Colonic adenomatous polyp with florid presence of monoclonal lambda Russell bodies: Case report and etiopathogenic hypothesis / Pólipo adenomatoso colónico con presencia florida de cuerpos de Russell monoclonales lambda: comunicación de un caso e hipótesis etiopatogénica

Russell bodies (RBs) are round eosinophilic intracytoplasmic inclusions formed by condensed immunoglobulins in mature plasma cells, which are called Mott cells. These cells are rarely found in the gastric tract, with even less cases reported in the colorectal region. There are still many questions about this event, as it is still unknown the relationship between the agents reported of increasing the probability of appearance of these cells and the generation of RBs. In this case report we describe the fifth patient presenting an infiltration of Mott cells in a colorectal polyp, being the second case with a monoclonal origin without a neoplastic cause, and the first one monoclonal for lambda. A comparison with previously similar reported cases is also done, and a possible etiopathogenic hypothesis proposed. (AU)

Los cuerpos de Russell (RB) son inclusiones intracitoplasmáticas eosinofílicas redondas formadas por inmunoglobulinas condensadas en las células plasmáticas maduras, que se denominan células de Mott. Estas células rara vez se encuentran en el tracto gástrico, y son aún más infrecuentes en la región colorrectal. Actualmente hay muchas dudas sobre este evento, ya que se desconoce la relación entre los agentes causantes de aumentar la probabilidad de aparición tanto de estas células como de la de RB. En este caso describimos al quinto paciente con un pólipo colorrectal, localizado en el tracto colorrectal e infiltrado por células de Mott, siendo el segundo caso de origen monoclonal sin causa neoplásica y el primero monoclonal para lambda. También se hace una comparación con casos similares previamente reportados y se propone una hipótesis etiopatogénica. (AU)

ABCA4 mediated traumatic proliferative vitreoretinopathy associated with PI3K/Akt signaling pathway.

Background: Proliferative vitreoretinopathy (PVR) is the main cause of retinal detachment. However, the underlying mechanism of PVR is complex and has not yet been fully elucidated. The PI3K/Akt/mTOR signaling pathway is involved in angiogenesis and plays an important role in cell proliferation and tumor formation. Therefore, our study was designed to investigate the potential biological mechanisms of alleviating ARPE-19 cell and traumatic PVR model involving PI3K/Akt signaling pathway by targeting ABCA4. Materials and methods: ARPE-19 cell model was induced by ABCA4 overexpression vector and si-ABCA4, then the ABCA4 overexpression vector and si-ABCA4 were constructed, the plasmids were expanded for cell transfection and verification. In addition, OE-ABCA4, shRNA NC and si-ABCA4 were transfected into ARPE-19 cells. Cell viability was detected by CCK-8 assay, cell cycle was determined by flow cytometry. The expression level and location of ABCA4 were detected by immunofluorescence. Finally, rabbit traumatic PVR model was induced by surgery, the adenovirus was injected into the vitreous body respectively, and the fundus observation was performed by direct ophthalmoscope observation combined with fundus photography, and the retinal routine histopathology HE staining was performed. Analysis of P21, CDK4, Cyclin D1, BAX, BAD, and ABCA4 was used by quantitative RT-PCR and Western blot. Besides, the expression level of ABCA4, AKT, p-AKT, PI3K, p-PI3K, P38, p-P38, JNK, p-JNK, ERK, and p-ERK was detected by Western blot. Results: All results indicated that the viability of cells with high expression of ABC4A increased, while the viability of cells with inhibition of ABC4A decreased, the number of cells with high ABC4A expression was significantly higher, and the migration level of cells was significantly reduced after ABC4A inhibition (P < 0.05). ABC4A could affect cell apoptosis by affecting G1/G2 phase. The cell proliferation level was significantly increased with high expression of ABC4A. High expression of ABC4A increased phosphorylation levels, including p-AKT, p-PIK3, and p-P38, while inhibition of ABC4A decreased the expression levels of these proteins (P < 0.05). Inhibition of ABC4A could significantly improve retinopathy, indicating that the proliferation ability of cells was restored after inhibition of ABC4A. Conclusions: Our finding suggested that inhibition of ABC4A ameliorated the injury degree of traumatic PVR and performed the potential anti-PVR effect via inhibiting PI3K/Akt signaling pathway, while promoting cell proliferation in both rabbit and ARPE-19 cells PVR model. The study has a certain innovation by building a traumatic PVR model to explore whether the ABCA4 participates in the regulation of the PI3K/AKT signaling pathway and the pathological mechanism of PVR regulation. At the same time, ABCA4's participation in the regulation of PI3K/Akt signaling pathway can prevent and delay the occurrence and development of PVR, which has positive significance for improving the survival rate and quality of life of patients, and also provides an important basis for its therapeutic mechanism. Therefore, our study demonstrated a significant strategy for inhibiting traumatic PVR via targeting PI3K/Akt/ABCA4 pathway.

