Unraveling the prognostic significance of RGS gene family in gastric cancer and the potential implication of RGS4 in regulating tumor-infiltrating fibroblast.

Regulator of G-protein signaling (RGS) proteins are regulators of signal transduction mediated by G protein-coupled receptors (GPCRs). Current studies have shown that some molecules in the RGS gene family are related to the occurrence, development and poor prognosis of malignant tumors. However, the RGS gene family has been rarely studied in gastric cancer. In this study, we explored the mutation and expression profile of RGS gene family in gastric cancer, and evaluated the prognostic value of RGS expression. Then we established a prognostic model based on RGS gene family and performed functional analysis. Further studies showed that RGS4, as an independent prognostic predictor, may play an important role in regulating fibroblasts in the immune microenvironment. In conclusion, this study explores the value of RGS gene family in gastric cancer, which is of great significance for predicting the prognosis and guiding the treatment of gastric cancer.

Hedgehog ligand and receptor cooperatively regulate EGFR stability and activity in non-small cell lung cancer.

PURPOSE: The hyperactivation of epidermal growth factor receptor (EGFR) plays a crucial role in non-small cell lung cancer (NSCLC). Hedgehog (Hh) signaling has been implicated in the tumorigenesis and progression of various cancers, however, its function in NSCLC cells remains controversial. Herein, we present a novel finding that challenges the current understanding of Hh signaling in tumor growth. METHODS: Expression of Hh ligands and receptor were assessed using TCGA datasets, immunoblotting and immunohistochemical. Biological function of Hh ligands and receptor in NSCLC were tested using colony formation, cell count kit-8 (CCK-8) and xenograft assays. Biochemical effect of Hh ligands and receptor on regulating EGFR stability and activity were checked via immunoblotting. RESULTS: Expression of Hh ligands and receptor was suppressed in NSCLC tissues, and the lower expression levels of these genes were associated with poor prognosis. Ptch1 binds to EGFR and facilitates its poly-ubiquitylation and degradation independent of downstream transcriptional signaling. Moreover, Hh ligands cooperate with Ptch1 to regulate the protein stability and activity of EGFR. This unique mechanism leads to a suppressive effect on NSCLC tumor growth. CONCLUSION: Non-canonical Hh signaling pathway, involving cooperation between Hh ligands and their receptor Ptch1, facilitates the degradation of EGFR and attenuates its activity in NSCLC. These findings provide novel insights into the regulation of EGFR protein stability and activity, offer new diagnostic indicators for molecular typing of NSCLC and identify potential targets for targeted therapy of this challenging disease.

Diagnostic value of one-step nucleic acid amplification for sentinel lymph node metastasis in cytokeratin 19-positive tumors: evidence from bioinformatics and meta-analysis.

Background: The status of the sentinel lymph nodes (SLNs) was an important prognostic factor in varies cancers. A one-step nucleic acid amplification (OSNA) assay, a molecular-based whole-node analysis method based on CK19 mRNA copy number, was developed to diagnose lymph node metastases. We aimed to evaluate the value of OSNA for the diagnosis of sentinel lymph node metastasis in CK19 positive cancers. CK19 mRNA and protein expression for pan-caner analysis were obtained from TCGA and the Human protein atlas database. Methods: Two researchers independently searched the PubMed, Cochrane Library and Web of Science databases for qualified articles published before December 1, 2023. A meta-analysis was performed using MetaDisc and STATA. Risk bias and quality assessments of the included studies were evaluated, and a subgroup analysis was performed. Ten cancer types were found to be CK19 positively expressed and 7 of 10 had been reported to use OSNA for SLN detection. Results: After literature review, there were 61 articles included in the meta-analysis, which consisted of 7115 patients with 18007 sentinel lymph nodes. The pooled sensitivity and specificity of OSNA were 0.87 and 0.95 in overall patients. Moreover, we found the background CK19 expression in normal tissue affected the diagnostic accuracy of OSNA. In breast cancer, we performed subgroup analysis. OSNA exhibited to be a stable method across different population groups and various medical centers. In addition, when 250 copies/µl was chosen as the cutoff point of CK19 mRNA, there were a relatively higher sensitivity and AUC in detecting SLN micro-metastasis than 5000 copies/µl. Discussion: OSNA can predict the occurrence of SLN metastasis accurately in CK19 positive cancers, especially in breast cancer, colorectal cancer, lung cancer, gastric cancer and endometrial cancer. Our study warrants future studies investigating the clinical application of OSNA in pancreatic, ovarian and bladder cancers.

