Immunotherapeutic hydrogel for co-delivery of STAT3 siRNA liposomes and lidocaine hydrochloride for postoperative comprehensive management of NSCLC in a single application.

Despite standard treatment for non-small cell lung cancer (NSCLC) being surgical resection, cancer recurrence and complications, such as induction of malignant pleural effusion (MPE) and significant postoperative pain, usually result in treatment failure. In this study, an alginate-based hybrid hydrogel (SOG) is developed that can be injected into the resection surface of the lungs during surgery. Briefly, endoplasmic reticulum-modified liposomes (MSLs) pre-loaded with the signal transducer and activator of transcription 3 (STAT3) small interfering RNA and lidocaine hydrochloride are encapsulated in SOG. Once applied, MSLs strongly downregulated STAT3 expression in the tumor microenvironment, resulting in the apoptosis of lung cancer cells and polarization of tumor-associated macrophages towards the M1-like phenotype. Meanwhile, the release of lidocaine hydrochloride (LID) was beneficial for pain relief and natural killer cell activation. Our data demonstrated MSL@LID@SOG not only efficiently inhibited tumor growth but also potently improved the quality of life, including reduced MPE volume and pain relief in orthotopic NSCLC mouse models, even with a single administration. MSL@LID@SOG shows potential for comprehensive clinical management upon tumor resection in NSCLC, and may alter the treatment paradigms for other cancers.

TGF-ß1 Triggers Salivary Hypofunction via Attenuating Protein Secretion and AQP5 Expression in Human Submandibular Gland Cells.

Aging-related salivary gland degeneration usually causes poor oral health. Periductal fibrosis frequently occurs in the submandibular gland of the elderly. Transforming growth factor ß1 (TGF-ß1) is the primary driving factor for fibrosis, which exhibits an increase in the fibrotic submandibular gland tissue. This study aimed to investigate the effects of TGF-ß1 on the human submandibular gland (HSG) cell secretory function and its influences on aquaporin 5 (AQP5) expressions and distribution. We found that TGF-ß1 reduces the protein secretion amount of HSG and leads to the abundance alteration of 151 secretory proteins. Data are available via ProteomeXchange with the identifier PXD043185. The majority of HSG secretory proteins (84.11%) could be matched to the human saliva proteome. Meanwhile, TGF-ß1 enhances the expression of COL4A2, COL5A1, COL7A1, COL1A1, COL2A1, and α-SMA, hinting that TGF-ß1 possesses the potential to drive HSG fibrosis-related events. Besides, TGF-ß1 also attenuates the AQP5 expression and its membrane distribution in HSGs. The percentage for TGF-ß1-induced AQP5 reduction (52.28%) is much greater than that of the TGF-ß1-induced secretory protein concentration reduction (16.53%). Taken together, we concluded that TGF-ß1 triggers salivary hypofunction via attenuating protein secretion and AQP5 expression in HSGs, which may be associated with TGF-ß1-driven fibrosis events in HSGs.

Beneficial or detrimental: Recruiting more types of benign cases for cancer diagnosis based on salivary glycopatterns.

With the advantages of convenient, painless and non-invasive collection, saliva holds great promise as a valuable biomarker source for cancer detection, pathological assessment and therapeutic monitoring. Salivary glycopatterns have shown significant potential for cancer screening in recent years. However, the understanding of benign lesions at non-cancerous sites in cancer diagnosis has been overlooked. Clarifying the influence of benign lesions on salivary glycopatterns and cancer screening is crucial for advancing the development of salivary glycopattern-based diagnostics. In this study, 2885 samples were analyzed using lectin microarrays to identify variations in salivary glycopatterns according to the number, location, and type of lesions. By utilizing our previously published data of tumor-associated salivary glycopatterns, the performance of machine learning algorithm for cancer screening was investigated to evaluate the effect of adding benign disease cases to the control group. The results demonstrated that both the location and number of lesions had discernible effects on salivary glycopatterns. And it was also revealed that incorporating a broad range of benign diseases into the controls improved the classifier's performance in distinguishing cancer cases from controls. This finding holds guiding significance for enhancing salivary glycopattern-based cancer screening and facilitates their practical implementation in clinical settings.

