Advances, recognition, and interpretation of molecular heterogeneity among conventional and subtype histology of urothelial carcinoma (UC): a survey among urologic pathologists and comprehensive review of the literature.

AIMS: Urothelial carcinoma (UC) demonstrates significant molecular and histologic heterogeneity. The WHO 2022 classification has hinted at adding molecular signatures to the morphologic diagnosis. As morphology and associated molecular repertoire may potentially translate to choices of and response to therapy and relapse rate, broader acceptability of recognizing these key features among uropathologists is needed. This prompted an international survey to ascertain the practice patterns in classical/subtype UC among uropathologists across the globe. METHODS AND RESULTS: A survey instrument was shared among 98 uropathologists using SurveyMonkey software. Anonymized respondent data were analysed. The response rate was 85%. A majority were in concordance with the profiles of luminal (93%) and basal (82%) types. Opinion on the FGFR3 testing platform was variable. While 95% concurred that TERT promoter mutation is the key driver in UC, 72% had the opinion that APOBEC mutagenesis is the main signature in muscle invasive bladder cancer (MIBC). Uropathologists have divergent opinions on MIBC and ERCC2 mutations. Among the participants, 94% would quantify aggressive micropapillary and sarcomatoid histology, while 88% would reevaluate another transurethral resection of the bladder tumour specimen in nonmuscle invasive tumour with micropapillary, small cell, or sarcomatoid histology. A leading number agreed to specific molecular signatures of micropapillary (93%), plasmacytoid (97%), and small cell (86%) subtypes. Ninety-six percent of participants agreed that a small-cell component portends a more aggressive course and should be treated with neoadjuvant chemotherapy and 63% would perform HER2/neu testing only on oncologist's request in advanced tumours. Ninety percent agreed that microsatellite instability testing, although not a standard protocol, should be considered in young patients with upper tract UC. Eighty-six percent agreed that UC with high tumour mutational burden would be a better candidate for immunotherapy. CONCLUSION: In the era of precision medicine, enhanced understanding of molecular heterogeneity of UC will contribute to better therapeutic options, novel biomarker discovery, innovative management protocols, and outcomes. Our survey provides a broad perspective of pathologists' perceptions and experience regarding incorporation of histomolecular approaches to "personalize" therapy. Due to variable clinical adoption, there is a need for additional data using uniform study criteria. This will drive generation of best practice guidelines in this area for widespread and consistent clinical utility.

Discovery of common molecular signatures and drug repurposing for COVID-19/Asthma comorbidity: ACE2 and multi-partite networks.

Angiotensin-converting enzyme 2 (ACE2) is identified as the functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of the ongoing global coronavirus disease-2019 (COVID-19) pandemic. This study aimed to elucidate potential therapeutic avenues by scrutinizing approved drugs through the identification of the genetic signature associated with SARS-CoV-2 infection in individuals with asthma. This exploration was conducted through an integrated analysis, encompassing interaction networks between the ACE2 receptor and common host (co-host) factors implicated in COVID-19/asthma comorbidity. The comprehensive analysis involved the identification of common differentially expressed genes (cDEGs) and hub-cDEGs, functional annotations, interaction networks, gene set variation analysis (GSVA), gene set enrichment analysis (GSEA), and module construction. Interaction networks were used to identify overlapping disease modules and potential drug targets. Computational biology and molecular docking analyzes were utilized to discern functional drug modules. Subsequently, the impact of the identified drugs on the expression of hub-cDEGs was experimentally validated using a mouse model. A total of 153 cDEGs or co-host factors associated with ACE2 were identified in the COVID-19 and asthma comorbidity. Among these, seven significant cDEGs and proteins - namely, HRAS, IFNG, JUN, CDH1, TLR4, ICAM1, and SCD-were recognized as pivotal host factors linked to ACE2. Regulatory network analysis of hub-cDEGs revealed eight top-ranked transcription factors (TFs) proteins and nine microRNAs as key regulatory factors operating at the transcriptional and post-transcriptional levels, respectively. Molecular docking simulations led to the proposal of 10 top-ranked repurposable drug molecules (Rapamycin, Ivermectin, Everolimus, Quercetin, Estradiol, Entrectinib, Nilotinib, Conivaptan, Radotinib, and Venetoclax) as potential treatment options for COVID-19 in individuals with comorbid asthma. Validation analysis demonstrated that Rapamycin effectively inhibited ICAM1 expression in the HDM-stimulated mice group (p < 0.01). This study unveils the common pathogenesis and genetic signature underlying asthma and SARS-CoV-2 infection, delineated by the interaction networks of ACE2-related host factors. These findings provide valuable insights for the design and discovery of drugs aimed at more effective therapeutics within the context of lung disease comorbidities.