GRIK1 promotes glioblastoma malignancy and is a novel prognostic factor of poor prognosis.

Primary tumors of the central nervous system (CNS) are classified into over 100 different histological types. The most common type of glioma is derived from astrocytes, and the most invasive glioblastoma (WHO IV) accounts for over 57% of these tumors. Glioblastoma (GBM) is the most common and fatal tumor of the CNS, with strong growth and invasion capabilities, which makes complete surgical resection almost impossible. Despite various treatment methods such as surgery, radiotherapy, and chemotherapy, glioma is still an incurable disease, and the median survival time of patients with GBM is shorter than 15 months. Thus, molecular mechanisms of GBM characteristic invasive growth need to be clarified to improve the poor prognosis. Glutamate ionotropic receptor kainate type subunit 1 (GRIK1) is essential for brain function and is involved in many mental and neurological diseases. However, GRIK1's pathogenic roles and mechanisms in GBM are still unknown. Single-nuclear RNA sequencing of primary and recurrent GBM samples revealed that GRIK1 expression was noticeably higher in the recurrent samples. Moreover, immunohistochemical staining of an array of GBM samples showed that high levels of GRIK1 correlated with poor prognosis of GBM, consistent with The Cancer Genome Atlas database. Knockdown of GRIK1 retarded GBM cells growth, migration, and invasion. Taken together, these findings show that GRIK1 is a unique and important component in the development of GBM and may be considered as a biomarker for the diagnosis and therapy in individuals with GBM.

MTCH2 stimulates cellular proliferation and cycles via PI3K/Akt pathway in breast cancer.

The MTCH2 protein is located on the mitochondrial outer membrane and regulates mitochondria-related cell death. This study set out to investigate the role of MTCH2 in the underlying pathophysiological mechanisms of breast cancer (BC). MTCH2 expression levels in BC were analyzed using bioinformatics prior to verification by cell lines in vitro. Experiments of over-expression and siRNA-mediated knockdown of MTCH2 were conducted to assess its biological functions, including its effects on cellular proliferation and cycle progression. Xenografts were utilised for in vivo study and signaling pathway alterations were examined to identify the mechanisms driven by MTCH2 in BC proliferation and cell-cycle regulation. MTCH2 was up-regulated in BC and correlated with patients' overall survival. Over-expression of MTCH2 promoted cellular proliferation and cycle progression, while silencing MTCH2 had the opposite effect. Xenograft experiments were utilised to confirm the in vitro cellular findings and it was identified that the PI3K/Akt signaling pathway was activated by MTCH2 over-expression and suppressed by its silencing. Moreover, the activation of IGF-1R rescued cellular growth and cycle arrest induced by MTCH2-silencing. Overall, this study reveals that expression of MTCH2 in BC is upregulated and potentiates cellular proliferation and cycle progression via the PI3K/Akt pathway.

How to make full use of dental pulp stem cells: an optimized cell culture method based on explant technology.

