Chimeric antigen receptor dendritic cells targeted delivery of a single tumoricidal factor for cancer immunotherapy.

BACKGROUND: Chimeric antigen receptor (CAR)-T cells have been used to treat blood cancers by producing a wide variety of cytokines. However, they are not effective in treating solid cancers and can cause severe side-effects, including cytokine release syndrome. TNFα is a tumoricidal cytokine, but it markedly increases the protein levels of cIAP1 and cIAP2, the members of inhibitor of apoptosis protein (IAP) family of E3 ubiquitin ligase that limits caspase-induced apoptosis. Degradation of IAP proteins by an IAP antagonist does not effectively kill cancer cells but enables TNFα to strongly induce cancer cell apoptosis. It would be a promising approach to treat cancers by targeted delivery of TNFα through an inactive adoptive cell in combination with an IAP antagonist. METHODS: Human dendritic cells (DCs) were engineered to express a single tumoricidal factor, TNFα, and a membrane-anchored Mucin1 antibody scFv, named Mucin 1 directed DCs expressing TNFα (M-DCsTNF). The efficacy of M-DCsTNF in recognizing and treating breast cancer was tested in vitro and in vivo. RESULTS: Mucin1 was highly expressed on the surface of a wide range of human breast cancer cell lines. M-DCsTNF directly associated with MDA-MB-231 cells in the bone of NSG mice. M-DCsTNF plus an IAP antagonist, SM-164, but neither alone, markedly induce MDA-MB-231 breast cancer cell apoptosis, which was blocked by TNF antibody. Importantly, M-DCsTNF combined with SM-164, but not SM-164 alone, inhibited the growth of patient-derived breast cancer in NSG mice. CONCLUSION: An adoptive cell targeting delivery of TNFα combined with an IAP antagonist is a novel effective approach to treat breast cancer and could be expanded to treat other solid cancers. Unlike CAR-T cell, this novel adoptive cell is not activated to produce a wide variety of cytokines, except for additional overexpressed TNF, and thus could avoid the severe side effects such as cytokine release syndrome.

The Diagnostic and Predictive Value of Biomarkers for Pulmonary Fibrosis in Patients with Coronavirus Disease 2019.

Introduction: In coronavirus disease 2019 (COVID-19), particularly in older people, dysregulated immune response and aberrant repair can result in varied severity secondary pulmonary fibrosis (PF). By detecting some indicators, the occurrence and prognosis of fibrosis can be measured, providing directions for COVID-19 treatment. Methods: The research study lasted for 3 months and involved 88 COVID-19 patients. According to the chest radiological examination, 47 (53.41%) individuals were found to have no PF, while 41 (46.59%) showed PF. Clinical data such as inflammation markers, imaging findings, blood gas analysis, and hospital stay length were collected. Results: With area under the curve values of 0.7413, 0.7741, and 0.7048, respectively, and the study of the receiver operating characteristic curve demonstrated that mucin 1 (MUC1), carcinoembryonic antigen (CEA), and CXC chemokine receptor 10 (CXCL10) could diagnose the presence of COVID-19 PF. To evaluate the possibility of PF following severe acute respiratory syndrome coronavirus-2 infection, we established particular values for MUC1, CEA, and CXCL10 (1.296 ng/ml, 4.315 ng/ml, and 32.77 ng/ml, respectively). The survival curve for hospital days indicated that the length of hospital stays positively correlated with these three factors (P < 0.01). Transforming growth factor-beta did not correlate significantly with the severity of COVID-19 or PF. Conclusion: The results of this study suggested that the MUC1, CEA, and CXCL10 can be employed to explore the severity of secondary PF in COVID-19.

Mucin 1 expression is regulated by hsa_circ_0055054/microRNA­122­5p and promotes hepatocellular carcinoma development.