Mixed-Grade Urothelial Carcinoma: Insights Into Clinical Behavior and Prognostic Implications Compared to Pure Low-Grade and High-Grade Urothelial Carcinomas.

CONTEXT.­: Low-grade urothelial carcinoma (LGUC) and high-grade urothelial carcinoma (HGUC) are distinguished based on architectural and cytological features, with the anticipation that HGUC exhibits more aggressive behavior and a worse prognosis compared to LGUC. The current World Health Organization classification recognizes mixed-grade urothelial carcinoma (MGUC, for the purposes of this study) as a separate category that behaves like LGUC if the high-grade component is <5% and states that any tumor with ≥5% high-grade component should be graded as HGUC. OBJECTIVE.­: To evaluate the risk of tumor recurrence, grade, and stage progression of MGUC compared to LGUC and HGUC. DESIGN.­: A total of 150 de novo noninvasive polypoid urothelial carcinomas (41 cases of MGUC, 59 of LGUC, and 50 of HGUC) were included. Tumor recurrence, grade, and stage progression were compared among the MGUC, LGUC, and HGUC cases. RESULTS.­: Tumor recurrence was observed in 14 of 41 (34.2%) of MGUC, 33 of 59 (55.9%) of LGUC, and 28 of 50 (56%) of HGUC. Grade progression occurred in 5 of 41 (12.2%) of MGUC cases and 5 of 59 (8.5%) of LGUC cases. No stage progression was observed in LGUC or MGUC cases, while 7 of 50 (14%) of HGUC cases showed stage progression. MGUC was associated with lower odds and hazard of recurrence compared to LGUC. The rate of grade progression was higher in MGUC and occurred after a shorter interval compared to LGUC. CONCLUSIONS.­: MGUC showed a prognosis closer to LGUC. Our study supports the current recommendation to classify tumors with <5% high-grade component as MGUC, as these tumors display clinical characteristics and outcomes close to that of pure LGUC.

Dual role of mesenchymal stem/stromal cells and their cell-free extracellular vesicles in colorectal cancer.

Colorectal cancer (CRC) is one of the main causes of cancer-related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer-related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell-cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell-free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC-derived exosomes for possible cell-free therapy in CRC.

Ductal, intraductal, and cribriform carcinoma of the prostate: Molecular characteristics and clinical management.

Prostatic acinar adenocarcinoma accounts for approximately 95% of prostate cancer (CaP) cases. The remaining 5% of histologic subtypes of CaP are known to be more aggressive and have recently garnered substantial attention. These histologic subtypes - namely, prostatic ductal adenocarcinoma (PDA), intraductal carcinoma of the prostate (IDC-P), and cribriform carcinoma of the prostate (CC-P) - typically exhibit distinct growth characteristics, genomic features, and unique oncologic outcomes. For example, PTEN mutations, which cause uncontrolled cell growth, are frequently present in IDC-P and CC-P. Germline mutations in homologous DNA recombination repair (HRR) genes (e.g., BRCA1, BRCA2, ATM, PALB2, and CHEK2) are discovered in 40% of patients with IDC-P, while only 9% of patients without ductal involvement had a germline mutation. CC-P is associated with deletions in common tumor suppressor genes, including PTEN, TP53, NKX3-1, MAP3K7, RB1, and CHD1. Evidence suggests abiraterone may be superior to docetaxel as a first-line treatment for patients with IDC-P. To address these and other critical pathological attributes, this review examines the molecular pathology, genetics, treatments, and oncologic outcomes associated with CC-P, PDA, and IDC-P with the objective of creating a comprehensive resource with a centralized repository of information on PDA, IDC-P, and CC-P.