Introduction: Dental pulp stem cells from humans possess self-renewal and versatile differentiation abilities. These cells, known as DPSC, are promising for tissue engineering due to their outstanding biological characteristics and ease of access without significant donor site trauma. Existing methods for isolating DPSC mainly include enzyme digestion and explant techniques. Compared with the enzymatic digestion technique, the outgrowth method is less prone to cell damage and loss during the operation, which is essential for DPSC with fewer tissue sources. Methods: In order to maximize the amount of stem cells harvested while reducing the cost of DPSC culture, the feasibility of the optimized explant technique was evaluated in this experiment. Cell morphology, minimum cell emergence time, the total amount of cells harvested, cell survival, and proliferative and differentiation capacity of DPSC obtained with different numbers of explant attachments (A1-A5) were evaluated. Results: There was a reduction in the survival rate of the cells in groups A2-A5, and the amount of harvested DPSC decreased in A3-A5 groups, but the DPSC harvested in groups A1-A4 had similar proliferative and differentiation abilities. However, starting from group A5, the survival rate, proliferation and differentiation ability of DPSC decreased significantly, and the adipogenic trend of the cells became more apparent, indicating that the cells had begun to enter the senescence state. Discussion: The results of our study demonstrated that the DPSC obtained by the optimized explant method up to 4 times had reliable biological properties and is available for tissue engineering.

Defining the contribution of Troy-positive progenitor cells to the mouse esophageal epithelium.

Progenitor cells adapt their behavior in response to tissue demands. However, the molecular mechanisms controlling esophageal progenitor decisions remain largely unknown. Here, we demonstrate the presence of a Troy (Tnfrsf19)-expressing progenitor subpopulation localized to defined regions along the mouse esophageal axis. Lineage tracing and mathematical modeling demonstrate that Troy-positive progenitor cells are prone to undergoing symmetrical fate choices and contribute to esophageal tissue homeostasis long term. Functionally, TROY inhibits progenitor proliferation and enables commitment to differentiation without affecting fate symmetry. Whereas Troy expression is stable during esophageal homeostasis, progenitor cells downregulate Troy in response to tissue stress, enabling proliferative expansion of basal cells refractory to differentiation and reestablishment of tissue homeostasis. Our results demonstrate functional, spatially restricted progenitor heterogeneity in the esophageal epithelium and identify how dynamic regulation of Troy coordinates tissue generation.

Breast Hemangiomas: Imaging Features With Histopathology Correlation.

Breast hemangiomas are rare benign vascular lesions. In a previously performed review of approximately 10,000 breast surgical pathology results, roughly 0.15% (15/~10,000) were hemangiomas. Hemangiomas are more frequent in women and have a documented age distribution of 1.5 to 82 years. They are most often subcutaneous or subdermal and anterior to the anterior mammary fascia but may rarely be seen in the pectoralis muscles or chest wall. On imaging, breast hemangiomas typically present as oval or round masses, often measuring less than 2.5 cm, with circumscribed or mostly circumscribed, focally microlobulated margins, equal or high density on mammography, and variable echogenicity on US. Calcifications, including phleboliths, can be seen. Color Doppler US often shows hypovascularity or avascularity. MRI appearance can vary, although hemangiomas are generally T2 hyperintense and T1 hypointense with variable enhancement. Pathologic findings vary by subtype, which include perilobular, capillary, cavernous, and venous hemangiomas. If core biopsy pathology results are benign, without atypia, and concordant with imaging and clinical findings, surgical excision is not routinely indicated. Because of histopathologic overlap with well-differentiated or low-grade angiosarcomas, surgical excision may be necessary for definitive diagnosis. Findings that are more common with angiosarcomas include size greater than 2 cm, hypervascularity on Doppler US, irregular shape, and invasive growth pattern.

FNDC5 inhibits malignant growth of human cervical cancer cells via restraining PI3K/AKT pathway.