ITPRIPL1 binds CD3ε to impede T cell activation and enable tumor immune evasion.

Cancer immunotherapy has transformed treatment possibilities, but its effectiveness differs significantly among patients, indicating the presence of alternative pathways for immune evasion. Here, we show that ITPRIPL1 functions as an inhibitory ligand of CD3ε, and its expression inhibits T cells in the tumor microenvironment. The binding of ITPRIPL1 extracellular domain to CD3ε on T cells significantly decreased calcium influx and ZAP70 phosphorylation, impeding initial T cell activation. Treatment with a neutralizing antibody against ITPRIPL1 restrained tumor growth and promoted T cell infiltration in mouse models across various solid tumor types. The antibody targeting canine ITPRIPL1 exhibited notable therapeutic efficacy against naturally occurring tumors in pet clinics. These findings highlight the role of ITPRIPL1 (or CD3L1, CD3ε ligand 1) in impeding T cell activation during the critical "signal one" phase. This discovery positions ITPRIPL1 as a promising therapeutic target against multiple tumor types.

Enhanced detection of ligand-PPARγ binding based on surface plasmon resonance through complexation with SRC1- or NCOR2-related polypeptide.

A previous study reported the use of a biosensing technique based on surface plasmon resonance (SPR) for the ligand binding detection of peroxisome proliferator activator receptor gamma (PPARγ). This detection was designed based on the structural properties of PPARγ. Because of cross-linked protein inactivation and the low molecular weight of conventional ligands, direct ligand binding detection based on SPR has low stability and repeatability. In this study, we report an indirect response methodology based on SPR technology in which anti-His CM5 chip binds fresh PPARγ every cycle, resulting in more stable detection. We developed a remarkable improvement in ligand-protein binding detectability in vitro by introducing two coregulator-related polypeptides into this system. In parallel, a systematic indirect response methodology can reflect the interaction relationship between ligands and proteins to some extent by detecting the changes in SA-SRC1 and GST-NCOR2 binding to PPARγ. Rosiglitazone, a PPARγ agonist with strong affinity, is a potent insulin-sensitizing agent. Some ligands may be competitively exerted at the same sites of PPARγ (binding rosiglitazone). We demonstrated using indirect response methodology that selective PPARγ modulator (SPPARM) candidates of PPARγ can be found by competing for the binding of the rosiglitazone site on PPARγ, although they may have no effect on polypeptides and PPARγ binding.

Identification of novel protein biomarkers from the blood and urine for the early diagnosis of bladder cancer via proximity extension analysis.

BACKGROUND: Bladder cancer (BC) is a very common urinary tract malignancy that has a high incidence and lethality. In this study, we identified BC biomarkers and described a new noninvasive detection method using serum and urine samples for the early detection of BC. METHODS: Serum and urine samples were retrospectively collected from patients with BC (n = 99) and healthy controls (HC) (n = 50), and the expression levels of 92 inflammation-related proteins were examined via the proximity extension analysis (PEA) technique. Differential protein expression was then evaluated by univariate analysis (p < 0.05). The expression of the selected potential marker was further verified in BC and adjacent tissues by immunohistochemistry (IHC) and single-cell sequencing. A model was constructed to differentiate BC from HC by LASSO regression and compared to the detection capability of FISH. RESULTS: The univariate analysis revealed significant differences in the expression levels of 40 proteins in the serum (p < 0.05) and 17 proteins in the urine (p < 0.05) between BC patients and HC. Six proteins (AREG, RET, WFDC2, FGFBP1, ESM-1, and PVRL4) were selected as potential BC biomarkers, and their expression was evaluated at the protein and transcriptome levels by IHC and single-cell sequencing, respectively. A diagnostic model (a signature) consisting of 14 protein markers (11 in serum and three in urine) was also established using LASSO regression to distinguish between BC patients and HC (area under the curve = 0.91, PPV = 0.91, sensitivity = 0.87, and specificity = 0.82). Our model showed better diagnostic efficacy than FISH, especially for early-stage, small, and low-grade BC. CONCLUSION: Using the PEA method, we identified a panel of potential protein markers in the serum and urine of BC patients. These proteins are associated with the development of BC. A total of 14 of these proteins can be used to detect early-stage, small, low-grade BC. Thus, these markers are promising for clinical translation to improve the prognosis of BC patients.