Choroidal Circulation in 8- to 30-Year-Old Chinese, Measured by SS-OCT/OCTA: Relations to Age, Axial Length, and Choroidal Thickness.

Purpose: The purpose of this study was to evaluate and explore the determinants of choroidal vascularity and choriocapillaris perfusion in a Chinese population aged 8 to 30 years old. Methods: Three hundred eighty eyes from 380 subjects aged 8 to 30 years were included in this cross-sectional study. Submacular choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), and choriocapillaris flow deficit (CcFD) were estimated using images obtained from optical coherence tomography (OCT). Results: In this population, the mean ChT was 260.4 ± 63.3 µm, TCA was 1.56 ± 0.38 mm2, LA was 0.94 ± 0.25 mm2, and SA was 0.62 ± 0.15 mm2. The mean CVI was 60.25 ± 3.21% and CcFD was 11.95 ± 1.98%. Multivariable analyses showed that higher CVI and LA was associated with older age, thicker ChT, and shorter AL; and lower CcFD was associated with shorter AL. However, the associations were not uniformly rectilinear between CcFD and age. Specifically, CcFD was positively associated with age in subjects ≤19 years old and negatively associated with age in subjects >19 years old. Conclusions: Development of the choroidal medium- and large-sized vascular layers and choriocapillaris was different across patients aged 8 to 30 years old. Greater axial length was associated with attenuated choroidal circulation. Choroidal thickness correlated well with choroidal vascularity, but not with choriocapillaris perfusion. Further comprehensive and longitudinal assessment of choroidal vasculature and choriocapillaris perfusion will help greatly to understand the physiological and pathological mechanisms responsible for myopia.

Mutual regulation between glycosylation and transforming growth factor-ß isoforms signaling pathway.

Transforming growth factor-beta (TGF-ß) superfamily members orchestrate a wide breadth of biological processes. Through Sma and Mad (Smad)-related dependent or noncanonical pathways, TGF-ß members involve in the occurrence and development of many diseases such as cancers, fibrosis, autoimmune diseases, cardiovascular diseases and brain diseases. Glycosylation is one kind of the most common posttranslational modifications on proteins or lipids. Abnormal protein glycosylation can lead to protein malfunction and biological process disorder, thereby causing serious diseases. Previously, researchers commonly make comprehensive systematic overviews on the roles of TGF-ß signaling in a specific disease or biological process. In recent years, more and more evidences associate glycosylation modification with TGF-ß signaling pathway, and we can no longer disengage and ignore the roles of glycosylation from TGF-ß signaling to make investigation. In this review, we provide an overview of current findings involved in glycosylation within TGF-ßs and theirs receptors, and the interaction effects between glycosylation and TGF-ß subfamily signaling, concluding that there is an intricate mutual regulation between glycosylation and TGF-ß signaling, hoping to present the glycosylation regulatory patterns that concealed in TGF-ßs signaling pathways.

Advances in IgA glycosylation and its correlation with diseases.

Immunoglobulin A (IgA) is the most abundant immunoglobulin synthesized in the human body. It has the highest concentration in the mucosa and is second only to IgG in serum. IgA plays an important role in mucosal immunity, and is the predominant antibody used to protect the mucosal surface from pathogens invasion and to maintain the homeostasis of intestinal flora. Moreover, The binding IgA to the FcαRI (Fc alpha Receptor I) in soluble or aggregated form can mediate anti- or pro- inflammatory responses, respectively. IgA is also known as one of the most heavily glycosylated antibodies among human immunoglobulins. The glycosylation of IgA has been shown to have a significant effect on its immune function. Variation in the glycoform of IgA is often the main characteration of autoimmune diseases such as IgA nephropathy (IgAN), IgA vasculitis (IgAV), systemic lupus erythematosus (SLE), and rheumatoid arthritis (RA). However, compared with the confirmed glycosylation function of IgG, the pathogenic mechanism of IgA glycosylation involved in related diseases is still unclear. This paper mainly summarizes the recent reports on IgA's glycan structure, its function, its relationship with the occurrence and development of diseases, and the potential application of glycoengineered IgA in clinical antibody therapeutics, in order to provide a potential reference for future research in this field.