The abnormal expression of mucin 1 (MUC1) is a major cause of poor prognosis in patients with hepatocellular carcinoma (HCC). Competitive endogenous RNA demonstrates a novel regulatory mechanism that can affect the biological behavior of tumors. In the present study, the regulatory functions of hsa_circ_0055054 as well as those of microRNA (miR/miRNA) 122-5p on MUC1 expression and its role in HCC cell proliferation, migration and invasion, were evaluated. MUC1 expression was assessed using western blotting and reverse transcription-quantitative PCR. The phenotypic functions of the HCC cell lines were evaluated following MUC1 knockdown using Cell Counting Kit-8, wound healing and Transwell assays. Bioinformatics tools were used to identify specific miRNAs and circular (circ)RNAs that interact with and can regulate MUC1. The stability of circRNAs was assessed using a Ribonuclease R assay. The binding of circRNA/miRNA/MUC1 was assessed using dual-luciferase reporter assays and cellular function tests. Finally, in vivo experiments were performed using animal models. The results demonstrated that in MHCC97L cells, MUC1 and hsa_circ_0055054 were expressed at high levels while miR-122-5p was downregulated. The proliferation, migration and invasion of MHCC97L cells were suppressed by low MUC1 expression. hsa_circ_0055054 knockdown or miR-122-5p overexpression both led to a decrease in MUC1 expression. In MHCC97L cells with a low MUC1 expression caused by hsa_circ_0055054 knockdown, miR-122-5p inhibition resulted in the increased proliferation, migration and invasion of MHCC97L cells. In combination, the results of the present study indicate that hsa_circ_0055054 knockdown in MHCC97L cells leads to an increased expression of miR-122-5p and decreased expression of MUC1, which results in the inhibition of MHCC97L cell proliferation, migration and invasion.

Overcoming effector T cell exhaustion in ovarian cancer ascites with a novel adenovirus encoding for a MUC1 bispecific antibody engager and IL-2 cytokine.

T cell-focused cancer immunotherapy including checkpoint inhibitors and cell therapies has been rapidly evolving over the past decade. Nevertheless, there remains a major unmet medical need in oncology generally and immuno-oncology specifically. We have constructed an oncolytic adenovirus, Ad5/3-E2F-d24-aMUC1aCD3-IL-2 (TILT-322), which is armed with a human aMUC1aCD3 T cell engager and IL-2. TILT-322 treatment stimulated T cell cytotoxicity through the increased presence of granzyme B, perforin, and interferon-gamma. Additional immune profiling indicated TILT-322 increased gamma delta T cell activation and impacted other cell types such as natural killer cells and natural killer-like T cells that are traditionally involved in cancer immunotherapy. TILT-322 treatment also decreased the proportion of exhausted CD8+ T cells as demarked by immune checkpoint expression in ovarian ascites samples. Overall, our data showed that TILT-322 treatment led to an enhanced T cell activation and reversed T cell exhaustion translating into high antitumor efficacy when given locally or intravenously. The analysis of blood and tumors isolated from an in vivo patient-derived ovarian cancer xenograft model suggested TILT-322 mediated tumor control through improved T cell functions. Therefore, TILT-322 is a promising novel anti-tumor agent for clinical translation.

MUC1 aptamer-tethered H40-TEPA-PEG nanoconjugates for targeted siRNA-delivery and gene silencing in breast cancer cells.

With a prevalence of 12.5% of all new cancer cases annually, breast cancer stands as the most common form of cancer worldwide. The current therapies utilized for breast cancer are constrained and ineffective in addressing the condition. siRNA-based gene silencing is a promising method for treating breast cancer. We have developed an aptamer-conjugated dendritic multilayered nanoconjugate to treat breast cancer. Initially, we transformed the hydroxyl groups of the hyperbranched bis-MPA polyester dendrimer into carboxylic groups. Subsequently, we linked these carboxylic groups to tetraethylenepentamine to form a positively charged dendrimer. In addition, the mucin-1 (MUC1) aptamer was attached to the dendrimer using a heterobifunctional polyethylene glycol. Characterizing dendrimers involved 1H NMR and dynamic light scattering techniques at every production stage. A gel retardation experiment was conducted to evaluate the successful binding of siRNA with targeted and non-targeted dendrimers. The targeted dendrimers exhibited no harmful effects on the NIH-3T3 fibroblast cells and RBCs, indicating their biocompatible characteristics. Confocal microscopy demonstrated significant higher uptake of targeted dendrimers than non-targeted dendrimers in MCF-7 breast cancer cells. The real-time PCR results demonstrated that the targeted dendrimers exhibited the most pronounced inhibition of the target gene expression compared to the non-targeted dendrimers and lipofectamine-2000. The caspase activation study confirmed the functional effect of survivin silencing by dendrimer, which led to the induction of apoptosis in breast cancer cells. The findings indicated that Mucin-1 targeted hyperbranched bis-MPA polyester dendrimer carrying siRNA could successfully suppress the expression of the target gene in breast cancer cells.