Identification of Glandular (Acinar)/Tubule Formation in Invasive Carcinoma of the Breast: A Study to Determine Concordance Using the World Health Organization Definition.

CONTEXT.­: The Nottingham Grading System (NGS) developed by Elston and Ellis is used to grade invasive breast cancer (IBC). Glandular (acinar)/tubule formation is a component of NGS. OBJECTIVE.­: To investigate the ability of pathologists to identify individual structures that should be classified as glandular (acinar)/tubule formation. DESIGN.­: A total of 58 hematoxylin-eosin photographic images of IBC with 1 structure circled were classified as tubules (41 cases) or nontubules (17 cases) by Professor Ellis. Images were sent as a PowerPoint (Microsoft) file to breast pathologists, who were provided with the World Health Organization definition of a tubule and asked to determine if a circled structure represented a tubule. RESULTS.­: Among 35 pathologists, the κ statistic for assessing agreement in evaluating the 58 images was 0.324 (95% CI, 0.314-0.335). The median concordance rate between a participating pathologist and Professor Ellis was 94.1% for evaluating 17 nontubule cases and 53.7% for 41 tubule cases. A total of 41% of the tubule cases were classified correctly by less than 50% of pathologists. Structures classified as tubules by Professor Ellis but often not recognized as tubules by pathologists included glands with complex architecture, mucinous carcinoma, and the "inverted tubule" pattern of micropapillary carcinoma. A total of 80% of participants reported that they did not have clarity on what represented a tubule. CONCLUSIONS.­: We identified structures that should be included as tubules but that were not readily identified by pathologists. Greater concordance for identification of tubules might be obtained by providing more detailed images and descriptions of the types of structures included as tubules.

Translational research of new developments in targeted therapy of colorectal cancer.

A severe global health concern is the rising incidence and mortality rate of colorectal cancer (CRC). Chemotherapy, which is typically used to treat CRC, is known to have limited specificity and can have noticeable side effects. A paradigm shift in cancer treatment has been brought about by the development of targeted therapies, which has led to the appearance of pharmacological agents with improved efficacy and decreased toxicity. Epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), human epidermal growth factor receptor 2 (HER2), and BRAF are among the molecular targets covered in this review that are used in targeted therapy for CRC. The current discussion also covers advancements in targeted therapeutic approaches, such as antibody-drug conjugates, immune checkpoint inhibitors, and chimeric antigen receptor (CAR) T-cell therapy. A review of the clinical trials and application of these particular therapies in treating CRC is also done. Despite the improvements in targeted therapy for CRC, problems such as drug resistance and patient selection remain to be solved. Despite this, targeted therapies have offered fresh possibilities for identifying and treating CRC, paving the way for the development of personalized medicine and extending the life expectancy and general well-being of CRC patients.

miR-199a-3p suppresses neuroinflammation by directly targeting MyD88 in a mouse model of bone cancer pain.

