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)

Single-cell sequencing analysis confirms the association of ANRIL with the increased smooth muscle cell proliferation and migration gene signatures in pulmonary artery hypertension in silico.

PURPOSE: Smooth muscle cell (SMC) dysregulation is part of the pathological basis of pulmonary artery hypertension (PAH). We aimed to explore the heterogeneity of SMCs in PAH. METHODS: The profile GSE210248 was obtained from NCBI Gene Expression Omnibus, containing the scRNA-seq data of pulmonary arteries (PA) from three patients with PAH and three healthy donors. After quality control, normalization, and dimension reduction, cell clustering analysis was performed. Differential expression analysis and functional enrichment analysis were carried out successively in smooth muscle cells (SMCs). The enrichment scores of cell cycle and cell migration gene sets in SMCs were calculated. Then, the Spearman correlation coefficients between antisense non-coding RNA in the INK4 locus (ANRIL) expression and two gene sets were computed. RESULTS: Eight cell clusters were identified in PA from samples. The proportion of SMCs was increased in PAH samples. SMCs were divided into five subclusters with diverse biological functions. Muscle contraction-related SMC1 was decreased, while extracellular matrix organization-related SMC2, immune and inflammatory response-related SMC4 and SMC5 were increased in PAH samples compared with healthy donors. The enrichment scores of cell cycle and cell migration gene sets in SMCs were higher in PAH samples than in donors. ANRIL was down-regulated significantly in PAH samples and was negatively related to the scores of two gene sets. CONCLUSION: SMCs exhibited significant heterogeneity in PAH. The altered abilities of SMC proliferation and migration in PAH were associated with ANRIL expression.

Cellular and Transcriptional Response of Human Astrocytes to Hybrid Protein Materials.

Collagen is a major component of the tissue matrix, and soybean can regulate the tissue immune response. Both materials have been used to fabricate biomaterials for tissue repair. In this study, adult and fetal human astrocytes were grown in a soy protein isolate (SPI)-collagen hybrid gel or on the surface of a cross-linked SPI-collagen membrane. Hybrid materials reduced the cell proliferation rate compared to materials generated by collagen alone. However, the hybrid materials did not significantly change the cell motility compared to the control collagen material. RNA-sequencing (RNA-Seq) analysis showed downregulated genes in the cell cycle pathway, including CCNA2, CCNB1, CCNB2, CCND1, CCND2, and CDK1, which may explain lower cell proliferation in the hybrid material. This study also revealed the downregulation of genes encoding extracellular matrix (ECM) components, including HSPG2, LUM, SDC2, COL4A1, COL4A5, COL4A6, and FN1, as well as genes encoding chemokines, including CCL2, CXCL1, CXCL2, CX3CL1, CXCL3, and LIF, for adult human astrocytes grown on the hybrid membrane compared with those grown on the control collagen membrane. The study explored the cellular and transcriptional responses of human astrocytes to the hybrid material and indicated a potential beneficial function of the material in the application of neural repair.

Identification of PTPN12 Phosphatase as a Novel Negative Regulator of Hippo Pathway Effectors YAP/TAZ in Breast Cancer.

The Hippo pathway plays crucial roles in governing various biological processes during tumorigenesis and metastasis. Within this pathway, upstream signaling stimuli activate a core kinase cascade, involving MST1/2 and LATS1/2, that subsequently phosphorylates and inhibits the transcriptional co-activators YAP and its paralog TAZ. This inhibition modulates the transcriptional regulation of downstream target genes, impacting cell proliferation, migration, and death. Despite the acknowledged significance of protein kinases in the Hippo pathway, the regulatory influence of protein phosphatases remains largely unexplored. In this study, we conducted the first gain-of-functional screen for protein tyrosine phosphatases (PTPs) regulating the Hippo pathway. Utilizing a LATS kinase biosensor (LATS-BS), a YAP/TAZ activity reporter (STBS-Luc), and a comprehensive PTP library, we identified numerous novel PTPs that play regulatory roles in the Hippo pathway. Subsequent experiments validated PTPN12, a master regulator of oncogenic receptor tyrosine kinases (RTKs), as a previously unrecognized negative regulator of the Hippo pathway effectors, oncogenic YAP/TAZ, influencing breast cancer cell proliferation and migration. In summary, our findings offer valuable insights into the roles of PTPs in the Hippo signaling pathway, significantly contributing to our understanding of breast cancer biology and potential therapeutic strategies.