Cervical cancer (CxCa) is the fourth most frequent cancer in women. This study aimed to determine the role and underlying mechanism of fibronectin type III domain-containing protein 5 (FNDC5) in inhibiting CxCa growth. Experiments were performed in human CxCa tissues, human CxCa cell lines (HeLa and SiHa), and xenograft mouse model established by subcutaneous injection of SiHa cells in nude mice. Bioinformatics analysis showed that CxCa patients with high FNDC5 levels have a longer overall survival period. FNDC5 expression was increased in human CxCa tissues, HeLa and SiHa cells. FNDC5 overexpression or FNDC5 protein not only inhibited proliferation, but also restrained invasion and migration of HeLa and SiHa cells. The effects of FNDC5 were prevented by inhibiting integrin with cilengitide, activating PI3K with recilisib or activating Akt with SC79. FNDC5 inhibited the phosphorylation of PI3K and Akt, which was attenuated by recilisib. PI3K inhibitor LY294002 showed similar effects to FNDC5 in HeLa and SiHa cells. Intravenous injection of FNDC5 (20 µg/day) for 14 days inhibited the tumor growth, and reduced the proliferation marker Ki67 expression and the Akt phosphorylation in the CxCa xenograft mouse model. These results indicate that FNDC5 inhibits the malignant phenotype of CxCa cells through restraining PI3K/Akt signaling. Upregulation of FNDC5 may play a beneficial role in retarding the tumor growth of CxCa.

Three-dimensional bioprinted GelMA/GO composite hydrogel for stem cell osteogenic differentiation both in vitro and in vivo.

In this study, we evaluated the use of graphene oxide (GO) mixed with methyl methacrylate gelatin (GelMA) for the construction of a microenvironmental implant to repair bone defects in orthopedic surgery. A scaffold containing a GelMA/GO composite with mesenchymal stem cells (MSCs) was constructed using three-dimensional bioprinting. The survival and osteogenic capacity of MSCs in the composite bioink were evaluated using cell viability and proliferation assays, osteogenesis-related gene expression analysis, and implantation under the skin of nude mice. The printing process had little effect on cell viability. We found that GO enhanced cell proliferation but had no significant effect on cell viability. In vitro experiments suggested that GO promoted material-cell interactions and the expression of osteogenesis-related genes. In vivo experiments showed that GO decreased the degradation time of the material and increased calcium nodule deposition. In contrast to pure GelMA, the addition of GO created a suitable microenvironment to promote the differentiation of loaded exogenous MSCs in vitro and in vivo, providing a basis for the repair of bone defects.

Optimal Treatment Parameters for Ultrasound-Stimulated Microbubbles in Upregulating Proliferation and Stemness of Bone Marrow Mesenchymal Stem Cells.

OBJECTIVES: Ultrasound-targeted microbubble disruption (UTMD) is a widely used technique to improve the differentiation and proliferation capacity of mesenchymal stem cells (MSCs), but the optimal therapeutic parameters for UTMD are unclear. In this study, we aimed to find the appropriate peak negative pressure (PNP), which is a key parameter for enhancing the stemness properties and proliferation of MSCs. METHODS: Experiments were performed in UTMD group, ultrasound (US) group under different PNP exposure conditions (0.5, 1.0, and 1.5 MPa), and control group. Apoptosis safety was analyzed by flow cytometry and MSC proliferation was measured at 12, 24, and 36 hours after irradiation by cell counting kit 8. The expression of the stemness genes NANOG, OCT-4, and SOX-2 were determined by enzyme-linked immunosorbent assay (ELISA) or reverse transcription polymerase chain reaction. RESULTS: The results showed that the 1.5 MPa UTMD-treated group had the highest proliferation capacity of MSCs at 24 hours. ELISA or quantitative reverse transcription polymerase chain reaction results showed that UTMD treatment of the 1.5 MPa group significantly upregulated the expression of the stemness genes NANOG, SOX-2, and OCT-4. CONCLUSIONS: In conclusion, the appropriate peak PNP value of UTMD was 1.5 MPa, and 1.5 MPa-mediated UTMD group obviously promoted MSCs proliferation and maintained stemness by upregulating the expression of stemness genes.

ACSL4 accelerates osteosarcoma progression via modulating TGF-ß/Smad2 signaling pathway.