Profuse color-evolution based aptasensor for mucin 1 detection utilizing urease-mediated color mixing of the mixed pH indicator.

Mucin 1 is a significant tumor marker, and developing portable and cost-effective methods for its detection is crucial, especially in resource-limited areas. Herein, we developed an innovative approach for mucin 1 detection using a visible multicolor aptasensor. Urease-encapsulated DNA microspheres were used to mediate multicolor change facilitated by the color mixing of the mixed pH indicator, a mixed methyl red and bromocresol green solution. Distinct color changes were exhibited in response to varying mucin 1 concentrations. Notably, the color mixing of the mixed pH indicator was used to display various hues of colors, broadening the range of color variation. And color tonality is much easier to differentiate than color intensity, improving the resolution with naked-eyes. Besides, the variation of color from red to green (a pair of complementary colors) enhanced the color contrast, heightening sensitivity for visual detection. Importantly, the proposed method was successfully applied to detect mucin 1 in real samples, demonstrating a clear differentiation of colors between the samples of healthy individuals and breast cancer patients. The use of a mixed pH indicator as a multichromatic substrate offers the merits of low cost, fast response to pH variation, and plentiful color-evolution. And the incorporation of calcium carbonate microspheres to encapsulate urease ensures stable urease activity and avoids the need for extra urease decoration. The color-mixing dependent strategy opens a new way for multicolor detection of MUC1, characterized by vivid color changes.

Paeoniflorigenone inhibits ovarian cancer metastasis through targeting the MUC1/Wnt/ß­catenin pathway.

Ovarian cancer (OC) is one of the most common gynecological malignancies. Currently, chemoradiotherapy is the primary clinical treatment approach for OC; however, it has severe side effects and a high rate of recurrence. Thus, there is an urgent need to develop innovative therapeutic options. Paeoniflorigenone (PFG) is a monoterpene compound isolated from the traditional Chinese medicine Paeoniae Radix Rubra. PFG can inhibit the proliferation of tumor cells; however, its anticancer activity against OC has yet to be elucidated. Mucin 1 (MUC1) is highly expressed in various malignant tumors, and is associated with tumor proliferation, metastasis and epithelial­mesenchymal transition (EMT). In addition, MUC1 affects numerous signaling pathways in tumor cells. In order to develop a possible treatment approach for metastatic OC, the antitumor activity of PFG in OC cells was investigated using Cell Counting Kit­8 assay, Edu assay, flow cytometry, Transwell assay and western blot analysis. In addition, it was assessed how PFG affects MUC1 expression and function. The experiments revealed that PFG significantly inhibited OC cell proliferation, migration, invasion and EMT. PFG also induced S­phase cell cycle arrest in OC cells. Furthermore, PFG inhibited MUC1 promoter activity, which led to a decrease in MUC1 protein expression. By contrast, MUC1 promoted OC progression, including cell proliferation, cell cycle progression and cell migration. Stable knockdown of MUC1 in OC cells improved the ability of PFG to block the Wnt/ß­catenin pathway, and to limit tumor cell invasion and migration, whereas MUC1 overexpression partially counteracted the antitumor effects of PFG. In conclusion, the present study demonstrated that PFG may inhibit the MUC1/Wnt/ß­catenin pathway to induce anti­metastatic, anti­invasive and anti­EMT effects on OC. Notably, MUC1 may be a direct target of PFG. Thus, PFG holds promise as a specific antitumor agent for the treatment of OC.

Unveiling the role of APOM gene in liver cancer: Investigating the impact of hsa-miR-4489/MUC1-mediated ferroptosis on the advancement of hepatocellular carcinoma cells.