Effect of subanesthetic dose of esketamine on postoperative pain in elderly patients undergoing laparoscopic gastrointestinal tumor Surgery:A prospective, double-blind, randomized controlled trial.

Purpose: Postoperative pain is prevalent and severe complication in elderly surgical patients. Multiple studies propose that a small dose of esketamine administered intraoperatively can alleviate postoperative pain and curtail opioid usage. We aimed to evaluate the impact of esketamine on postoperative acute pain among elderly patients with gastrointestinal tumors. Patients and methods: This is a prospective, parallel-group, randomized controlled trial. Ninety patients aged 60 and above, undergoing resection of gastrointestinal tumors, were randomly assigned to two groups: esketamine group (Group S, a single dose of 0.25 mg/kg and 0.1 mg/kg/h infusion) and control group (Group C, saline). Visual Analogue Scale (VAS) pain scores were the primary outcome. Remifentanil consumption, instances of rescue analgesia, delirium, sleep quality, postoperative recovery quality, serum levels of inflammatory cytokines, and adverse events within 72 h post-surgery were secondary outcomes, respectively. Results: Data of 87 of 99 eligible patients were analyzed. VAS scores at rest in Group S were lower than those in Group C at 6 h [1.2 (0.6, 1.6) vs 1.6 (1.0, 2.0), P = 0.003], 12 h [1.4 (1.0, 2.0) vs 2.0 (1.5, 2.0), P < 0.001], and 24 h [1.8 (1.3, 2.0) vs 2.2 (1.6, 2.6), P < 0.001] postoperatively. At 6 h post-surgery, VAS score during coughing was lower in Group S than Group C [2.0 (2.0, 2.3) vs 2.0 (2.0, 3.0), P = 0.009]. The instances of rescue analgesia were fewer in group S compared to group C (P = 0.007). Furthermore, the esketamine group showed improved sleep quality and QoR-15 score (P < 0.05) postoperatively. Conclusion: Intravenous administration of esketamine as an adjunct to general anesthesia can decrease the intensity of pain for 24 h without additional adverse effects after laparoscopic gastrointestinal tumor surgery.

Elevated splenic 18F-fluorodeoxyglucose positron emission tomography/computed tomography activity is associated with 5-year risk of recurrence in non-metastatic invasive ductal carcinoma of the breast.

OBJECTIVE: To construct prediction models including baseline 18F-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) metabolic parameters of tumoural lesions and non-tumour lymphoid tissue for recurrence-free survival within 5 years (5y-RFS) after imaging examination in patients with invasive ductal carcinomas (IDCs) of the breast. METHODS: The study included 101 consecutive female patients. Univariable and multivariable Cox regression were used to identify clinicopathological and metabolic parameters associated with risk of recurrence. Four prediction models based on the results of multivariable analysis were constructed and visualized as nomograms. Performance of each nomogram was evaluated using the concordance index (C-index), integrated discrimination improvement, decision curve analysis (DCA), and calibration curve. RESULTS: N3 status, total metabolic tumour volume, the maximum standardized uptake value of spleen, and spleen-to-liver ratio were significant predictors of 5y-RFS. The nomogram including all significant predictors demonstrated superior predictive performance for 5y-RFS, with a C-index of 0.907 (95% CI, 0.833-0.981), greatest net benefit on DCA, good accuracy on calibration curves, and excellent risk stratification on Kaplan-Meier curves. CONCLUSIONS: The model that included metabolic parameters of the spleen had the best performance for predicting 5y-RFS in patients with IDCs of the breast. This model may guide personalized treatment decisions and inform patients and clinicians about prognosis. ADVANCES IN KNOWLEDGE: This research identifies 18F-FDG PET/CT metabolic parameters of non-tumour lymphoid tissue as predictors of recurrence in breast cancer.

p32 regulates glycometabolism and TCA cycle to inhibit ccRCC progression via copper-induced DLAT lipoylation oligomerization.

