Isthmin-1 promotes growth and progression of colorectal cancer through the interaction with EGFR and YBX-1.

While previous studies have indicated the involvement of Isthmin 1 (ISM1), a secreted protein, in cancer development, the precise mechanisms have remained elusive. In this study, we unveiled that ISM1 is significantly overexpressed in both the blood and tissue samples of colorectal cancer (CRC) patients, correlating with their poor prognosis. Functional experiments demonstrated that enforced ISM1 expression significantly enhances CRC proliferation, migration, invasion and tumor growth. Notably, our investigation reveals an interaction of ISM1 with epidermal growth factor receptor (EGFR), a member of the receptor tyrosine kinase (RTK) family of CRC cells. The binding of ISM1 triggered EGFR activation and initiate downstream signaling pathways. Meanwhile, intracellular ISM1 interacted with Y-box binding protein 1 (YBX1), enhancing its transcriptional regulation on EGFR. Furthermore, our research uncovered the regulation of ISM1 expression by the hypoxia-inducible transcription factor HIF-1α in CRC cells. Mechanistically, we identified HIF-1α as a direct regulator of ISM1, binding to a hypoxia response element on its promoter. This novel mechanism illuminated potential therapeutic targets, offering insights into restraining HIF-1α/ISM1/EGFR-driven CRC progression and metastasis.

Identifying a panel of nine genes as novel specific model in endometriosis noninvasive diagnosis.

OBJECTIVE: To study biomarkers to develop a novel diagnosis model for endometriosis and validate it using clinical samples. DESIGN: We used publicly available data sets and weighted gene coexpression network analysis to identify differentially expressed genes. Ten machine learning algorithms were used to develop an integrative model for predicting endometriosis. The accuracy and robustness of the model were validated using data sets and clinical samples. SETTING: Department of Obstetrics and Gynecology, Tangdu Hospital, Air Force Medical University, Xi'an, Shaanxi, China. PATIENT(S): The study included clinical patients between the ages of 20 and 40 years who required laparoscopic surgery and who had not undergone hormone therapy within the previous 3 months. All the healthy individuals had given birth to a child at least once in their lives. Patients with inflammatory conditions, malignant diseases, immune diseases, myoma, or adenomyosis were excluded. Paraffin blocks of the samples were collected (case, n = 5; control, n = 5). Blood samples of 58 individuals were collected (case, n = 28; control, n = 30). INTERVENTION(S): None. MAIN OUTCOME MEASURE(S): The areas under the receiver operator characteristic curve of our diagnostic model were measured for data sets and clinical samples. Multiplex immunohistochemical staining and real-time quantitative polymerase chain reaction assays were used for the validation of the model from tissue slides and peripheral blood samples. RESULT(S): A nine-gene panel endometriosis messenger RNA score (EMScore), was constructed to distinguish the patients with endometriosis from healthy individuals using algorithms. The EMScore accurately predicted endometriosis, and the areas under the receiver operator characteristic curve of our diagnostic model were 0.920, and 0.942 for tissue and blood samples, respectively. Moreover, the EMScore outperformed other acknowledged signatures for predicting endometriosis across seven clinical cohorts. Overall, the EMScore constitutes a sensitive and specific noninvasive diagnostic method for endometriosis. CONCLUSION(S): We developed the EMScore, a novel model that can aid in the diagnosis of endometriosis using peripheral blood samples. This study will contribute to the development of improved clinical noninvasive and sensitive diagnostic tools for endometriosis. These nine genes might be potential target molecules for treating endometriosis.

A Disintegrin and Metalloprotease 10 Expressions Modulate Potential Metastatic and Thrombus Formation in Pancreatic Carcinoma.

Background: Clinical investigations repurposing a disintegrin and metalloproteases 10 (ADAM10) as metastatic and thrombus marker have achieved encouraging results, but the mechanism behind this association remains unclear. Methods: This study was carried out in NingXia and Wuhan, China from 2017 to 2021. The effects of ADAM10 expression on the metastatic and thrombus-associated genes: tissue factor (TF), P-selectin glycoprotein ligand-1 (PSGL-1), cathepsin G (CTSG) and mucin 1 (MUC1) were examined by immunofluorescence, qRTPCR and Western blotting analysis. Metastatic and thrombotic behaviors were evaluated using NODSCID mouse model. Results: The ADAM10 expression controlled the migration and invasion of pancreatic carcinoma cell-1(PANC-1), and significantly regulated the metastatic and thrombus-associated genes (P<0.05). ADAM10 and MUC1 were regulated and aberrantly expressed by a dependent mechanism. Moreover, ADAM10 expression induced the progression of adenocarcinoma cells and thrombus formation in vivo. Conclusion: Regulation of ADAM10 expression in cancer cells might effectively pave the way for a more potent anti-metastatic and anti-thrombotic approach and could regulate the invasion and migration of cancer cells.