Primary liver cancer has consistently exhibited a high prevalence and fatality rate, necessitating the investigation of associated diagnostic markers and inhibition mechanisms to effectively mitigate its impact. The significance of apolipoprotein M (ApoM) in impeding the progression of neoplastic ailments is progressively gaining recognition. However, a comprehensive understanding of its underlying mechanism in liver cancer advancement remains to be elucidated. Recent evidence indicates a potential association between ApoM and polyunsaturated fatty acids (PUFAs), with the peroxidation of phospholipids (PLs) containing PUFAs being recognized as a crucial element in the occurrence of ferroptosis. This prompts us to investigate the impact of the APOM gene on the progression of liver cancer through the ferroptosis pathway and elucidate its underlying mechanisms. The findings of this study indicate that the liver cancer cell model, which was genetically modified to overexpress the APOM gene, demonstrated a heightened ferroptosis effect. Moreover, the observed inhibition of the GSH (Glutathione) - GPX4 (Glutathione Peroxidase 4) regulatory axis suggests that the role of this axis in inhibiting ferroptosis is weakened. Through intersection screening and validation, we found that Mucin 1,cell surface associated (MUC1) can inhibit ferroptosis and is regulated by the APOM gene. Bioinformatics analysis and screening identified miR-4489 as a mediator between the two. Experimental results using the dual luciferase reporter gene confirmed that has-miR-4489 targets MUC1's 3'-UTR and inhibits its expression. In conclusion, this study provides evidence that the APOM gene induces a down-regulation in the expression of the ferroptosis-inhibiting gene MUC1, mediated by miR-4489, thereby impeding the advancement of liver cancer cells through the facilitation of ferroptosis.

Colorimetric aptasensor based on magnetic beads and gold nanoparticles for detecting mucin 1.

In this work, a colorimetric aptasensor based on magnetic beads (MBs), gold nanoparticles (AuNPs) and Horseradish Peroxidase (HRP) was prepared for the detection of mucin 1 (MUC1). Complementary DNA of the MUC1 aptamer (Apt) immobilized on the MBs was combined with the prepared AuNPs-Apt-HRP complex (AuNPs@Apt-HRP). In the presence of MUC1, it specifically bound to Apt, resulting in the detachment of gold nanoparticles from the MBs. After magnetic separation, AuNPs@Apt-HRP was separated into the supernatant and reacted with 3,3',5,5'-Tetramethylbenzidine (TMB) to produce color reaction from colorless to blue. The linear range of MUC1 was from 75 to 500 µg/mL (R2 = 0.9878), and the detection limit was 41.95 µg/mL. The recovery rate of MUC1 in human serum was 99.18 %∼101.15 %. This method is simple and convenient. Moreover, it does not require complex and expensive equipment for detection of MUC1. It provides value for the development of MUC1 colorimetric sensors and a promising strategy for the determination of MUC1 in clinical diagnosis.

Pressure and multicolor dual-mode detection of mucin 1 based on the pH-regulated dual-enzyme mimic activities of manganese dioxide nanosheets.

Mucin 1 is an essential tumor biomarker, and developing cost-effective and portable methods for mucin 1 detection is crucial in resource-limited settings. Herein, the pH-regulated dual-enzyme mimic activities of manganese dioxide nanosheets were demonstrated, which were integrated into an aptasensor for dual-mode detection of mucin 1. Under acidic conditions, manganese dioxide nanosheets with oxidase mimic activities catalyzed the oxidation of 3,3',5,5'-tetramethylbenzidine sulfate, producing visible multicolor signals; while under basic conditions, manganese dioxide nanosheets with catalase mimic activities were used as catalyst for the decomposition of hydrogen peroxide, generating gas pressure signals. The proposed method allows the naked eye detection of mucin 1 through multicolor signal readout and the quantitative detection of mucin 1 with a handheld pressure meter or a UV-vis spectrophotometer. The study demonstrates that manganese dioxide nanosheets with pH-regulated dual-enzyme mimic activities can facilitate multidimensional transducing signals. The use of manganese dioxide nanosheets for the transduction of different signals avoids extra labels and simplifies the operation procedures. Besides, the signal readout mode can be selected according to the available detection instruments. Therefore, the use of manganese dioxide nanosheets with pH-regulated dual-enzyme mimic activities for dual-signal readout provides a new way for mucin 1 detection.