A key player in mitochondrial respiration, p32, often referred to as C1QBP, is mostly found in the mitochondrial matrix. Previously, we showed that p32 interacts with DLAT in the mitochondria. Here, we found that p32 expression was reduced in ccRCC and suppressed progression and metastasis in ccRCC animal models. We observed that increasing p32 expression led to an increase in oxidative phosphorylation by interacting with DLAT, thus, regulating the activation of the pyruvate dehydrogenase complex (PDHc). Mechanistically, reduced p32 expression, in concert with DLAT, suppresses PDHc activity and the TCA cycle. Furthermore, our research discovered that p32 has a direct binding affinity for copper, facilitating the copper-induced oligomerization of lipo-DLAT specifically in ccRCC cells. This finding reveals an innovative function of the p32/DLAT/copper complex in regulating glycometabolism and the TCA cycle in ccRCC. Importantly, our research provides important new understandings of the underlying molecular processes causing the abnormal mitochondrial metabolism linked to this cancer.

Discovery of galectin-8 as an LILRB4 ligand driving M-MDSCs defines a class of antibodies to fight solid tumors.

LILRB4 is an immunosuppressive receptor, and its targeting drugs are undergoing multiple preclinical and clinical trials. Currently, the absence of a functional LILRB4 ligand in solid tumors not only limits the strategy of early antibody screening but also leads to the lack of companion diagnostic (CDx) criteria, which is critical to the objective response rate in early-stage clinical trials. Here, we show that galectin-8 (Gal-8) is a high-affinity functional ligand of LILRB4, and its ligation induces M-MDSC by activating STAT3 and inhibiting NF-κB. Significantly, Gal-8, but not APOE, can induce MDSC, and both ligands bind LILRB4 noncompetitively. Gal-8 expression promotes in vivo tumor growth in mice, and the knockout of LILRB4 attenuates tumor growth in this context. Antibodies capable of functionally blocking Gal-8 are able to suppress tumor growth in vivo. These results identify Gal-8 as an MDSC-driving ligand of LILRB4, and they redefine a class of antibodies for solid tumors.

Inhibition of FABP5 attenuates inflammatory bowel disease by modulating macrophage alternative activation.

Fatty acid binding protein 5 (FABP5) is an intracellular chaperone of fatty acid molecules that regulates lipid metabolism and cell growth. However, its role in intestinal inflammation remains enigmatic. Through examination of human tissue samples and single-cell data, we observed a significant upregulation of FABP5 within the mucosa of patients afflicted with ulcerative colitis (UC) and Crohn's disease (CD), predominantly localized in intestinal macrophages. Herein, we investigate the regulation of FABP5-IN-1, a FABP5 inhibitor, on various cells of the gut in an inflammatory environment. Our investigations confirmed that FABP5 ameliorates DSS-induced colitis in mice by impeding the differentiation of macrophages into M1 macrophages in vitro and in vivo. Furthermore, following FABP5-IN-1 intervention, we observed a notable restoration of intestinal goblet cells and tuft cells, even under inflammatory conditions. Additionally, FABP5-IN-1 exhibits a protective effect against DSS-induced colitis by promoting the polarization of macrophages towards the M2 phenotype in vivo. In summary, FABP5-IN-1 confers protection against DSS-induced acute colitis through a multifaceted approach, encompassing the reduction of inflammatory macrophage infiltration, macrophage polarization, regulating Th17/Treg cells to play an anti-inflammatory role in IBD. The implications for IBD are underscored by the comprehensive in vivo and in vitro experiments presented in this article, thereby positioning FABP5 as a promising and novel therapeutic target for the treatment of IBD.

Diversity and connectedness of brine shrimp viruses in global hypersaline ecosystems.

