Correlation between periacinar retraction clefting and the expression of E-cadherin and Beta-catenin proteins in prostatic adenocarcinoma

Periacinar retraction clefting represents a criteria favoring prostatic adenocarcinoma diagnosis. In the present study, tissues from 53 cases of prostate morphologically diagnosed as prostatic adenocarcinoma and the adjacent nonneoplastic prostatic tissue were evaluated for the presence and the extent of periacinar retraction clefting. Immunohistochemistry (IHC) was used to evaluate the expression of E-cadherin and β-catenin, and this expression was compared with GSC, sPSA, positive surgical margins, BCR, TNM stage, and periacinar retraction clefting. Our study confirmed that periacinar retraction clefting is significantly more extensive in prostatic adenocarcinoma than in nonneoplastic prostatic tissue (P<0.001).We found a decreased expression of E-cadherin and β-catenin in prostatic adenocarcinoma and a negative correlation with GSC, positive surgical margins, BCR, and T stage. Periacinar clefting was positively correlated with the intensity of E-cadherin staining (rho=0.398; P=0.003), the percentage of E-cadherin staining (rho=0.367; P=0.007), the intensity of β-catenin staining (rho= 0.374; P=0.006) and the percentage of β-catenin staining (rho=0.347; P=0.011) in prostatic adenocarcinoma. However, in 4 (7.54%) samples with Gleason score (GSC) 7 (4+3) and with a mixed population of positive and negative cells, E-cadherin staining was weak to negative in the cells of tumor glands with periacinar clefts and positive in tumor glands with no periacinar clefts. This suggests that E-cadherin might play a role in the origin of periacinar clefting in higher grade tumors

Exploring the Relationship between E-Cadherin and β-Catenin Cell Adhesion Proteins and Periacinar Retraction Clefting in Prostatic Adenocarcinoma

Background: Periacinar retraction clefts represent a histopathological criterion supporting the diagnosis of prostatic adenocarcinoma. The origin of these clefts in prostatic adenocarcinoma remains unclear. Exploring the established functions of E-cadherin and β-catenin as intercellular adhesion proteins, and aiming to elucidate the origin of periacinar retraction clefting, we conducted a correlation study between the immunohistochemical expression of E-cadherin and β-catenin and the presence of periacinar retraction clefts in prostatic adenocarcinoma. Methods: We examined 53 cases of morphologically diagnosed prostatic adenocarcinoma, assessing both the neoplastic and adjacent nonneoplastic prostatic tissues for the existence and degree of periacinar retraction clefts. Additionally, we analyzed the immunohistochemical expression of E-cadherin and β-catenin proteins in prostatic tissue and explored their correlation with periacinar retraction clefts, and Gleason score, Grade Group, preoperative serum prostate specific-antigen (sPSA) levels, surgical margin status, and Tumor, Node, Metastasis (TNM) stage in prostatic adenocarcinoma. Results: Our study confirms that periacinar retraction clefting is significantly more extensive in prostatic adenocarcinoma than in nonneoplastic prostatic tissue (p p = 0.010) and (rho = 0.340; p = 0.012)) immunostaining in prostatic adenocarcinoma. Conclusions: Periacinar retraction clefts stand out as a dependable criterion in the diagnosis of prostatic adenocarcinoma. E-cadherin and β-catenin proteins are potential markers indicative of tumor progression and invasiveness in prostatic adenocarcinoma. Our discovery of a positive correlation between immunostaining of E-cadherin and β-catenin proteins and periacinar retraction clefts in prostatic adenocarcinoma aligns with the notion that periacinar retraction clefting is more characteristic of Gleason Grade3 pattern in prostatic adenocarcinomas, whereas the immunohistochemical expression of E-cadherin and β-catenin shows a decrease with increasing histopathological tumor grade

Probing milk extracellular vesicles for intestinal delivery of RNA therapies

Acknowledgements: We thank Kailin Qin from King’s College London for his valuable assistance in capturing TEM images.Funder: King’s-China Scholarship Council PhD Scholarship ProgrammeAbstract Background Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. Results Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D ‘apical-out’ and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. Conclusions Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application. Graphical Abstract </jats:sec

Probing milk extracellular vesicles for intestinal delivery of RNA therapies

Abstract Background Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. Results Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D ‘apical-out’ and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. Conclusions Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application. Graphical Abstrac

Probing milk extracellular vesicles for intestinal delivery of RNA therapies

Background Oral delivery remains unattainable for nucleic acid therapies. Many nanoparticle-based drug delivery systems have been investigated for this, but most suffer from poor gut stability, poor mucus diffusion and/or inefficient epithelial uptake. Extracellular vesicles from bovine milk (mEVs) possess desirable characteristics for oral delivery of nucleic acid therapies since they both survive digestion and traverse the intestinal mucosa. Results Using novel tools, we comprehensively examine the intestinal delivery of mEVs, probing whether they could be used as, or inform the design of, nanoparticles for oral nucleic acid therapies. We show that mEVs efficiently translocate across the Caco-2 intestinal model, which is not compromised by treatment with simulated intestinal fluids. For the first time, we also demonstrate transport of mEVs in novel 3D ‘apical-out’ and monolayer-based human intestinal epithelial organoids (IEOs). Importantly, mEVs loaded with small interfering RNA (siRNA) induced (glyceraldehyde 3-phosphate dehydrogenase, GAPDH) gene silencing in macrophages. Using inflammatory bowel disease (IBD) as an example application, we show that administration of anti-tumour necrosis factor alpha (TNFα) siRNA-loaded mEVs reduced inflammation in a IBD rat model. Conclusions Together, this work demonstrates that mEVs could either act as natural and safe systems for oral delivery or nucleic acid therapies, or inform the design of synthetic systems for such application. Graphical Abstract</p