Osteosarcoma (OS) is a malignant bone sarcoma arising from mesenchymal stem cells. The biological role of Acyl-CoA synthetase long-chain family member 4 (ACSL4), recently identified as an oncogene in numerous tumor types, remains largely unclear in OS. In this study, we investigated the expression of ACSL4 in OS tissues using immunohistochemistry staining (IHC) staining of a human tissue microarray and in OS cells by qPCR assay. Our findings revealed a significant up-regulation of ACSL4 in both OS tissues and cells. To further understand its biological effects, we conducted a series of loss-of-function experiments using ACSL4-depleted MNNG/HOS and U-2OS cell lines, focusing on OS cell proliferation, migration, and apoptosis in vitro. Our results demonstrated that ACSL4 knockdown remarkably suppressed OS cell proliferation, arrested cells in the G2 phase, induced cell apoptosis, and inhibited cell migration. Additionally, a subcutaneous xenograft mice model was established to validate the in vivo impact of ACSL4, revealing ACSL4 silencing impaired tumor growth in the OS xenograft mice. Additionally, we discovered that ACSL4 could regulate the phosphorylation level of Smad2 through cooperative interactions, and treatment with a TGF-ß inhibitor weakened the promoting effects of ACSL4 overexpression. In short, ACSL4 regulated OS progression by modulating TGF-ß/Smad2 signaling pathway. These findings underscore ACSL4 as a promising therapeutic target for OS patients and contribute novel insights into the pathogenesis of OS.

Transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae.

Congenital infection caused by vertical transmission of microsporidia N. bombycis can result in severe economic losses in the silkworm-rearing industry. Whole-transcriptome analyses have revealed non-coding RNAs and their regulatory networks in N. bombycis infected embryos and larvae. However, transcriptomic changes in the microsporidia proliferation and host responses in congenitally infected embryos and larvae remains unclear. Here, we simultaneously compared the transcriptomes of N. bombycis and its host B. mori embryos of 5-day and larvae of 1-, 5- and 10-day during congenital infection. For the transcriptome of N. bombycis, a comparison of parasite expression patterns between congenital-infected embryos and larva showed most genes related to parasite central carbon metabolism were down-regulated in larvae during infection, whereas the majority of genes involved in parasite proliferation and growth were up-regulated. Interestingly, a large number of distinct or shared differentially expressed genes (DEGs) were revealed by the Venn diagram and heat map, many of them were connected to infection related factors such as Ricin B lectin, spore wall protein, polar tube protein, and polysaccharide deacetylase. For the transcriptome of B. mori infected with N. bombycis, beyond numerous DEGs related to DNA replication and repair, mRNA surveillance pathway, RNA transport, protein biosynthesis, and proteolysis, with the progression of infection, a large number of DEGs related to immune and infection pathways, including phagocytosis, apoptosis, TNF, Toll-like receptor, NF-kappa B, Fc epsilon RI, and some diseases, were successively identified. In contrast, most genes associated with the insulin signaling pathway, 2-oxacarboxylic acid metabolism, amino acid biosynthesis, and lipid metabolisms were up-regulated in larvae compared to those in embryos. Furthermore, dozens of distinct and three shared DEGs that were involved in the epigenetic regulations, such as polycomb, histone-lysine-specific demethylases, and histone-lysine-N-methyltransferases, were identified via the Venn diagram and heat maps. Notably, many DEGs of host and parasite associated with lipid-related metabolisms were verified by RT-qPCR. Taken together, simultaneous transcriptomic analyses of both host and parasite genes lead to a better understanding of changes in the microsporidia proliferation and host responses in embryos and larvae in N. bombycis congenital infection.

Effect of CHST11, a novel biomarker, on the biological functionalities of clear cell renal cell carcinoma.

Clear cell renal cell carcinoma (ccRCC) is a common malignant tumor, and the role of carbohydrate sulfotransferase 11 (CHST11) in this cancer remains unclear. Here, by using bioinformatics methods, we comprehensively analyzed the relationship between CHST11 and clinical significance, immune infiltration, functional enrichment, m6A methylation, and protein-protein interaction networks. We found that CHST11 expression was significantly higher in ccRCC samples than in normal tissues. Additionally, CHST11 levels correlated with the clinicopathological features of ccRCC patients and functioned as a prognostic factor for patient survival. Functional analysis revealed the involvement of CHST11 in metabolic pathways. Immune infiltration and m6A methylation analysis suggested the association of CHST11 with immune cell abundance in the tumor microenvironment and specific methylation patterns in ccRCC. The in vitro analysis of the clinical samples and ccRCC cell lines demonstrated that the overexpression of CHST11 promotes ccRCC cell proliferation, migration, and invasion, while its suppression has the opposite effect. Thus, CHST11 may play a remarkable role in the occurrence and progression of ccRCC. Functionally, CHST11 promotes the aggressiveness of ccRCC cells. These findings provide insights into the role of CHST11 in ccRCC progression.Registry and the Registration No. of the study/trial: No. 2021K034.