Tl(I) and Tl(III)-induce genotoxicity, reticulum stress and autophagy in PC12 Adh cells.

Thallium (Tl) and its two cationic species, Tl(I) and Tl(III), are toxic for most living beings. In this work, we investigated the effects of Tl (10-100 µM) on the viability and proliferation capacity of the adherent variant of PC12 cells (PC12 Adh cells). While both Tl(I) and Tl(III) halted cell proliferation from 24 h of incubation, their viability was ~ 90% even after 72 h of treatment. At 24 h, increased levels of γH2AX indicated the presence of DNA double-strand breaks. Simultaneously, increased expression of p53 and its phosphorylation at Ser15 were observed, which were associated with decreased levels of p-AKTSer473 and p-mTORSer2448. At 72 h, the presence of large cytoplasmic vacuoles together with increased autophagy predictor values suggested that Tl may induce autophagy in these cells. This hypothesis was corroborated by images obtained by transmission electron microscopy (TEM) and from the decreased expression at 72 h of incubation of SQSTM-1 and increased LC3ß-II to LC3ß-I ratio. TEM images also showed enlarged ER that, together with the increased expression of IRE1-α from 48 h of incubation, indicated that Tl-induced ER stress preceded autophagy. The inhibition of autophagy flux with chloroquine increased cell mortality, suggesting that autophagy played a cytoprotective role in Tl toxicity in these cells. Together, results indicate that Tl(I) or Tl(III) are genotoxic to PC12 Adh cells which respond to the cations inducing ER stress and cytoprotective autophagy.

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.

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.

HMGB2 Release Promotes Pulmonary Hypertension and Predicts Severity and Mortality of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary hypertension (PH) is a progressive and life-threatening disease characterized by pulmonary vascular remodeling, which involves aberrant proliferation and apoptosis resistance of the pulmonary arterial smooth muscle cells (PASMCs), resembling the hallmark characteristics of cancer. In cancer, the HMGB2 (high-mobility group box 2) protein promotes the pro-proliferative/antiapoptotic phenotype. However, the function of HMGB2 in PH remains uninvestigated. METHODS: Smooth muscle cell (SMC)-specific HMGB2 knockout or HMGB2-OE (HMGB2 overexpression) mice and HMGB2 silenced rats were used to establish hypoxia+Su5416 (HySu)-induced PH mouse and monocrotaline-induced PH rat models, respectively. The effects of HMGB2 and its underlying mechanisms were subsequently elucidated using RNA-sequencing and cellular and molecular biology analyses. Serum HMGB2 levels were measured in the controls and patients with pulmonary arterial (PA) hypertension. RESULTS: HMGB2 expression was markedly increased in the PAs of patients with PA hypertension and PH rodent models and was predominantly localized in PASMCs. SMC-specific HMGB2 deficiency or silencing attenuated PH development and pulmonary vascular remodeling in hypoxia+Su5416-induced mice and monocrotaline-treated rats. SMC-specific HMGB2 overexpression aggravated hypoxia+Su5416-induced PH. HMGB2 knockdown inhibited PASMC proliferation in vitro in response to PDGF-BB (platelet-derived growth factor-BB). In contrast, HMGB2 protein stimulation caused the hyperproliferation of PASMCs. In addition, HMGB2 promoted PASMC proliferation and the development of PH by RAGE (receptor for advanced glycation end products)/FAK (focal adhesion kinase)-mediated Hippo/YAP (yes-associated protein) signaling suppression. Serum HMGB2 levels were significantly increased in patients with PA hypertension, and they correlated with disease severity, predicting worse survival. CONCLUSIONS: Our findings indicate that targeting HMGB2 might be a novel therapeutic strategy for treating PH. Serum HMGB2 levels could serve as a novel biomarker for diagnosing PA hypertension and determining its prognosis.