Molecular pathway of pancreatic cancer-associated neuropathic pain.

The pancreas is a heterocrine gland that has both exocrine and endocrine parts. Most pancreatic cancer begins in the cells that line the ducts of the pancreas and is called pancreatic ductal adenocarcinoma (PDAC). PDAC is the most encountered pancreatic cancer type. One of the most important characteristic features of PDAC is neuropathy which is primarily due to perineural invasion (PNI). PNI develops tumor microenvironment which includes overexpression of fibroblasts cells, macrophages, as well as angiogenesis which can be responsible for neuropathy pain. In tumor microenvironment inactive fibroblasts are converted into an active form that is cancer-associated fibroblasts (CAFs). Neurotrophins they also increase the level of Substance P, calcitonin gene-related peptide which is also involved in pain. Matrix metalloproteases are the zinc-associated proteases enzymes which activates proinflammatory interleukin-1ß into its activated form and are responsible for release and activation of Substance P which is responsible for neuropathic pain by transmitting pain signal via dorsal root ganglion. All the molecules and their role in being responsible for neuropathic pain are described below.

Mucin 1 and venous thrombosis in tumor-bearing mice and patients with cancer.

INTRODUCTION: Mucins released from epithelial tumors have been proposed to play a role in cancer-associated thrombosis. Mucin1 (MUC1) is a transmembrane mucin that is overexpressed in a variety of human malignancies, including breast and pancreatic cancer. We analyzed the association of MUC1 and venous thrombosis in a mouse tumor model and in patients with cancer. MATERIALS AND METHODS: We used a human pancreatic cancer cell line HPAF-II that expresses a high level of MUC1. We grew HPAF-II tumors in the pancreas of Crl:NU-Foxn1nu male mice. MUC1 in plasma and extracellular vesicles (EVs) isolated from plasma was measured using an enzyme-linked immunosorbent assay. MUC1 in EVs and venous thrombi from tumor-bearing mice was assessed by western blotting. We measured MUC1 in plasma from healthy controls and patients with stomach, colorectal or pancreatic cancer with or without venous thromboembolism. RESULTS AND DISCUSSION: MUC1 was detected in the plasma of mice bearing HPAF-II tumors and was associated with EVs. MUC1 was present in venous thrombi from mice bearing HFAP-II tumors. Recombinant MUC1 did not induce platelet aggregation. Levels of MUC1 were higher in patients with pancreatic cancer compared with healthy controls. In contrast to the mouse model, MUC1 was present in EV-free plasma in samples from healthy controls and patients with cancer. There was no significant difference in the levels of MUC1 in cancer patients with or without VTE. Our data did not find any evidence that MUC1 contributed to VTE in patients with cancer.

The Role of MUC1 in Renal Cell Carcinoma.

Mucins are a family of high-molecular-weight glycoproteins. MUC1 is widely studied for its role in distinct types of cancers. In many human epithelial malignancies, MUC1 is frequently overexpressed, and its intracellular activities are crucial for cell biology. MUC1 overexpression can enhance cancer cell proliferation by modulating cell metabolism. When epithelial cells lose their tight connections, due to the loss of polarity, the mucins become dispersed on both sides of the epithelial membrane, leading to an abnormal mucin interactome with the membrane. Tumor-related MUC1 exhibits certain features, such as loss of apical localization and aberrant glycosylation that might cause the formation of tumor-related antigen epitopes. Renal cell carcinoma (RCC) accounts for approximately 3% of adult malignancies and it is the most common kidney cancer. The exact role of MUC1 in this tumor is unknown. Evidence suggests that it may play a role in several oncogenic pathways, including proliferation, metabolic reprogramming, chemoresistance, and angiogenesis. The purpose of this review is to explore the role of MUC1 and the meaning of its overexpression in epithelial tumors and in particular in RCC.

Double-enhanced sandwich electrochemiluminescence aptasensor based on g-C3N4-Au-luminol nanocomposites and ZnCuS nanosheets for highly sensitive detection of mucin 1.