AIMS: Pain is a profoundly debilitating symptom in cancer patients, leading to disability, immobility, and a marked decline in their quality of life. This study aimed to investigate the potential roles of miR-199a-3p in a murine model of bone cancer pain induced by tumor cell implantation in the medullary cavity of the femur. MATERIALS AND METHODS: We assessed pain-related behaviors, including the paw withdrawal mechanical threshold (PWMT) and the number of spontaneous flinches (NSF). To investigate miRNA expression and its targets in astrocytes, we employed a combination of RNA-seq analysis, qRT-PCR, Western blotting, EdU, TUNEL, ChIP, ELISA, and luciferase reporter assays in mice (C3H/HeJ) with bone cancer pain and control groups. KEY FINDINGS: On days 10, 14, 21, and 28 post-surgery, we observed significant differences in PWTL, PWMT, and NSF when compared to the sham group (P < 0.001). qRT-PCR assays and miRNA sequencing results confirmed reduced miR-199a-3p expression in astrocytes of mice with bone cancer pain. Gain- and loss-of-function experiments demonstrated that miR-199a-3p suppressed astrocyte activation and the expression of inflammatory cytokines. In vitro investigations revealed that miR-199a-3p mimics reduced the levels of inflammatory factors in astrocytes and MyD88/NF-κB proteins. Furthermore, treatment with a miR-199a-3p agonist resulted in reduced expression of MyD88, TAK1, p-p65, and inflammatory mediators, along with decreased astrocyte activation in the spinal cord. SIGNIFICANCE: Collectively, these findings demonstrate that upregulation of miR-199a-3p may offer a therapeutic avenue for mitigating bone cancer pain in mice by suppressing neuroinflammation and inhibiting the MyD88/NF-κB signaling pathway.

Evolution of the HIF targeted therapy in clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is the most common type of kidney cancer, affecting hundreds of thousands of people worldwide and can affect people of any age. The pathogenesis of ccRCC is most commonly due to biallelic loss of the tumor suppressor gene VHL. VHL is the recognition subunit of an E3-ubiquitin-ligase-complex essential for degradation of the hypoxia-inducible factors (HIF) 1α and 2α. Dysfunctional degradation of HIF results in overaccumulation, which is particularly concerning with the HIF2α subunit. This leads to nuclear translocation, dimerization, and transactivation of numerous HIF-regulated genes responsible for cell survival and proliferation in ccRCC. FDA-approved therapies for RCC have primarily focused on targeting downstream effectors of HIF, then incorporated immunotherapeutics, and now, novel approaches are moving back to HIF with a focus on interfering with upstream targets. This review summarizes the role of HIF in the pathogenesis of ccRCC, novel HIF2α-focused therapeutic approaches, and opportunities for ccRCC treatment.

Progressing nanotechnology to improve targeted cancer treatment: overcoming hurdles in its clinical implementation.

The use of nanotechnology has the potential to revolutionize the detection and treatment of cancer. Developments in protein engineering and materials science have led to the emergence of new nanoscale targeting techniques, which offer renewed hope for cancer patients. While several nanocarriers for medicinal purposes have been approved for human trials, only a few have been authorized for clinical use in targeting cancer cells. In this review, we analyze some of the authorized formulations and discuss the challenges of translating findings from the lab to the clinic. This study highlights the various nanocarriers and compounds that can be used for selective tumor targeting and the inherent difficulties in cancer therapy. Nanotechnology provides a promising platform for improving cancer detection and treatment in the future, but further research is needed to overcome the current limitations in clinical translation.

Molecular mechanisms of long non-coding RNAs in differentiation of T Helper17 cells.

T helper (Th) 17 cells are one of the most important T cell subsets in a number of autoimmune and chronic inflammatory diseases. During infections, Th17 cells appear to play an important role in the clearance of extracellular pathogens. Th17 cells, on the other hand, are engaged in inflammation and have been linked to the pathophysiology of a number of autoimmune illnesses and human inflammatory disorders. A diverse group of RNA molecules known as lncRNAs serve critical functions in gene expression regulation. They may interact with a wide range of molecules, including DNA, RNA, and proteins, and have a complex structure. LncRNAs, which have restricted or no protein-coding activity, are implicated in a number of illnesses due to their regulatory impact on a variety of biological processes such as cell proliferation, apoptosis, and differentiation. Several lncRNAs have been associated with Th7 cell development in the context of immune cell differentiation. In this article, we cover new studies on the involvement of lncRNAs in Th17 cell differentiation in a variety of disorders, including auto-immune diseases, malignancies, asthma, heart disease, and infections.

A thorough understanding of the role of lncRNA in prostate cancer pathogenesis; Current knowledge and future research directions.