Development of rapamycin-encapsulated exosome-mimetic nanoparticles-in-PLGA microspheres for treatment of hemangiomas.

We have previously developed several kinds of rapamycin-encapsulated nanoparticles to achieve sustained release of rapamycin to treat hemangioma. However, lack of intrinsic targeting and easy clearance by the immune system are major hurdles that artificial fabricated nanoparticles must overcome. We constructed rapamycin-encapsulated macrophage-derived exosomes mimic nanoparticles-in-microspheres (RNM), to achieve the goal of continuous targeted therapy of hemangiomas. The rapamycin-encapsulated exosome mimic nanoparticles (RN) were firstly prepared by the extrusion-based method from the U937 cells (the human macrophage cell line). After then, RN was encapsulated with PLGA (poly(lactic-co-glycolic acid)) microspheres to obtain RNM. The release profile, targeting activity, and biological activity of RN and RNM were investigated on hemangioma stem cells (HemSCs). RN has a size of 100 nm in diameter, with a rapamycin encapsulation efficacy (EE) of 83%. The prepared microspheres RNM have a particle size of ~30 µm), and the drug EE of RNM is 34%. The sustained release of RNM can remarkably be achieved for 40 days. As expected, RN and RNM showed effective inhibition of cellular proliferation, significant cellular apoptosis, and remarkable repressed expression of angiogenesis factors in HemSCs. Our results showed that RNM is an effective approach for prolonged and effective delivery of rapamycin to hemangiomas.

Ultra-Sensitive and Selective Electrochemical Bio-Fluid Biopsy for Oral Cancer Screening.

The early diagnosis of recurrence and metastasis is critically important for decreasing the morbidity and mortality associated with oral cancers. Although liquid biopsy methods hold great promise that provide a successive "time-slice" profile of primary and metastatic oral cancer, the development of non-invasive, rapid, simple, and cost-effective liquid biopsy techniques remains challenging. In this study, an ultrasensitive and selective electrochemical liquid biopsy is developed for oral cancer screening based on tracking trace amounts of cancer biomarker by functionalized asymmetric nano-channels. Detection via antigen-antibody reactions is assayed by evaluating changes in ionic current. Upon the recognition of cancer biomarker antigens in bio-fluids, the inner wall of nano-channel immobilized with the corresponding antibodies undergoes molecular conformation transformation and surface physicochemical changes, which significantly regulate the ion transport through the nano-channel and help achieve sensitivity with a detection limit of 10-12 g mL-1 . Furthermore, owing to the specificity of the monoclonal antibody for the antigen, the nano-channel exhibits high selectivity for the biomarker than for structurally similar biological molecules present in bio-fluids. The effectiveness of this technique is confirmed through the diagnosis of clinical cases of oral squamous cell carcinoma. This study presents a novel diagnostic tool for oral cancer detection in bio-fluids.

Enhanced rapamycin delivery to hemangiomas by lipid polymer nanoparticles coupled with anti-VEGFR antibody.

The most common tumors in children are infantile hemangiomas which could cause morbidity and severe complications. The development of novel alternative drugs to treat infantile hemangiomas is necessary, since Hemangeol is the only US Food and Drug Administration-approved drug for infantile hemangiomas. However, Hemangeol has several disadvantages, including a high frequency of administration and adverse effects. Rapamycin is a well­established antiangiogenic drug, and we have previously developed rapamycin lipid polymer nanoparticles (R­PLNPs) as a local sustained­release drug delivery system to achieve controlled rapamycin release and to decrease the frequency of administration and side effects of rapamycin. To improve the targeting of R­PLNPs to infantile hemangiomas in the present study, R­PLNPs were modified to include an antibody against vascular endothelial growth factor receptor (VEGF). The characteristics, and the anti­hemangioma activity of the resulting R­PLNPs coupled with the anti­VEGFR2 antibody (named R­PLNPs­V) were examined in vitro and in vivo. R­PLNPs­V possessed a small size (115 nm) and sustained drug release for 6 days. The anti­VEGFR2 antibody promoted the targeting and cytotoxic effect of R­PLNPs­V to human hemangioma endothelial cells and human umbilical vein endothelial cells. Using a subcutaneous infantile hemangioma xenograft in mice, the in vivo therapeutic effect (evaluated with hemangioma weight, volume, and microvessel density) of R­PLNPs­V was demonstrated to be superior compared with rapamycin alone and other non­targeted nanoparticles, without any total body weight loss. In summary, R­PLNPs­V could facilitate targeted delivery and sustained release of rapamycin to infantile hemangiomas, and thus may represent a promising candidate treatment for infantile hemangiomas.