The traditional luminol electrochemiluminescence (ECL) sensing suffers from low signal response and instability issues. Here, an Au/ZnCuS double-enhanced g-C3N4-supported luminol ECL aptasensor is constructed for the sensitive detection of human mucin 1 (MUC1). In this platform, g-C3N4 of a large specific surface area is beneficial to load more luminol illuminants. Au nanoparticles promote the decomposition of H2O2 coreactants to generate more reactive oxygen (•OH and O2•-) intermediates, while ZnCuS can immobilize the aptamer and simultaneously catalyze H2O2 decomposition, realizing the double-wing signal amplification. Under optimal conditions, this sensor shows a good detection capability within 1.0 × 10-4-1.0 × 103 ng mL-1 and a low detection limit of 5.0 × 10-5 ng mL-1, as well as ideal stability, selectivity, and reproducibility. This double-enhanced aptasensor highlights a new signal-enhancement approach for early biomarker detection.

Efficacy of MUC1-targeted CAR-NK cells against human tongue squamous cell carcinoma.

Introduction: The clinical efficacy of CAR-NK cells against CD19-expressing blood cancers has been demonstrated, and they have shown potential for treating solid tumors as well. However, the efficacy of CAR-NK cells for treating human oral tongue squamous cell carcinoma (OTSCC) has not been examined. Methods: We assessed MUC1 expression in human OTSCC tissue and a cell line using immunohistochemistry and immunofluorescence. We constructed NK cells that express CAR targeted to MUC1 from pluripotent stem cells (iPSC-derived MUC1-targeted CAR-NK cells) and evaluated their effectiveness against OTSCC in vitro using the xCELLigence Real-Time Cell Analysis system and CCK8 assay, and in vivo by measuring xenograft growth daily in BNDG mice treated with MUC1-targeted CAR-NK cells. As controls, we used iPSC-derived NK cells and NK-free media, which were CAR-free and blank, respectively. Results: MUC1 expression was detected in 79.5% (66/83) of all OTSCC patients and 72.7% (24/33) of stage III and IV. In stage III and IV MUC1 positive OTSCC, 63.6% (21/33) and 48.5% (16/33) patients had a MUC1-positive cancer cell rate of more than 50% and 80%, respectively. The iPSC-derived MUC1-targeted CAR-NK cells exhibited significant cytotoxicity against MUC1-expressing OTSCC cells in vitro, in a time- and dose-dependent manner, and showed a significant inhibitory effect on xenograft growth compared to both the iPSC-derived NK cells and the blank controls. We observed no weight loss, severe hematological toxicity or NK cell-mediated death in the BNDG mice. Conclusion: The MUC1-targeted CAR-NK cells had significant efficacy against human OTSCC, and their promising therapeutic response warrants further clinical trials.

Baseline Blood Levels of Mucin-1 Are Associated with Crucial On-Treatment Adverse Outcomes in Patients with Idiopathic Pulmonary Fibrosis Receiving Antifibrotic Pirfenidone.

Mucin-1 is a multi-functional glycoprotein expressed by type II alveolocytes and may be detectable in the circulation following pulmonary fibrosis. The prognostic utility of baseline pre-treatment blood levels of mucin-1 in patients with idiopathic pulmonary fibrosis (IPF) receiving antifibrotics has not yet been fully established. We retrospectively studied a cohort of patients (from two hospitals) with IPF who were receiving pirfenidone for >12 weeks. Baseline blood mucin-1 levels were measured via sandwich enzyme-linked immunosorbent assays. We investigated the performance of mucin-1 levels in longitudinally predicting the risks of acute exacerbation of IPF (AE-IPF) and severe adverse outcomes (SAO), including lung transplantation and death. Seventy patients were included; 20 developed AE-IPF; and 31 had SAO during the follow-up period. Patients with baseline mucin-1 levels ≥2.5 ng/mL had enhanced risks of AE-IPF (adjusted hazard ratio [aHR], 14.07; 95% confidence interval [CI], 4.26-46.49) and SAO within 2 years (aHR, 7.87; 95% CI, 2.86-21.70) and anytime during the follow-up (aHR, 4.68; 95% CI, 2.11-10.39). The risks increased across subgroups with increasing mucin-1 levels. Patients in the "mucin-1 ≥ 2.5" group also exhibited an accelerated decline in DLCO. This study supports baseline blood mucin-1 levels as a biomarker for IPF that predicts adverse outcomes during pirfenidone treatment.