In the entire world, prostate cancer (PCa) is one of the most common and deadly cancers. Treatment failure is still common among patients, despite PCa diagnosis and treatment improvements. Inadequate early diagnostic markers and the emergence of resistance to conventional therapeutic approaches, particularly androgen-deprivation therapy, are the causes of this. Long non-coding RNAs (lncRNAs), as an essential group of regulatory molecules, have been reported to be dysregulated through prostate tumorigenesis and hold great promise as diagnostic targets. Besides, lncRNAs regulate the malignant features of PCa cells, such as proliferation, invasion, metastasis, and drug resistance. These multifunctional RNA molecules interact with other molecular effectors like miRNAs and transcription factors to modulate various signaling pathways, including AR signaling. This study aimed to compile new knowledge regarding the role of lncRNA through prostate tumorigenesis in terms of their effects on the various malignant characteristics of PCa cells; in light of these characteristics and the significant potential of lncRNAs as diagnostic and therapeutic targets for PCa. AVAILABILITY OF DATA AND MATERIALS: Not applicable.

Pathological role of inflammation in ocular disease progress and its targeting by mesenchymal stem cells (MSCs) and their exosome; current status and prospect.

Because of their unique capacity for differentiation to a diversity of cell lineages and immunosuppressive properties, mesenchymal stem cells (MSC) are being looked at as a potential new treatment option in ophthalmology. The MSCs derived from all tissue sources possess immunomodulatory attributes through cell-to-cell contact and releasing a myriad of immunomodulatory factors (IL-10, TGF-ß, growth-related oncogene (GRO), indoleamine 2,3 dioxygenase (IDO), nitric oxide (NO), interleukin 1 receptor antagonist (IL-1Ra), prostaglandin E2 (PGE2)). Such mediators, in turn, alter both the phenotype and action of all immune cells that serve a pathogenic role in the progression of inflammation in eye diseases. Exosomes from MSCs, as natural nano-particles, contain the majority of the bioactive components of parental MSCs and can easily by-pass all biological barriers to reach the target epithelial and immune cells in the eye without interfering with nearby parenchymal cells, thus having no serious side effects. We outlined the most recent research on the molecular mechanisms underlying the therapeutic benefits of MSC and MSC-exosome in the treatment of inflammatory eye diseases in the current article.

The developing role of extracellular vesicles in autoimmune diseases: special attention to mesenchymal stem cell-derived extracellular vesicles.

Autoimmune diseases are complex, chronic inflammatory conditions initiated by the loss of immunological tolerance to self-antigens. Nowadays, there is no effective and useful therapy for autoimmune diseases, and the existing medications have some limitations due to their nonspecific targets and side effects. During the last few decades, it has been established that mesenchymal stem cells (MSCs) have immunomodulatory functions. It is proposed that MSCs can exert an important therapeutic effect on autoimmune disorders. In parallel with these findings, several investigations have shown that MSCs alleviate autoimmune diseases. Intriguingly, the results of studies have demonstrated that the effective roles of MSCs in autoimmune diseases do not depend on direct intercellular communication but on their ability to release a wide spectrum of paracrine mediators such as growth factors, cytokines and extracellular vehicles (EVs). EVs that range from 50 to 5,000 nm were produced by almost any cell type, and these nanoparticles participate in homeostasis and intercellular communication via the transfer of a broad range of biomolecules such as modulatory proteins, nucleic acids (DNA and RNA), lipids, cytokines, and metabolites. EVs derived from MSCs display the exact properties of MSCs and can be safer and more beneficial than their parent cells. In this review, we will discuss the features of MSCs and their EVs, EVs biogenesis, and their cargos, and then we will highlight the existing discoveries on the impacts of EVs from MSCs on autoimmune diseases such as multiple sclerosis, arthritis rheumatic, inflammatory bowel disease, Type 1 diabetes mellitus, systemic lupus erythematosus, autoimmune liver diseases, Sjögren syndrome, and osteoarthritis, suggesting a potential alternative for autoimmune conditions therapy.