Cytosolic DNA sensor AIM2 promotes KRAS-driven lung cancer independent of inflammasomes.

Constitutively active KRAS mutations are among the major drivers of lung cancer, yet the identity of molecular co-operators of oncogenic KRAS in the lung remains ill-defined. The innate immune cytosolic DNA sensor and pattern recognition receptor (PRR) Absent-in-melanoma 2 (AIM2) is best known for its assembly of multiprotein inflammasome complexes and promoting an inflammatory response. Here, we define a role for AIM2, independent of inflammasomes, in KRAS-addicted lung adenocarcinoma (LAC). In genetically defined and experimentally induced (nicotine-derived nitrosamine ketone; NNK) LAC mouse models harboring the KrasG12D driver mutation, AIM2 was highly upregulated compared with other cytosolic DNA sensors and inflammasome-associated PRRs. Genetic ablation of AIM2 in KrasG12D and NNK-induced LAC mouse models significantly reduced tumor growth, coincident with reduced cellular proliferation in the lung. Bone marrow chimeras suggest a requirement for AIM2 in KrasG12D-driven LAC in both hematopoietic (immune) and non-hematopoietic (epithelial) cellular compartments, which is supported by upregulated AIM2 expression in immune and epithelial cells of mutant KRAS lung tissues. Notably, protection against LAC in AIM2-deficient mice is associated with unaltered protein levels of mature Caspase-1 and IL-1ß inflammasome effectors. Moreover, genetic ablation of the key inflammasome adapter, ASC, did not suppress KrasG12D-driven LAC. In support of these in vivo findings, AIM2, but not mature Caspase-1, was upregulated in human LAC patient tumor biopsies. Collectively, our findings reveal that endogenous AIM2 plays a tumor-promoting role, independent of inflammasomes, in mutant KRAS-addicted LAC, and suggest innate immune DNA sensing may provide an avenue to explore new therapeutic strategies in lung cancer.

Exploring the Therapeutic Potential of Flavonoids in the Management of Cancer.

Flavonoids are a class of polyphenolic compounds that can be classified into six distinct categories, namely isoflavonoids, flavanones, flavanols, flavonols, flavones, and anthocyanidins. These compounds are naturally occurring and can be found in a diverse range of plant species. Flavonoids, a class of bioactive compounds, are mostly obtained through the consumption of vegetables, fruits and plant-derived beverages such as wine, cocoa-based products and green tea. Flavonoids have been demonstrated to exhibit a diverse range of anticancer properties. These include the modulation of activities of enzymes involved in scavenging reactive oxygen species, involvement in cell cycle arrest, induction of apoptosis and autophagy, as well as suppression of cancer cell proliferation and invasiveness. Flavonoids exhibit a dual role in maintaining reactive oxygen species balance. They function as antioxidants in regular physiological conditions, while also demonstrating significant pro-oxidant properties in cancer cells. This prooxidant activity induces apoptotic pathways and downregulates pro-inflammatory signalling pathways. The paper explores the biochemical characteristics, bioavailability, anticancer efficacy, and modes of action of flavonoids.

Eukaryotic initiation factor 3a promotes the development of diffuse large B-cell lymphoma through regulating cell proliferation.