High Expression Level of α2-3-Linked Sialic Acids on Salivary Glycoproteins of Breastfeeding Women May Help to Protect Them from Avian Influenza Virus Infection.

Terminal sialic acids (Sia) on soluble glycoprotein of saliva play an important role in the clearance of influenza virus. The aim of this study is to investigate the alteration of sialylation on the salivary proteins of women during the lactation period and its effect on the saliva binding ability to virus. In total, 210 saliva samples from postpartum women with and without breastfeeding were collected, and the expression level of α2-3/6-linked Sia on the whole salivary proteins and specific glycoproteins of IgA and MUC5B from different groups were tested and verified using lectin microarray, blotting analysis and ELISA based method. The H1N1 vaccine and three strains of Avian influenza virus (AIV) were used for the saliva binding assay. Results showed that the variation in salivary expression level of α2-3-linked Sia was much more obvious than the α2-6-linked Sia, which was up-regulated significantly in the breastfeeding groups compared to the non-breastfeeding groups at the same postpartum stage. Furthermore, the binding abilities of salivary glycoproteins to AIV strains and H1N1 vaccine were increased in breastfeeding groups accordingly. This finding adds new evidence for the maternal benefit of breastfeeding and provides new thinking to protect postpartum women from AIV infection.

Differences in Retinal and Choroidal Vasculature and Perfusion Related to Axial Length in Pediatric Anisomyopes.

Purpose: The purpose of this study was to evaluate the interocular differences in choroidal vasculature, choriocapillaris perfusion, and retinal microvascular network, and to explore their associations with interocular asymmetry in axial lengths (ALs) in children with anisomyopia. Methods: Refractive error, AL, and other biometric parameters were measured in 70 children with anisomyopia. Using optical coherence tomography (OCT) and OCT-angiography, we measured the submacular choroidal thickness (ChT), total choroidal area (TCA), luminal area (LA), stromal area (SA), choroidal vascularity index (CVI), choriocapillaris flow deficit (CcFD), retinal vessel density (VD), and foveal avascular zone (FAZ) area. Results: The mean interocular differences in spherical equivalent refraction and AL were -2.26 ± 0.94 diopters and 0.95 ± 0.46 mm, respectively. Submacular ChT, TCA, LA, SA, and CVI were all significantly lower in the more myopic (longer AL) eyes than in the less myopic (shorter AL) fellow eyes. In eyes with longer ALs, both the CcFD and FAZ areas were significantly greater, whereas the superficial and deep retinal VDs were significantly less. After adjusting for corneal power and intraocular pressure, interocular differences in LA (ß = -0.774), SA (ß = -0.991), and CcFD (ß = 0.040) were significantly associated with interocular asymmetry in AL (all P < 0.05). Conclusions: In pediatric anisomyopes, eyes with longer ALs tended to have lower choroidal vascularity and choriocapillaris perfusion than the contralateral eyes with shorter ALs. Longitudinal investigations would be useful follow-ups to test for a causal role of choroidal circulation in human myopia.

Pregnancy-associated decrease of Siaα2-3Gal-linked glycans on salivary glycoproteins affects their binding ability to avian influenza virus.

Salivary glycoproteins are known as an important barrier to inhibit influenza infection by presenting sialic acid (Sia) ligands that can bind with viral hemagglutination. Here, to further understand why pregnant women are more vulnerable to avian influenza virus (AIV), we investigated the alteration of protein sialylation in the saliva of women during pregnancy and postpartum, and its impact on the saliva binding affinity to AIV. Totally 1200 saliva samples were collected, the expression levels of terminal α2-3/6-linked Sia on salivary proteins were tested and validated, and the binding activities of salivary proteins were assessed against 3 strains of AIV and the H1N1 vaccine. Result showed that the expression of terminal α2-3-linked Sia in the saliva of women decreased dramatically during pregnancy compared to that of non-pregnancy control, especially for women in the second or third trimester (fold change = 0.53 and 0.37, p < 0.001). And their salivary protein binding ability to AIV declined accordingly. The variation of terminal α2-3-linked Sia on salivary MUC5B and IgA was consistent with the above results. This study indicates that the decrease of terminal α2-3-linked Sia on salivary glycoproteins of pregnant women affects their binding ability to AIV, which may provide new insights into AIV prevention and control.