UV and solar-based photocatalytic degradation of organic pollutants from ceramics industrial wastewater by Fe-doped ZnS nanoparticles.

UV and solar-based photocatalytic degradation of 2,4-dichlorophenol (2,4-DCP) as an organic contaminant in ceramics industry wastewater by ZnS and Fe-doped ZnS NPs was the focus of this research. Nanoparticles were prepared using a chemical precipitation process. The cubic, closed-packed structure of undoped ZnS and Fe-doped ZnS NPs was formed in spherical clusters, according to XRD and SEM investigations. According to optical studies, the optical band gaps of pure ZnS and Fe-doped ZnS nanoparticles are 3.35 and 2.51 eV, respectively, and Fe doping increased the number of carriers with high mobility, improved carrier separation and injection efficiency, and increased photocatalytic activity under UV or visible light. Doping of Fe increased the separation of photogenerated electrons and holes and facilitated charge transfer, according to electrochemical impedance spectroscopy investigations. Photocatalytic degradation studies revealed that in the present pure ZnS and Fe-doped ZnS nanoparticles, 100% treatment of 120 mL of 15 mg/L phenolic compound was obtained after 55- and 45-min UV-irradiation, respectively, and complete treatment was attained after 45 and 35-min solar light irradiation, respectively. Because of the synergistic effects of effective surface area, more effective photo-generated electron and hole separation efficiency, and enhanced electron transfer, Fe-doped ZnS demonstrated high photocatalytic degradation performance. The study of Fe-doped ZnS's practical photocatalytic treatment capability for removing 120 mL of 10 mg/L 2,4-DCP solution made from genuine ceramic industrial wastewater revealed Fe-doped ZnS's excellent photocatalytic destruction of 2,4-DCP from real industrial wastewater.

The bioengineered and multifunctional nanoparticles in pancreatic cancer therapy: Bioresponisive nanostructures, phototherapy and targeted drug delivery.

The multidisciplinary approaches in treatment of cancer appear to be essential in term of bringing benefits of several disciplines and their coordination in tumor elimination. Because of the biological and malignant features of cancer cells, they have ability of developing resistance to conventional therapies such as chemo- and radio-therapy. Pancreatic cancer (PC) is a malignant disease of gastrointestinal tract in which chemotherapy and radiotherapy are main tools in its treatment, and recently, nanocarriers have been emerged as promising structures in its therapy. The bioresponsive nanocarriers are able to respond to pH and redox, among others, in targeted delivery of cargo for specific treatment of PC. The loading drugs on the nanoparticles that can be synthetic or natural compounds, can help in more reduction in progression of PC through enhancing their intracellular accumulation in cancer cells. The encapsulation of genes in the nanoparticles can protect against degradation and promotes intracellular accumulation in tumor suppression. A new kind of therapy for cancer is phototherapy in which nanoparticles can stimulate both photothermal therapy and photodynamic therapy through hyperthermia and ROS overgeneration to trigger cell death in PC. Therefore, synergistic therapy of phototherapy with chemotherapy is performed in accelerating tumor suppression. One of the important functions of nanotechnology is selective targeting of PC cells in reducing side effects on normal cells. The nanostructures are capable of being surface functionalized with aptamers, proteins and antibodies to specifically target PC cells in suppressing their progression. Therefore, a specific therapy for PC is provided and future implications for diagnosis of PC is suggested.

Solar light driven enhanced photocatalytic treatment of azo dye contaminated water based on Co-doped ZnO/ g-C3N4 nanocomposite.