BACKGROUND: One-third of diffuse large B-cell lymphoma (DLBCL) patients suffer relapse after standard treatment. Eukaryotic initiation factor 3a (eIF3a) is a key player in the initial stage of translation, which has been widely reported to be correlated with tumorigenesis and therapeutic response. This study aimed to explore the biological role of eIF3a, evaluate its prognostic and therapeutic potential in DLBCL. METHODS: RNA-seq datasets from GEO database were utilized to detect the expression and prognostic role of eIF3a in DLBCL patients. Protein level of eIF3a was estimated by western blot and immunohistochemical. Next, DLBCL cells were transfected with lentiviral vector either eIF3a-knockdown or empty to assess the biological role of eIF3a. Then, samples were divided into 2 clusters based on eIF3a expression and differentially expressed genes (DEGs) were identified. Function enrichment and mutation analysis of DEGs were employed to detect potential biological roles. Moreover, we also applied pan-cancer and chemosensitivity analysis for deep exploration. RESULTS: eIF3a expression was found to be higher in DLBCL than healthy controls, which was associated with worse prognosis. The expression of eIF3a protein was significantly increased in DLBCL cell lines compared with peripheral blood mononuclear cells (PBMCs) from healthy donors. eIF3a knockdown inhibited the proliferation of DLBCL cells and the expression of proliferation-related proteins and increase cell apoptosis rate. Besides, 114 DEGs were identified which had a close linkage to cell cycle and tumor immune. eIF3a and DEGs mutations were found to be correlated to chemosensitivity and vital signal pathways. Pan-cancer analysis demonstrated that high eIF3a expression was associated with worse prognosis in several tumors. Moreover, eIF3a expression was found to be related to chemosensitivity of several anti-tumor drugs in DLBCL, including Vincristine and Wee1 inhibitor. CONCLUSIONS: We firstly revealed the high expression and prognostic role of eIF3a in DLBCL, and eIF3a might promote the development of DLBCL through regulating cell proliferation and apoptosis. eIF3a expression was related to immune profile and chemosensitivity in DLBCL. These results suggest that eIF3a could serve as a potential prognostic biomarker and therapeutic target in DLBCL.

Long noncoding RNA UNC5B-AS1 suppresses cell proliferation by sponging miR-24-3p in glioblastoma multiforme.

BACKGROUND: Glioblastoma multiforme (GBM) is the most common primary CNS tumor, characterized by high mortality and heterogeneity. However, the related lncRNA signatures and their target microRNA (miRNA) for GBM are still mostly unknown. Therefore, it is critical that we discover lncRNA markers in GBM and their biological activities. MATERIALS AND METHODS: GBM-related RNA-seq data were obtained from the Cancer Genome Atlas (TCGA) database. The "edger" R package was used for differently expressed lncRNAs (DELs) identification. Then, we forecasted prospective miRNAs that might bind to lncRNAs by Cytoscape software. Survival analysis of those miRNAs was examined by the starBase database, and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the miRNAs' target genes was conducted by the Gene Set Enrichment Analysis (GSEA) database and R software. Moreover, the proliferative ability of unc-5 netrin receptor B antisense RNA 1 (UNC5B-AS1) cells was evaluated by Cell Counting Kit-8 (CCK-8) analysis. Mechanistically, the regulatory interaction between UNC5B-AS1 and miRNA in GBM biological processes was studied using CCK-8 analysis. RESULTS: Our results indicated that overexpression of UNC5B-AS1 has been shown to suppress GBM cell growth. Mechanistically, miR-24-3p in GBM was able to alleviate the anti-oncogenic effects of UNC5B-AS1 on cell proliferation. CONCLUSION: The discovery of the novel UNC5B-AS1-miR-24-3p network suggests possible lncRNA and miRNA roles in the development of GBM, which may have significant ramifications for the analysis of clinical prognosis and the development of GBM medications.

NEDD1 overexpression increases cell proliferation, tumor immune escape, and drug resistance in LUAD.

