and photoacoustic imaging (PAI) by comparing the signal-to-background ratio of both probes in a mouse model of myositis caused by Escherichia coli infection. In view of the difference in penetration depth between the two imaging modalities, we further applied RX2 for FLI of E. coli-infected wounds and RX3 for PAI of E. coli-infected inflammatory bowel disease, suggesting the great potential of both probes for early diagnosis of bacterial infections.

Can DKI-MRI predict recurrence and invasion of peritumoral zone of hepatocellular carcinoma after transcatheter arterial chemoembolization?

BACKGROUND: Hepatocellular carcinoma (HCC) is a major cause of cancer-related mortality worldwide. Transcatheter arterial chemoembolization (TACE) has been performed as a palliative treatment for patients with HCC. However, HCC is easy to recur after TACE. Magnetic resonance imaging (MRI) has clinical potential in evaluating the TACE treatment effect for patients with liver cancer. However, traditional MRI has some limitations. AIM: To explore the clinical potential of diffusion kurtosis imaging (DKI) in predicting recurrence and cellular invasion of the peritumoral liver zone of HCC after TACE. METHODS: Seventy-six patients with 82 HCC nodules were recruited in this study and underwent DKI after TACE. According to pathological examinations or the overall modified response evaluation criteria in solid tumors (mRECIST) criterion, 48 and 34 nodules were divided into true progression and pseudo-progression groups, respectively. The TACE-treated area, peritumoral liver zone, and far-tumoral zone were evaluated on DKI-derived metric maps. Non-parametric U test and receiver operating characteristic curve (ROC) analysis were used to evaluate the prediction performance of each DKI metric between the two groups. The independent t-test was used to compare each DKI metric between the peritumoral and far-tumoral zones of the true progression group. RESULTS: DKI metrics, including mean diffusivity (MD), axial diffusivity (DA), radial diffusivity (DR), axial kurtosis (KA), and anisotropy fraction of kurtosis (Fak), showed statistically different values between the true progression and pseudo-progression groups (P < 0.05). Among these, MD, DA, and DR values were higher in pseudo-progression lesions than in true progression lesions, whereas KA and FAk values were higher in true progression lesions than in pseudo-progression lesions. Moreover, for the true progression group, the peritumoral zone showed significantly different DA, DR, KA, and FAk values from the far-tumoral zone. Furthermore, MD values of the liver parenchyma (peritumoral and far-tumoral zones) were significantly lower in the true progression group than in the pseudo-progression group (P < 0.05). CONCLUSION: DKI has been demonstrated with robust performance in predicting the therapeutic response of HCC to TACE. Moreover, DKI might reveal cellular invasion of the peritumoral zone by molecular diffusion-restricted change.

Genetic correlation between female infertility and mental health and lifestyle factors: A linkage disequilibrium score regression study.

Background and Aims: Female fertility is a heterogeneous condition of complete psychosocial and physical well-being. Observational studies have revealed that women with infertility have varying degrees of poor mental status and lifestyle choices in varying degrees. However, the genetic contribution to female infertility remains elusive. Our study aimed to explore the genetic correlations between female infertility and mental health and lifestyle factors. Methods: The genome-wide association study (GWAS) data sets of characteristics related to mental health and lifestyle were obtained from the IEU OpenGWAS database. The GWAS data sets of female infertility were derived from the Finggen database. Linkage disequilibrium score regression was performed to systematically estimate the pairwise genetic correlations between female infertility and a set of mental health- and lifestyle-related traits. Results: The genetic correlation analysis revealed a moderate and positive genetic correlation between depressive symptoms, major depressive disorder, and female infertility. Similarly, worry and the personality trait of neuroticism displayed a moderate positive genetic correlation with female infertility. Adversely, a negative and moderate genetic correlation was observed between strenuous sports or exercises and female infertility. Conclusion: The study demonstrated genetic correlations between female infertility and mental health status, including depression, worry, and neuroticism. Additionally, we observed that females with better physical activity may have reduced risks of female infertility. These findings would serve as a fundamental resource for understanding the genetic mechanisms of the effects of mental health and lifestyle factors on female infertility.

Reversal of Solvatochromism: A New Strategy to Construct Activatable Two-photon Fluorescent Probes for Sensing.