The current research concentrated on the Co-precipitation synthesis of g-C3N4 (CN), ZnO, ZnO/CN, and Co-doped ZnO/CN nanocomposite, as well as the solar light enhanced photocatalytic treatment of Reactive Red 120 (RR120) from genuine wool textile effluent. The 3D flower-like structure of Co-doped ZnO distributed on the surface of CN thin sheets, according to structural studies employing XRD and SEM examinations Electrochemical experiments exhibited that the Co-doped ZnO/CN nanocomposite has a large electroactive surface area. The optical band-gap values of CN, ZnO, ZnO/CN, and Co-doped ZnO/CN nanocomposites were 2.68, 3.13, 2.38, and 2.23 eV, respectively, according to optical characterizations. The synergistic effects and heterojunction produced by Co-doped ZnO and CN can be linked to the narrow gap in nanocomposites. After 75, 60, 50, and 40 min of exposure to solar light, photocatalytic degradation assays for 250 mL of 20 mg/L RR120 solution in the presence of CN, ZnO, ZnO/CN, and Co-doped ZnO/CN nanocomposites demonstrated 100% dye treatment. The applicability of photocatalysts for decolorization of 250 mL of 10 mg/L RR120 prepared from actual wool textile wastewater was investigated, and the results showed that Co-doped ZnO/CN nanocomposites for treatment of RR120 from actual wool textile wastewater were highly efficient at photocatalytic degradation.

A novel co-culture model of human prostate epithelial and stromal cells for androgenic and antiandrogenic screening.

The risk assessment of endocrine-disrupting chemicals (EDCs) greatly relies on in vitro screening. A 3-dimensional (3D) in vitro prostate model that can reflect physiologically-relevant prostate epithelial and stromal crosstalk can significantly advance the current androgen assessment. This study built a prostate epithelial and stromal co-culture microtissue model with BHPrE and BHPrS cells in scaffold-free hydrogels. The optimal 3D co-culture condition was defined, and responses of the microtissue to androgen (dihydrotestosterone, DHT) and anti-androgen (flutamide) exposure were characterized using molecular and image profiling techniques. The co-culture prostate microtissue maintained a stable structure for up to seven days and presented molecular and morphological features of the early developmental stage of the human prostate. The cytokeratin 5/6 (CK5/6) and cytokeratin 18 (CK18) immunohistochemical staining indicated epithelial heterogeneity and differentiation in these microtissues. The prostate-related gene expression profiling did not efficiently differentiate androgen and anti-androgen exposure. However, a cluster of distinctive 3D image features was identified and could be applied in the androgenic and anti-androgenic effect prediction. Overall, the current study established a co-culture prostate model that provided an alternative strategy for (anti-)androgenic EDC safety assessment and highlighted the potential and advantage of utilizing image features to predict endpoints in chemical screening.

High cardiac output state due to pelvic arterio-venous shunt: a case report and review of the literature.

We are presenting a 35-year-old woman with past medical history of disseminated leiomyomatosis who presented with heart failure symptoms and was found to have post-capillary pulmonary hypertension and high cardiac output state in right heart catheterization secondary to a huge pelvic arterio-venous fistula.

Advances in mesenchymal stem/stromal cell-based therapy and their extracellular vesicles for skin wound healing.

Wound healing is a dynamic and complicated process containing overlapping phases. Presently, definitive therapy is not available, and the investigation into optimal wound care is influenced by the efficacy and cost-effectiveness of developing therapies. Accumulating evidence demonstrated the potential role of mesenchymal stem/stromal cell (MSC) therapy in several tissue injuries and diseases due to their high proliferation and differentiation abilities along with an easy collection procedure, low tumorigenesis, and immuno-privileged status. MSCs have also accelerated wound repair in all phases through their advantageous properties, such as accelerating wound closure, improving re-epithelialization, elevating angiogenesis, suppressing inflammation, and modulating extracellular matrix (ECM) remodeling. In addition, the beneficial therapeutic impacts of MSCs are largely associated with their paracrine functions, including extracellular vesicles (EVs). Exosomes and microvesicles are the two main subgroups of EVs. These vesicles are heterogeneous bilayer membrane structures that contain several proteins, lipids, and nucleic acids. EVs have emerged as a promising alternative to stem cell-based therapies because of their lower immunogenicity, tumorigenicity, and ease of management. MSCs from various sources have been widely investigated in skin wound healing and regeneration. Considering these features, in this review, we highlighted recent studies that the investigated therapeutic potential of various MSCs and MSC-EVs in skin damages and wounds.