Background: Neural Precursor Cell Expressed Developmentally Down-Regulated Protein 1 (NEDD1) serves as a crucial factor in promoting cellular mitosis by directly facilitating wheel assembly and daughter centriole biogenesis at the lateral site of parent centrioles, ultimately driving centrosome replication. The amplification of centrosomes and the abnormal expression of centrosome-associated proteins contribute to the invasion and metastasis of non-small cell lung cancer cells. However, the specific mechanism by which NEDD1 contributes to the progression of lung adenocarcinoma (LUAD) remains unexplored. Therefore, the objective of this study is to uncover the role played by NEDD1 in LUAD. Methods: To verify the expression of NEDD1 in pan-carcinoma. The feasibility of NEDD1 as a prognostic marker for LUAD in TCGA and GEO databases was verified. Subsequently, Cox proportional hazard regression analysis was used to screen the prognostic factors of LUAD, so as to analyze the correlation between prognostic factors and NEDD1 expression. For another, NEDD1-related genes were screened for pathway enrichment analysis to verify their possible functions. In addition, the expression of NEDD1 in LUAD was verified by qPCR and IHC, then siRNA was used to construct NEDD1-knocked lung cancer cells for subsequent cytobehavioral experiments. Finally, the distribution of NEDD1 in single-cell samples was revealed, and then the correlation between its overexpression and LUAD immune escape and drug resistance was analyzed. Results: LUAD exhibits upregulation of NEDD1, which in turn promotes the proliferation, migration, invasion, and epithelial-mesenchymal transition of lung cancer cells, thereby contributing to a poor prognosis. Furthermore, the overexpression of NEDD1 is closely associated with immune escape and drug resistance in LUAD. Conclusion: NEDD1 serves as a reliable prognostic marker for LUAD, and its upregulation is associated with increased immune escape and drug resistance. Given these findings, NEDD1 holds potential as a novel therapeutic target for the treatment of LUAD.

Therapeutic potential of LINS01 histamine H3 receptor antagonists as antineoplastic agents for triple negative breast cancer.

The aims of this work were to evaluate the expression of histamine H3 receptor (H3R) in triple negative breast cancer (TNBC) samples and to investigate the antitumoral efficacy and safety of the LINS01 series of H3R antagonists, through in silico, in vitro, and in vivo approaches. Antitumor activity of LINS01009, LINS01010, LINS01022, LINS01023 was assayed in vitro in 4T1 and MDA-MB-231 TNBC cells (0.01-100 µM), and in vivo in 4T1 tumors orthotopically established in BALB/c mice (1 or 20 mg/kg). Additionally, H3R expression was assessed in 50 human TNBC samples. We have described a higher H3R mRNA expression in basal-like/TNBC tumors vs. matched normal tissue using TCGA Pan-Cancer Atlas data, and a higher H3R expression in human tumor samples vs. peritumoral tissue evidenced by immunohistochemistry associated with poorer survival. Furthermore, while all the essayed compounds showed antitumoral properties, LINS01022 and LINS01023 exhibited the most potent antiproliferative effects by: i) inducing cell apoptosis and suppressing cell migration in 4T1 and MDA-MB-231 TNBC cells, and ii) inhibiting cell growth in paclitaxel-resistant 4T1 cells (potentiating the paclitaxel antiproliferative effect). Moreover, 20 mg/kg LINS01022 reduced tumor size in 4T1 tumor-bearing mice, exhibiting a safe toxicological profile and potential for druggability estimated by ADME calculations. We conclude that the H3R is involved in the regulation of TNBC progression, offering promising therapeutic potential for the novel LINS01 series of H3R antagonists.

Deletion of PTP4A3 phosphatase in high grade serous ovarian cancer cells decreases tumorigenicity and produces marked changes in intracellular signaling pathways and cytokine release.