PDP1 promotes the progression of breast cancer through STAT3 pathway.

This study aimed to investigate the expression pattern and mechanisms of Pyruvate Dehydrogenase Phosphatase Catalytic Subunit 1 (PDP1) in the progression of breast cancer (BC). PDP1, known for its involvement in cell energy metabolism, was found to be overexpressed in BC tissues. Notably, low PDP1 expression aligns with improved overall survival (OS) in BC patients. In this study, we found that PDP1 was overexpressed among BC tissues and low PDP1 expression showed a better prognosis for the patients with BC. PDP1 knockdown suppressed cell amplification and migration and triggered cell apoptosis in BC cells. In vivo assessments through a xenograft model unveiled the pivotal role and underlying mechanisms of PDP1 knockdown. RNA sequencing and kyoto encyclopedia of genes and genomes analysis of RNAs from PDP1 knockdown and normal MCF7 cells revealed 1440 differentially expressed genes, spotlighting the involvement of the JAK/STAT3 signaling pathway in BC progression. Western blot results implied that PDP1 knockdown led to a loss of p-STAT3, whereas overexpression of PDP1 induced the p-STAT3 expression. Cell counting kit-8 assay showed that PDP1 overexpression significantly raised MDA-MB-231 and MCF7 cell viability while STAT3 inhibitor S3I-201 recovered the cell growth to normal level. To summarize, PDP1 promotes the progression of BC through STAT3 pathway by regulating p-STAT3. The findings contribute to understanding the molecular mechanisms underlying BC progression, and opening avenues for targeted therapeutic approaches.

Canagliflozin inhibits PASMCs proliferation via regulating SGLT1/AMPK signaling and attenuates artery remodeling in MCT-induced pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) was a devastating disease characterized by artery remodeling, ultimately resulting in right heart failure. The aim of this study was to investigate the effects of canagliflozin (CANA), a sodium-glucose cotransporter 2 inhibitor (SGLT2i) with mild SGLT1 inhibitory effects, on rats with PAH, as well as its direct impact on pulmonary arterial smooth muscle cells (PASMCs). PAH rats were induced by injection of monocrotaline (MCT) (40 mg/kg), followed by four weeks of treatment with CANA (30 mg/kg/day) or saline alone. Pulmonary artery and right ventricular (RV) remodeling and dysfunction in PAH were alleviated with CANA, as assessed by echocardiography. Hemodynamic parameters and structural of pulmonary arteriole, including vascular wall thickness and wall area, were reduced by CANA. RV hypertrophy index, cardiomyocyte hypertrophy, and fibrosis were decreased with CANA treatment. PASMCs proliferation was inhibited by CANA under stimulation by platelet-derived growth factor (PDGF)-BB or hypoxia. Activation of AMP kinase (AMPK) was induced by CANA treatment in cultured PASMCs in a time- and concentration-dependent manner. These effects of CANA were attenuated when treatment with compound C, an AMPK inhibitor. Abundant expression of SGLT1 was observed in PASMCs and pulmonary arteries, while SGLT2 expression was undetectable. SGLT1 increased in response to PDGF-BB or hypoxia stimulation, while PASMCs proliferation was inhibited and beneficial effects of CANA were counteracted by knockdown of SGLT1. Our research demonstrated for the first time that CANA inhibited the proliferation of PASMCs by regulating SGLT1/AMPK signaling and thus exerted an anti-proliferative effect on MCT-induced PAH.

The relationships of platelet-derived growth factor, microvascular proliferation, and tumor cell proliferation in canine high-grade oligodendrogliomas: Immunohistochemistry of 45 tumors and an AFOB-01 xenograft mouse model.