Study on the combined detection of mammography,ultrasound Doppler and serum tumor markers in the diagnosis of early breast cancer / 中国医学装备

Objective:To explore the values of single and combined detection of mammography,ultrasound Doppler and serum markers of tumor included serum prostate specific antigen(PSA),serum carbohydrate antigen 15-3(CA153),mucin 1(MUC1)and human growth differentiation factor 3(GDF3)in diagnosing early breast cancer.Methods:A total of 96 patients with breast cancer,who admitted to Tangshan People's Hospital from January 2018 to December 2021 and were confirmed by pathological examination,were selected as breast cancer group.At the same time,70 patients with benign breast diseases who received diagnosis and treatment in our hospital were selected as benign lesions group.In addition,50 normal people who were confirmed as health by physical examination in our hospital were selected as research subjects of healthy control group.The postoperative pathological examination was used as the gold standard to compare the diagnostic values of single mammography,ultrasonic Doppler examination,serum PSA,CA153,MUC1,GDF3 and the combined examination of them for breast cancer.Results:In the breast cancer group,78 cases of the 96 patients with breast cancer were diagnosed as malignant tumor by ultrasound on breast,with a positive detection rate of 81.3%,and 80 cases of them were diagnosed as malignant tumor by mammography X-ray examination,with a positive detection rate of 83.1%.The levels of serum PSA,CA153,MUC1 and GDF3 of breast cancer group were respectively higher than those of the benign lesion group and healthy control group,and the differences were statistically significant(t=8.783,10.361,11.258,18.965,9.564,12.658,12.688,20.163,P<0.05).Using breast cancer as the dependent variable,and using serum PSA,CA153,MUC1 and GDF3 as independent variable to perform Logistic regression analysis.The results of Logistic regression analysis indicated that serum PSA,CA153,MUC1 and GDF3 were important risk factors of breast cancer(OR value =1.165,1.168,1.472,1.248,P<0.05).The results of receiver operating characteristic(ROC)curve(95%CI),sensitivity and specificity of single application of each indicator of ultrasound on breast,mammography,serum PSA,CA153,MUC1 and GDF3 were respectively[0.723(0.595-0.851),82.56%and 67.32%],[0.761(0.636-0.886),85.79%and 65.36%],[0.833(0.726-0.941),81.48%and 85.73%],[0.837(0.738-0.926),61.25%and 70.17%],[0.768(0.648-0.889),71.49%and 80.87%],[0.613(0.469-0.758),52.94%and 50.57%].However,the AUC(95%CI),sensitivity and specificity of the combined application of 6 items were respectively 0.958(0.905-0.999),96.37%and 84.83%,which had higher diagnostic efficiency.Conclusion:The combined detection performance of mammography,ultrasound Doppler and serum PSA,CA153,MUC1 and GDF3 is higher than that of single each detection,which is helpful to conduct early identification and diagnosis for breast cancer.

Expressions of vascular endothelial growth factor A, mucin-1, colony-stimulating factor-1, heparin-binding epidermal growth factor-like growth factor, and fibroblast growth factor 2 genes in the female reproductive tracts of women with ectopic pregnancy: A case-control study.

Background: Ectopic pregnancy (EP) is defined as embryo implantation in a location other than the uterine cavity. Objective: We aimed to evaluate the expression of several genes, which may play a role in EP, in the ampulla region of fallopian tubes and endometrial tissue of women with EP. Materials and Methods: In this case-control study, 5 women who underwent salpingectomy due to EP, comprised the 5 pseudo-pregnant women as a control group. These participants referred to the Royan Institute, Shariati, and Arash hospital, Tehran, Iran during 2019-2021. We evaluated the expressions of vascular endothelial growth factor A, mucin-1, colony-stimulating factor-1, heparin-binding epidermal growth factor-like growth factor (HBEGF), and fibroblast growth factor 2 genes in the fallopian tube and endometrium of EP cases by real-time polymerase chain reaction using specific primers. Results: The vascular endothelial growth factor expression was significantly higher in the ampulla region of the controls. However, no significant differences were observed in endometrial tissue. Assessments of colony-stimulating factor-1 and fibroblast growth factor 2 showed no significant differences between the case and control groups. HBEGF showed significantly higher expression in the ampulla region of EP cases, but no significant difference was observed in HBEGF expression in the endometrial tissues of the study groups. Mucin-1expression was significantly higher in both study regions of the EP cases. Conclusion: Our results have strongly suggested that these genes play important roles in proper implantation, and disruptions in their expression patterns could lead to EP. However, more studies are needed to confirm the current findings.