The oncogenic protein tyrosine phosphatase PTP4A3 is frequently overexpressed in human ovarian cancers and is associated with poor patient prognosis. PTP4A3 is thought to regulate multiple oncogenic signaling pathways, including STAT3, SRC, and ERK. The objective of this study was to generate ovarian cancer cells with genetically depleted PTP4A3; to assess their tumorigenicity; to examine their cellular phenotype; and to uncover changes in their intracellular signaling pathways and cytokine release profiles. Genetic deletion of PTP4A3 using CRISPR/Cas9 enabled the generation of individual clones derived from single cells isolated from the polyclonal knockout population. We observed a >90% depletion of PTP4A3 protein levels by Western blotting in the clonal cell lines compared to the sham transfected wildtype population. The wildtype and polyclonal knockout cell lines shared similar monolayer growth rates, while the isolated clonal populations 2B4, 3C9, and 3C12 exhibited significantly lower monolayer growth characteristics consistent with their lower PTP4A3 levels. The clonal PTP4A3 knockout cell lines also had substantially lower in vitro colony formation efficiencies compared to the wildtype cells and were less tumorigenic in vivo The clonal knockout cells were markedly less responsive to IL-6-stimulated migration in a scratch wound assay compared to the wildtype cells. Antibody microarray assays documented differences in cytokine release and intracellular phosphorylation patterns in the PTP4A3 deleted clones. Bioinformatic network analyses indicated alterations in cellular signaling nodes. These biochemical changes could ultimately form the foundation for pharmacodynamic endpoints useful for emerging anti-PTP4A3 therapeutics. Significance Statement Clones of high grade serous ovarian cancer cells were isolated in which the oncogenic phosphatase PTP4A3 was deleted using CRISPR/Cas9 methodologies. The PTP4A3 null cells exhibited loss of in vitro proliferation, colony formation, and migration, and reduced in vivo tumorigenesis. Marked differences in intracellular protein phosphorylation and cytokine release were seen. The newly developed PTP4A3 knockout cells should provide useful tools to probe the role of PTP4A3 phosphatase in ovarian cancer cell survival, tumorigenicity and cell signaling.

Colonic adenomatous polyp with florid presence of monoclonal lambda Russell bodies: Case report and etiopathogenic hypothesis.

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.

Characterization of AICAR transformylase/IMP cyclohydrolase (ATIC) bifunctional enzyme from Candidatus Liberibacer asiaticus.

The bifunctional enzyme, 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR) transformylase/inosine monophosphate (IMP) cyclohydrolase (ATIC) is involved in catalyzing penultimate and final steps of purine de novo biosynthetic pathway crucial for the survival of organisms. The present study reports the characterization of ATIC from Candidatus Liberibacer asiaticus (CLasATIC) along with the identification of potential inhibitor molecules and evaluation of cell proliferative activity. CLasATIC showed both the AICAR Transformylase (AICAR TFase) activity for substrates, 10-f-THF (Km, 146.6 µM and Vmax, 0.95 µmol/min/mg) and AICAR (Km, 34.81 µM and Vmax, 0.56 µmol/min/mg) and IMP cyclohydrolase (IMPCHase) activitiy (Km, 1.81 µM and Vmax, 2.87 µmol/min/mg). The optimum pH and temperature were also identified for the enzyme activity. In-silico study has been conducted to identify potential inhibitor molecules through virtual screening and MD simulations. Out of many compounds, HNBSA, diosbulbin A and lepidine D emerged as lead compounds, exhibiting higher binding energy and stability for CLasATIC than AICAR. ITC study reports higher binding affinities for HNBSA and diosbulbin A (Kd, 12.3 µM and 34.2 µM, respectively) compared to AICAR (Kd, 83.4 µM). Likewise, DSC studies showed enhanced thermal stability for CLasATIC in the presence of inhibitors. CD and Fluorescence studies revealed significant conformational changes in CLasATIC upon binding of the inhibitors. CLasATIC demonstrated potent cell proliferative, wound healing and ROS scavenging properties evaluated by cell-based bioassays using CHO cells. This study highlights CLasATIC as a promising drug target with potential inhibitors for managing CLas and its unique cell protective, wound-healing properties for future biotechnological applications.

Activation of CTU2 expression by LXR promotes the development of hepatocellular carcinoma.