Brine shrimp (Artemia) has existed on Earth for 400 million years and has major ecological importance in hypersaline ecosystems. As a crucial live food in aquaculture, brine shrimp cysts have become one of the most important aquatic products traded worldwide. However, our understanding of the biodiversity, prevalence and global connectedness of viruses in brine shrimp is still very limited. A total of 143 batches of brine shrimp (belonging to seven species) cysts were collected from six continents including 21 countries and more than 100 geographic locations worldwide during 1977-2019. In total, 55 novel RNA viruses were identified, which could be assigned to 18 different viral families and related clades. Eleven viruses were dsRNA viruses, 16 were +ssRNA viruses, and 28 were-ssRNA viruses. Phylogenetic analyses of the RNA-directed RNA polymerase (RdRp) showed that brine shrimp viruses were often grouped with viruses isolated from other invertebrates and fungi. Remarkably, most brine shrimp viruses were related to those from different hosts that might feed on brine shrimp or share the same ecological niche. A notable case was the novel brine shrimp noda-like virus 3, which shared 79.25% (RdRp) and 63.88% (capsid proteins) amino acid identity with covert mortality nodavirus (CMNV) that may cause losses in aquaculture. In addition, both virome composition and phylogenetic analyses revealed global connectedness in certain brine shrimp viruses, particularly among Asia and Northern America. This highlights the incredible species diversity of viruses in these ancient species and provides essential data for the prevalence of RNA viruses in the global aquaculture industry. More broadly, these findings provide novel insights into the previously unrecognized RNA virosphere in hypersaline ecosystems worldwide and demonstrate that human activity might have driven the global connectedness of brine shrimp viruses.

Influences of Cognitive Function and Depressive Symptoms on Pain Trajectories During the First Year Following Hip Fracture Surgery: A Prospective Cohort Study.

OBJECTIVES: The purposes of this study were to explore trajectories for patterns of postoperative pain intensity during the first year following hip fracture surgery and the relationships between pain trajectory groups, cognitive impairment, and depressive symptoms. DESIGN: A prospective cohort correlational study. SETTING AND PARTICIPANTS: A total of 325 patients aged 60 years or older who had received hip fracture surgery at a 3000-bed medical center in northern Taiwan from September 2012 to March 2020. METHODS: Data were collected before hospital discharge and at 1, 3, 6, and 12 months postdischarge. Pain intensity was measured using a numeric rating scale; cognitive function was measured with the Taiwan version of the Mini-Mental State Examination; and depressive symptoms were measured by the Geriatric Depression Scale-Short Form. Patients with similar postoperative pain trajectories were categorized into groups and compared with group-based trajectory modeling. Cognitive impairment and depressive symptoms associated with each group were identified by logistic regression. RESULTS: Three different pain trajectory groups were identified: drastic decline-minimum pain (47.7%), gentle decline-mild pain (45.5%), and slight decline-moderate pain (6.8%). Patients with cognitive impairment [odds ratio (OR) 11.01, 95% CI 2.99-10.51] and at risk for depression (OR 49.09, 95% CI 10.46-230.30) were more likely to be in the moderate pain group than the minimum pain group. Patients with cognitive impairment (OR 2.07, 95% CI 1.25-3.42) were more likely to be in the mild pain group than the minimum pain group. Patients at risk for depression (OR 9.68, 95% CI 3.16-29.63) were more likely to be in the moderate pain group than the mild pain group. CONCLUSIONS AND IMPLICATIONS: Identifying postoperative pain trajectories can provide insight into the most appropriate pain management for older persons following hip fracture surgery. Attention should focus on assessments for cognitive impairment and risk of depression to prevent persistent postoperative pain. Future studies of older patients with clinically diagnosed cognitive impairment and depression are suggested.

In-Depth Proteome Profiling of Small Extracellular Vesicles Isolated from Cancer Cell Lines and Patient Serum.

Extracellular vesicle (EV) secretion has been observed in many types of both normal and tumor cells. EVs contain a variety of distinctive cargoes, allowing tumor-derived serum proteins in EVs to act as a minimally invasive method for clinical monitoring. We have undertaken a comprehensive study of the protein content of the EVs from several cancer cell lines using direct data-independent analysis. Several thousand proteins were detected, including many classic EV markers such as CD9, CD81, CD63, TSG101, and Syndecan-1, among others. We detected many distinctive cancer-specific proteins, including several known markers used in cancer detection and monitoring. We further studied the protein content of EVs from patient serum for both normal controls and pancreatic cancer and hepatocellular carcinoma. The EVs for these studies have been isolated by various methods for comparison, including ultracentrifugation and CD9 immunoaffinity column. Typically, 500-1000 proteins were identified, where most of them overlapped with the EV proteins identified from the cell lines studied. We were able to identify many of the cell-line EV protein markers in the serum EVs, in addition to the large numbers of proteins specific to pancreatic and HCC cancers.