Enhancing T Cell and Antibody Response in Mucin-1 Transgenic Mice through Co-Delivery of Tumor-Associated Mucin-1 Antigen and TLR Agonists in C3-Liposomes.

Mucin-1 (MUC1) is a highly relevant antigen for cancer vaccination due to its overexpression and hypo-glycosylation in a high percentage of carcinomas. To enhance the immune response to MUC1, our group has developed C3-liposomes that encapsulate the MUC1 antigen along with immunostimulatory compounds for direct delivery to antigen-presenting cells (APCs). C3-liposomes bind complement C3, which interacts with C3-receptors on APCs, resulting in liposomal uptake and the delivery of tumor antigens to APCs in a manner that mimics pathogenic uptake. In this study, MUC1 and Toll-like receptor (TLR) agonists were encapsulated in C3-liposomes to provoke an immune response in transgenic mice tolerant to MUC1. The immune response to the C3-bound MUC1 liposomal vaccine was assessed by ELISA, ELISpot, and flow cytometry. Co-administering TLR 7/8 agonists with MUC1 encapsulated in C3-liposomes resulted in a significant antibody response compared to non-encapsulated MUC1. This antibody response was significantly higher in females than in males. The co-encapsulation of three TLR agonists with MUC1 in C3-liposomes significantly increased antibody responses and eliminated sex-based differences. Furthermore, this immunization strategy resulted in a significantly increased T cell-response compared to other treatment groups. In conclusion, the co-delivery of MUC1 and TLR agonists via C3-liposomes greatly enhances the immune response to MUC1, highlighting its potential for antigen-specific cancer immunotherapy.

MeltSerts technology (brinzolamide ocular inserts via hot-melt extrusion): QbD-steered development, molecular dynamics, in vitro, ex vivo and in vivo studies.

The research work aimed to develop a robust sustained release biocompatible brinzolamide (BRZ)-loaded ocular inserts (MeltSerts) using hot-melt extrusion technology with enhanced solubility for glaucoma management. A 32 rotatable central composite design was employed for the optimization of the MeltSerts to achieve sustained release. The effect of two independent factors was examined: Metolose® SR 90SH-100000SR (HPMC, hydroxypropyl methyl cellulose) and Kolliphor® P 407 (Poloxamer 407, P407). The drug release (DR) of BRZ at 0.5 h and 8 h were adopted as dependent responses. The factorial analysis resulted in an optimum composition of 50.00 % w/w of HPMC and 15.00 % w/w of P407 which gave % DR of 9.11 at 0.5 h and 69.10 at 8 h. Furthermore, molecular dynamic simulations were performed to elucidate various interactions between BRZ, and other formulation components and it was observed that BRZ showed maximum interactions with HPC and HPMC with an occupancy of 92.82 and 52.87 %, respectively. Additionally, molecular docking studies were performed to understand the interactions between BRZ and mucoadhesive polymers with ocular mucin (MUC-1). The results indicated a docking score of only -5.368 for BRZ alone, whereas a significantly higher docking score was observed for the optimized Meltserts -6.977, suggesting enhanced retention time of the optimized MeltSerts. SEM images displayed irregular surfaces, while EDS analysis validated uniform BRZ distribution in the optimized formulation. The results of the ocular irritancy studies both ex vivo and in vivo demonstrated that MeltSerts are safe for ocular use. The results indicate that the developed MeltSerts Technology has the potential to manufacture ocular inserts with cost-effectiveness, one-step processability, and enhanced product quality. Nonetheless, it also offers a once-daily regimen, consequently decreasing the dosing frequency, preservative exposure, and ultimately better glaucoma management.