High-grade oligodendroglioma (HGOG) is the most common type of glioma in dogs and expresses platelet-derived growth factor receptor-α (PDGFR-α). Microvascular proliferation is often observed in HGOG. Therefore, the present study investigated the functional relationships between PDGFR-α, microvascular proliferation, and tumor cell proliferation in canine HGOG. The expression of PDGFR-α and PDGF-subunit A (PDGF-A) in tumor cells, as well as endothelial cells and pericytes of tumor-associated microvascular proliferations, in 45 canine HGOGs were examined immunohistochemically. Microvascular proliferation was observed in 24/45 cases (53%). PDGFR-α expression in tumor cells and microvascular proliferations was observed in 45/45 (100%) and 2/24 cases (8%), respectively. Furthermore, PDGF-A expression in tumor cells and microvascular proliferations was detected in 13/45 (29%) and 24/24 cases (100%), respectively. In vitro, stimulation of the canine HGOG cell line AOFB-01 with PDGF-A showed that the doubling time of AOFB-01 cells was significantly shorter with PDGF-A than without PDGF-A. Crenolanib (a PDGFR inhibitor) inhibited AOFB-01 cell proliferation. In vivo, the AOFB-01 xenograft mouse model was treated with crenolanib. Tumor xenografts were smaller in crenolanib-treated mice than in untreated control mice. PDGFR-α expression in tumor cells and PDGF-A expression in microvascular proliferations and tumor cells suggest autocrine and paracrine effects of PDGF-A in canine HGOG. The results of in vitro assays indicate that canine HGOG expresses functional PDGFR-α, which responds to PDGF-A. Therefore, PDGF-A produced by microvascular proliferations and tumor cells may promote the proliferation of PDGFR-α-expressing tumor cells in canine HGOG. PDGFR-α signaling has potential as a therapeutic target.

Design, synthesis and evaluation of new thiazolidin-4-ones as LPA1 receptor antagonists for breast cancer therapy.

Aim: Breast cancer has been a leading cause of mortality among women worldwide in recent years. Targeting the lysophosphatidic acid (LPA)-LPA1 pathway using small molecules could improve breast cancer therapy. Materials & methods: Thiazolidin-4-ones were developed and tested on MCF-7 cancer cells, and active compounds were analyzed for their effects on apoptosis, migration angiogenesis and LPA1 protein and gene expression. Results & conclusion: Compounds TZ-4 and TZ-6 effectively reduced the migration of MCF-7 cells, and induced apoptosis. TZ-4, TZ-6, TZ-8 and TZ-14 significantly reduced the LPA1 protein, LPA1 and angiogenesis gene expression in treated MCF-7 cells. Molecular docking and molecular dynamic simulation studies reveal the ligand interactions and stability of the LPA1-ligand complex. Developed thiazolidin-4-ones showed great potential as an LPA1-targeted approach to combating breast cancer.

Breast cancer is a major cause of death for women worldwide. Using small molecules to target the lysophosphatidic acid (LPA)­LPA₁ pathway could improve breast cancer treatment. We tested a type of molecule called thiazolidin-4-ones on breast cancer cells in the lab. We looked at how these molecules affected cell death, movement, blood vessel growth and the activity of the LPA₁ gene and protein. Some of these molecules, such as TZ-4 and TZ-6, reduced the movement of cancer cells and caused them to die. They also decreased the levels of LPA₁ protein and gene activity in the cells. We used computer simulations to see how these molecules interacted with the LPA₁ protein. Our findings suggest that thiazolidin-4-ones could be a promising treatment for breast cancer by targeting LPA₁.

HHLA2 promotes hepatoma cell proliferation, migration, and invasion via SPP1/PI3K/AKT signaling pathway.