Cytosolic thiouridylase 2 (CTU2) is an enzyme modifying transfer RNAs post-transcriptionally, which has been implicated in breast cancer and melanoma development. And we found CTU2 participated in hepatocellular carcinoma (HCC) progression here. HepG2 cells as well as xenograft nude mice model were employed to investigate the role of CTU2 in HCC development in vitro and in vivo respectively. Further, we defined CTU2 as a Liver X receptor (LXR) targeted gene, with a typical LXR element in the CTU2 promoter. CTU2 expression was activated by LXR agonist and depressed by LXR knockout. Interestingly, we also found CTU2 took part in lipogenesis by directly enhancing the synthesis of lipogenic proteins, which provided a novel mechanism for LXR regulating lipid synthesis. Meanwhile, lipogenesis was active during cell proliferation, particularly in tumor cells. Reduction of CTU2 expression was related to reduced tumor burden and synergized anti-tumor effect of LXR ligands by inducing tumor cell apoptosis and inhibiting cell proliferation. Taken together, our study identified CTU2 as an LXR target gene. Inhibition of CTU2 expression could enhance the anti-tumor effect of LXR ligand in HCC, identifying CTU2 as a promising target for HCC treatment and providing a novel strategy for the application of LXR agonists in anti-tumor effect.

Transient receptor potential vanilloid-1 (TRPV1) channels act as suppressors of the growth of glioma.

The aim of this study was to investigate the expression and function of the transient receptor potential vanilloid 1 (TRPV1) in glioma. We found that the expression of TRPV1 mRNA and protein were upregulated in glioma compared with normal brain by qPCR and western blot analysis. In order to investigate the function of TRPV1 in glioma, short hairpin RNA (shRNA) and the inhibitor of TRPV1 were used. In vitro, the activation of TRPV1 induced cell apoptosis with decreased migration capability and inhibited proliferation, which was abolished upon TRPV1 pharmacological inhibition and silencing. Mechanistically, TRPV1 modulated glioma proliferation through the protein kinase B (Akt) signaling pathway. More importantly, in immunodeficient (NOD-SCID) mouse xenograft models, tumor size was significantly increased when TRPV1 expression was disrupted by a shRNA knockdown approach in vivo. Altogether, our findings indicate that TRPV1 negatively controls glioma cell proliferation in an Akt-dependent manner, which suggests that targeting TRPV1 may be a potential therapeutic strategy for glioma.

Stasimon/Tmem41b is required for cell proliferation and adult mouse survival.

Stasimon/Tmem41b is a transmembrane protein with phospholipid scrambling activity that resides in the endoplasmic reticulum and has been implicated in autophagy, lipid metabolism, and viral replication. Stasimon/Tmem41b has also been linked to the function of sensory-motor circuits and the pathogenesis of spinal muscular atrophy. However, the early embryonic lethality of constitutive knockout in mice has hindered the analysis of spatial and temporal requirements of Stasimon/Tmem41b in vivo. To address this, we developed a novel mouse line harboring a conditional knockout allele of the Stasimon/Tmem41b gene in which exon 4 has been flanked by loxP sites (Stas/Tmem41bCKO). Cre-mediated recombination of Stas/Tmem41bCKO generates a functionally null allele (Stas/Tmem41bΔ4) resulting in loss of protein expression and embryonic lethality in the homozygous mouse mutant. Here, using a ubiquitously expressed, tamoxifen inducible Cre recombinase in the homozygous Stas/Tmem41bCKO mice, we demonstrate that postnatal depletion of Stasimon/Tmem41b rapidly arrests weight gain in adult mice and causes motor dysfunction and death approximately three weeks after tamoxifen treatment. Moreover, we show that depletion of Stasimon/Tmem41b severely affects cell proliferation in mouse embryonic fibroblasts. This study provides new insights into the essential requirement of Stasimon/Tmem41b for cellular and organismal fitness and expands the experimental toolkit to investigate its functions in the mammalian system.