Co-metabolic degradation and metabolite detection of hexabromocyclododecane by Shewanella oneidensis MR-1.

Hexabromocyclododecane (HBCD) is a widely used brominated flame retardant; however, it is a persistent organic pollutant as well as affects the human thyroid hormones and causes cancer. However, the degradation of HBCD has received little attention from researchers. Due to its bioaccumulative and hazardous properties, an appropriate strategy for its remediation is required. In this study, we investigated the biodegradation of HBCD using Shewanella oneidensis MR-1 under optimized conditions. The Box-Behnken design (BBD) was implemented for the optimization of the physical degradation parameters of HBCD. S. oneidensis MR-1 showed the best degradation performance at a temperature of 30 °C, pH 7, and agitation speed of 115 rpm, with an HBCD concentration of 1125 µg/L in mineral salt medium (MSM). The strain tolerated up to 2000 µg/L HBCD. Gas chromatography-mass spectrometry analysis identified three intermediates, including 2-bromo dodecane, 2,7,10-trimethyldodecane, and 4-methyl-1-decene. The results provide an insightful understanding of the biodegradation of HBCD by S. oneidensis MR-1 under optimized conditions and could pave the way for further eco-friendly applications. KEY POINTS: • HBCD biodegradation by Shewanella oneidensis • Optimization of HBCD biodegradation by the Box-Behnken analysis • Identification of useful metabolites from HBCD degradation.

[Effect of 4 kinds of prosthodontic materials on masticatory and gingival function].

PURPOSE: To investigate the effect of 4 kinds of prosthodontic materials on masticatory and gingival function. METHODS: A total of 167 patients with dental defects who underwent prosthodontic treatment from October 2019 to January 2022 were collected. They were randomly divided into 4 groups with 41 cases in the pure titanium group, 40 cases in the cobalt-chromium alloy group, 43 cases in the nickel-chromium alloy group and 43 cases in the zirconium dioxide group. The curative effect and satisfaction degree after 6 months of treatment in 4 groups were recorded and compared. The masticatory function (chewing efficiency, bite force), gingival function[plaque index(PLI), gingival index(GI) and sulcus bleeding index(SBI)], gingival crevicular fluid inflammation-related indicators[tumor necrosis factor alpha(TNF-α), interleukin-6(IL-6), aspartate aminotransferase(AST) and alkaline phosphatase (alkaline phosphatase, ALP)] before and after treatment were measured and compared in 4 groups. Statistical analysis was performed with SPSS 20.0 software package. RESULTS: There was no significant difference in curative effect in 4 groups(P＞0.05). Before and after treatment, there was no significant difference in mastication efficiency and bite force in 4 groups(P＞0.05). Before treatment, there was no significant difference in PLI, GI, SBI, gingival crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(P＞0.05). Compared with before treatment, PLI, GI and SBI in 4 groups were decreased after treatment (P＜0.05), and the decrease was in the order of cobalt-chromium alloy group≈nickel-chromium alloy group＜pure titanium group＜zirconia dioxide group. Before treatment, there was no significant difference in the weight of gingival crevicular fluid, TNF-α, IL-6, AST and ALP in gingival crevicular fluid in 4 groups(P＞0.05). The crevicular fluid weight, TNF-α, IL-6, AST and ALP in gingival crevicular fluid were significantly increased(P＜0.05), and the increase was in the order of zirconia group＜pure titanium group＜cobalt-chromium alloy group≈nickel-chromium alloy group. There was no significant difference in restoration integrity and color satisfaction in 4 groups(P＞0.05), but there was significant difference in marginal fitness and sensitivity satisfaction in 4 groups(P＜0.05). CONCLUSIONS: Pure titanium, cobalt-chromium alloy, nickel-chromium alloy and zirconium dioxide can be used for the treatment of dentition defects, and they all can obtain satisfactory chewing function. In addition, zirconium dioxide restoration has the effect of improving gingival function and inflammation-related indicators of gingival crevicular fluid with a broader application prospect.

Protection of ß cells against pro-inflammatory cytokine stress by the GDF15-ERBB2 signaling.