Hepatocellular carcinoma (HCC) stands as one of the most malignant tumors characterized by poor prognosis and high mortality rates. Emerging evidence underscores the crucial role of the B7 protein family in various cancers, including HCC. However, the involvement of the human endogenous retrovirus H long-terminal repeat-associated protein 2 (HHLA2, or B7-H5) in HCC remains unclear. Immunohistochemistry was employed to assess the differential expression of HHLA2 between HCC and normal liver tissues. A battery of assays, including CCK8, EdU, tablet clone-forming, Transwell, and wound healing assays, were conducted to elucidate the function and potential mechanisms of HHLA2 in the malignant biological behaviors of HCC. Additionally, a xenograft mouse model was established to evaluate the tumorigenicity of hepatoma cell lines exhibiting different HHLA2 expression levels in vivo. Western blot analysis was used to analyze HHLA2, secretory phosphoprotein 1 (SPP1), and PI3K/AKT/mTOR levels. HHLA2 exhibited elevated expression in HCC tissues, correlating with poor tumor differentiation and shortened overall survival in HCC patients. In vitro experiments demonstrated that HHLA2 overexpression (OE) promoted the proliferation, migration, and invasion of hepatoma cells, while in vivo experiments revealed that HHLA2 OE enhanced HCC tumor growth. Conversely, inhibition of HHLA2 expression yielded the opposite effect. Downregulation of SPP1 inhibited the proliferation, migration, and invasion induced by HHLA2 OE, and this effect was linked to the PI3K/AKT/mTOR signaling pathway. Our findings indicate that HHLA2 promotes the proliferation, migration, and invasion of hepatoma cells via the SPP1/PI3K/AKT signaling pathway, establishing it as a potential therapeutic target for HCC.

Bilateral vitrectomy in patients with proliferative diabetic retinopathy-characteristics and surgical outcomes.

PURPOSE: Comparing characteristics and outcomes of patients with bilateral proliferative diabetic retinopathy (PDR) undergoing concurrent and sequential vitrectomy. METHODS: Patients having bilateral vitrectomy were classified into concurrent (requiring bilateral surgery simultaneously) and sequential (indicating vitrectomy in one eye later) groups. Clinical characteristics and outcomes were compared, and correlation between the first and second-operated eyes was analyzed. RESULTS: One hundred eight and 126 eyes were in the concurrent and sequential groups, respectively. The sequential group was older (50 vs. 45 years, P = 0.017), had less retinal detachment (54 vs. 77%, P < 0.001), and better visual outcomes (0.79 vs. 1.30, P = 0.021), especially the second-operated eyes. The concurrent group had weaker correlations of disease severity (phi coefficient: 0.36 vs. 0.61) and post-operative visual acuity (r: 0.12 vs. 0.34) between the first- and second-operated eyes than the sequential group. Prior intravitreal injection of anti-vascular endothelial growth factor (odds ratio [OR] 0.37, 95% confidence interval [CI] 0.15-0.86, P = 0.025) predicted better outcomes, while post-operative neovascular glaucoma predicted worse outcomes (OR 6.5, 95% CI 1.7-27.9, P = 0.008). CONCLUSIONS: PDR patients requiring surgery concurrently were younger and had more severe diseases and worse outcomes. However, poor outcomes in the first eye did not predict similar outcomes in the second eye.

Quantity, distribution and phenotype of newly generated cells in the intact spinal cord of adult macaque monkeys.

The existence of proliferating cells in the intact spinal cord, their distribution and phenotype, are well studied in rodents. A limited number of studies also address the proliferation after spinal cord injury, in non-human primates. However, a detailed description of the quantity, distribution and phenotype of proliferating cells at different anatomical levels of the intact adult non-human primate spinal cord is lacking at present. In the present study, we analyzed normal spinal cord tissues from adult macaque monkeys (Macaca fuscata), infused with Bromo-2'-deoxyuridine (BrdU), and euthanized at 2h, 2 weeks, 5 weeks and 10 weeks after BrdU. We found a significantly higher density of BrdU + cells in the gray matter of cervical segments as compared to thoracic or lumbar segments, and a significantly higher density of proliferating cells in the posterior as compared to the anterior horn of the gray matter. BrdU + cells exhibited phenotype of microglia or endothelial cells (∼50%) or astroglial and oligodendroglial cells (∼40%), including glial progenitor phenotypes marked by the transcription factors Sox9 and Sox10. BrdU + cells also co-expressed other transcription factors known for their involvement in embryonic development, including Emx2, Sox1, Sox2, Ngn1, Olig1, Olig2, Olig3. In the central canal, BrdU + cells were located along the dorso-ventral axis and co-labeled for the markers Vimentin and Nestin. These results reveal the extent of cellular plasticity in the spinal cord of non-human primates under normal conditions.