Two-photon (TP) imaging with a donor-acceptor (D-A) type fluorophore is an emerging tool for bioimaging and sensing. However, current TP probes suffer from serious solvatochromic quenching in aqueous solution due to their strong intramolecular charge transfer (ICT) in excited states. In this work, based on solvatochromism reversal, we report a novel strategy to develop TP probes for bioimaging. Specifically, compared with the normal two-photon probes that showed a fluorescence off with ICT suppressed, the novel probes exhibited strong fluorescence in the aqueous solution when their ICT was inhibited. This strategy not only provides a new way for the design of high-performance TP probes, but also expands the biological analysis toolbox for use in living systems.

Metabolomics Analysis Discovers Estrogen Altering Cell Proliferation via the Pentose Phosphate Pathway in Infertility Patient Endometria.

Estrogen therapy is widely used as a supplementary treatment after hysteroscopy for female infertility patients owing to its protective function that improves endometrial regeneration and menstruation, inhibits recurrent adhesions, and improves subsequent conception rate. The endometrial protective function of such estrogen administration pre-surgery is still controversial. In the current study, 12 infertility patients were enrolled, who were treated with estrogen before hysteroscopy surgery. Using cutting-edge metabolomic analysis, we observed alterations in the pentose phosphate pathway (PPP) intermediates of the patient's endometrial tissues. Furthermore, using Ishikawa endometrial cells, we validated our clinical discovery and identified estrogen-ESR-G6PD-PPP axial function, which promotes estrogen-induced cell proliferation.

Physicochemical characterization and phase I study of CMAB008, an infliximab biosimilar produced by a different expression system.

BACKGROUND: Infliximab (Remicade), a chimeric monoclonal antibody against human TNFα, will inevitably face competition from biosimilar products, because of its effectiveness in autoimmune diseases and rapidly increasing market demand. According to guidelines for biosimilar development, the "biosimilar-expression system" may differ from that of the innovator, but more appropriate studies should be carried out to demonstrate the comparability between biosimilar and innovator. CMAB008 is an infliximab biosimilar candidate developed by the State Key Laboratory of Antibody Medicine and Targeted Therapy of China. Infliximab was expressed in SP2/0 cells, while CMAB008 was produced in a CHO-expression system. METHODS: In this study, infliximab and CMAB008 were compared on physicochemical and biological characterizations, including protein content, activity, physiochemical integrity, impurities, additives, and immunogenicity. RESULTS: The results showed that they were highly similar and comparable, except some differences in glycosylation. As glycosylation profiles can influence immunogenicity and occurrence of allergy or other adverse reactions of antibody therapeutics, primary tolerability and pharmacokinetics of CMAB008 were evaluated. In the phase I clinical trial, plasma concentration of CMAB008 and antidrug antibodies were also measured using ELISA and bridging ELISA, respectively. CMAB008 exhibited favorable clinical tolerability, no adverse events in the 3 mg/kg single-dose group (recommended therapeutic dosage), and no serious adverse events in the multiple-dose group. Also, no injection-site reactions were observed in the experiment. CONCLUSION: In summary, CMAB008 might have the potential to be an effective drug compared with infliximab.

Versatile characterization of glycosylation modification in CTLA4-Ig fusion proteins by liquid chromatography-mass spectrometry.

CTLA4-Ig is a highly glycosylated therapeutic fusion protein that contains multiple N- and O-glycosylation sites. Glycosylation plays a vital role in protein solubility, stability, serum half-life, activity, and immunogenicity. For a CTLA4-Ig biosimilar development program, comparative analytical data, especially the glycosylation data, can influence decisions about the type and amount of animal and clinical data needed to establish biosimilarity. Because of the limited clinical experience with biosimilars before approval, a comprehensive level of knowledge about the biosimilar candidates is needed to achieve subsequent development. Liquid chromatography-mass spectrometry (LC-MS) is a versatile technique for characterizing N- and O-glycosylation modification of recombinant therapeutic proteins, including 3 levels: intact protein analysis, peptide mapping analysis, and released glycans analysis. In this report, an in-depth characterization of glycosylation of a candidate biosimilar was carried out using a systematic approach: N- and O-linked glycans were identified and electron-transfer dissociation was then used to pinpoint the 4 occupied O-glycosylation sites for the first time. As the results show, the approach provides a set of routine tools that combine accurate intact mass measurement, peptide mapping, and released glycan profiling. This approach can be used to comprehensively research a candidate biosimilar Fc-fusion protein and provides a basis for future studies addressing the similarity of CTLA4-Ig biosimilars.