Inhibition of hemangioma growth using polymer-lipid hybrid nanoparticles for delivery of rapamycin.

Although infantile hemangiomas is benign, its rapid growth may induce serious complications. However, only one drug Hemangeol™ has been approved by US Food and Drug Administration (FDA) to treat infantile hemangiomas. Thus it is necessary to develop novel alternative drugs to treat infantile hemangiomas. Rapamycin is a well-know potent antiangiogenic agent, whereas the daily oral administration of rapamycin exerts undesired metabolic effects due to its inhibition of mechanistic target of rapamycin (mTOR) which is critical in cell metabolism. We hereby developed rapamycin-loaded polymer-lipid hybrid nanoparticles (Rapamycin-PLNPs) as a local controlled release system to realize local and sustained release of rapamycin, aiming to reduce the side effects and frequency of administration of rapamycin. Rapamycin-PLNPs are of a small size (129.1nm), desired drug encapsulation efficiency (63.7%), and sustained drug release for 5 days. Rapamycin-PLNPs were shown to be able to effectively bind to hemangioma endothelia cells (HemECs), induce significant proliferation inhibition and reduce expression of angiogenesis factors in HemECs. The therapeutic effect of Rapamycin-PLNPs against infantile hemangioma in vivo was superior to rapamycin, as reflected by reduced hemangioma volume, weight and microvessel density. Taken together, Rapamycin-PLNPs represent a very promising local approach in the treatment of infantile hemangiomas.

Serum uric acid is associated with increased risk of idiopathic venous thromboembolism in high HDL-C population: A case-control study.

Many studies have indicated that metabolic disorders are positively correlated with idiopathic venous thromboembolism (VTE), whereas the risk factor serum uric acid (SUA) for idiopathic VTE has yet to be investigated. In this retrospective case-control study, 276 idiopathic VTE patients and 536 gender- and age-matched control subjects were included. The subjects in the case and control groups exhibiting common known VTE risk factors and the patients with a first VTE onset in one month were excluded. For the control group, primary and secondary VTE patients were excluded. High-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol, total cholesterol, fasting blood glucose, and current smoking were significantly associated with idiopathic VTE in the univariate analysis. Hyperuricemia was detected in 56/276 (20.29%) idiopathic patients compared with 71/536 (13.25%) in the control group. HDL-C was considered the most prominent interactive factor for SUA in idiopathic VTE by the interaction analysis. After testing for the interaction terms, SUA was closely associated with idiopathic VTE in the high HDL-C population (P=0.0026 for interaction), while there was no such correlation in the low HDL-C group. The results indicated no obvious correlation between triglyceride and hypertension to idiopathic VTE. In conclusion, SUA is closely associated with an increased risk of idiopathic VTE in the high HDL-C population. The abnormality of SUA may act as an important linkage between atherosclerosis and idiopathic VTE through HDL-C.

Toll-like receptor-triggered calcium mobilization protects mice against bacterial infection through extracellular ATP release.

Extracellular ATP (eATP), released as a "danger signal" by injured or stressed cells, plays an important role in the regulation of immune responses, but the relationship between ATP release and innate immune responses is still uncertain. In this study, we demonstrated that ATP was released through Toll-like receptor (TLR)-associated signaling in both Escherichia coli-infected mice and lipopolysaccharide (LPS)- or Pam3CSK4-treated macrophages. This ATP release could be blocked completely only by N-ethylmaleimide (NEM), not by carbenoxolone (CBX), flufenamic acid (FFA), or probenecid, suggesting the key role of exocytosis in this process. Furthermore, LPS-induced ATP release could also be reduced dramatically through suppressing calcium mobilization by use of U73122, caffeine, and thapsigargin (TG). In addition, the secretion of interleukin-1ß (IL-1ß) and CCL-2 was enhanced significantly by ATP, in a time- and dose-dependent manner. Meanwhile, macrophage-mediated phagocytosis of bacteria was also promoted significantly by ATP stimulation. Furthermore, extracellular ATP reduced the number of invading bacteria and protected mice from peritonitis by activating purinergic receptors. Mechanistically, phosphorylation of AKT and ERK was overtly increased by ATP in antibacterial immune responses. Accordingly, if we blocked the P2X- and P2Y-associated signaling pathway by using suramin and pyridoxal phosphate-6-azo(benzene-2,4-disulfonic acid), tetrasodium salt (PPADS), the ATP-enhanced immune response was restrained significantly. Taken together, our findings reveal an internal relationship between danger signals and TLR signaling in innate immune responses, which suggests a potential therapeutic significance of calcium mobilization-mediated ATP release in infectious diseases.