Aim/hypothesis: Growth/differentiation factor 15 (GDF15) is a therapeutic target for a variety of metabolic diseases, including type 1 diabetes (T1D). However, the nausea caused by GDF15 is a challenging point for therapeutic development. In addition, it is unknown why the endogenous GDF15 fails to protect from T1D development. Here, we investigate the GDF15 signaling in pancreatic islets towards opening possibilities for therapeutic targeting in ß cells and to understand why this protection fails to occur naturally. Methods: GDF15 signaling in islets was determined by proximity-ligation assay, untargeted proteomics, pathway analysis, and treatment of cells with specific inhibitors. To determine if GDF15 levels would increase prior to disease onset, plasma levels of GDF15 were measured in a longitudinal prospective study of children during T1D development (n=132 cases vs. n=40 controls) and in children with islet autoimmunity but normoglycemia (n=47 cases vs. n=40 controls) using targeted mass spectrometry. We also investigated the regulation of GDF15 production in islets by fluorescence microscopy and western blot analysis. Results: The proximity-ligation assay identified ERBB2 as the GDF15 receptor in islets, which was confirmed using its specific antagonist, tucatinib. The untargeted proteomics analysis and caspase assay showed that ERBB2 activation by GDF15 reduces ß cell apoptosis by downregulating caspase 8. In plasma, GDF15 levels were higher (p=0.0024) during T1D development compared to controls, but not in islet autoimmunity with normoglycemia. However, in the pancreatic islets GDF15 was depleted via sequestration of its mRNA into stress granules, resulting in translation halting. Conclusions/interpretation: GDF15 protects against T1D via ERBB2-mediated decrease of caspase 8 expression in pancreatic islets. Circulating levels of GDF15 increases pre-T1D onset, which is insufficient to promote protection due to its localized depletion in the islets. These findings open opportunities for targeting GDF15 downstream signaling for pancreatic ß cell protection in T1D and help to explain the lack of natural protection by the endogenous protein.

The involvement of E3 ubiquitin ligases in the development and progression of colorectal cancer.

To date, colorectal cancer (CRC) still has limited therapeutic efficacy and poor prognosis and there is an urgent need for novel targets to improve the outcome of CRC patients. The highly conserved ubiquitination modification mediated by E3 ubiquitin ligases is an important mechanism to regulate the expression and function of tumor promoters or suppressors in CRC. In this review, we provide an overview of E3 ligases in modulating various biological processes in CRC, including proliferation, migration, stemness, metabolism, cell death, differentiation and immune response of CRC cells, emphasizing the pluripotency of E3 ubiquitin ligases. We further focus on the role of E3 ligases in regulating vital cellular signal pathways in CRC, such as Wnt/ß-catenin pathway and NF-κB pathway. Additionally, considering the potential of E3 ligases as novel targets in the treatment of CRC, we discuss what aspects of E3 ligases can be utilized and exploited for efficient therapeutic strategies.

14-3-3 [Formula: see text]-reported early synaptic injury in Alzheimer's disease is independently mediated by sTREM2.

INTRODUCTION: Synaptic loss is closely associated with tau aggregation and microglia activation in later stages of Alzheimer's disease (AD). However, synaptic damage happens early in AD at the very early stages of tau accumulation. It remains unclear whether microglia activation independently causes synaptic cleavage before tau aggregation appears. METHODS: We investigated 104 participants across the AD continuum by measuring 14-3-3 zeta/delta ([Formula: see text]) as a cerebrospinal fluid biomarker for synaptic degradation, and fluid and imaging biomarkers of tau, amyloidosis, astrogliosis, neurodegeneration, and inflammation. We performed correlation analyses in cognitively unimpaired and impaired participants and used structural equation models to estimate the impact of microglia activation on synaptic injury in different disease stages. RESULTS: 14-3-3 [Formula: see text] was increased in participants with amyloid pathology at the early stages of tau aggregation before hippocampal volume loss was detectable. 14-3-3 [Formula: see text] correlated with amyloidosis and tau load in all participants but only with biomarkers of neurodegeneration and memory deficits in cognitively unimpaired participants. This early synaptic damage was independently mediated by sTREM2. At later disease stages, tau and astrogliosis additionally mediated synaptic loss. CONCLUSIONS: Our results advertise that sTREM2 is mediating synaptic injury at the early stages of tau accumulation, underlining the importance of microglia activation for AD disease propagation.