Search

In vascular smooth muscle cells, Axl is a key receptor tyrosine kinase, because it is upregulated in injury, increases migration and neointima formation, and is activated by reactive oxygen species. Reaction of glutathione with cysteine residues (termed "glutathiolation") is an important posttranslational redox modification that may alter protein activity and protein-protein interactions. To investigate the mechanisms by which reactive oxygen species increase Axl-dependent vascular smooth muscle cell function we assayed for glutathiolated proteins that associated with Axl in a redox-dependent manner. We identified glutathiolated nonmuscle myosin heavy chain (MHC)-IIB as a novel Axl interacting protein. This interaction was specific in that other myosins did not interact with Axl. The endogenous ligand for Axl, Gas6, increased production of reactive oxygen species in vascular smooth muscle cells and also increased the association of Axl with MHC-IIB. Antioxidants ebselen and N-acetylcysteine decreased the association of Axl with MHC-IIB in response to both Gas6 and reactive oxygen species. Blocking the Axl-MHC-IIB interaction with the specific myosin II inhibitor blebbistatin decreased phosphorylation of Axl and activation of extracellular signal-regulated kinase 1/2 and Akt. Association of MHC-IIB with Axl was increased in balloon-injured rat carotid vessels. Finally, expression of MHC-IIB was upregulated in the neointima of the carotid artery after balloon injury similar to upregulation of Axl protein expression, as shown in our previous studies. These results demonstrate a novel interaction between Axl and MHC-IIB in response to reactive oxygen species. This interaction provides a direct link between Axl and molecular motors crucial for directed cell migration, which may mediate increased migration in vascular dysfunction. [ABSTRACT FROM AUTHOR]

Endothelial cells participate in the inflammatory and immune reactions. Endothelial cell activation is a recurrent phenomenon linked to the pathogenesis of diverse human diseases, such as acute and chronic inflammation and cardiovascular disorders. Pro-inflammatory cytokines (e.g., IL-1, TNF) are well-known activators of endothelial cells, since they strongly induce production of chemokines (e.g., IL-8, MCP-1) and cell adhesion molecules, resulting in an activation of inflammatory transcription factors such as NF-κB. We have established a cell-based reporter assay for the NF-κB-dependent gene activation in HUVEC. Using this assay system, we have identified a novel synthetic small molecule, APC0576, 5-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)-2-(4-(((S)-2,2-dimethylcyclopropanecarbonyl)amino)phenoxy)pyridine, as an inhibitor of IL-1-induced NF-κB-dependent gene activation without any adverse effects on the cell viability. APC0576 represses the IL-1-induced release of chemokines (e.g., IL-8, MCP-1) in HUVEC. This inhibitory effect occurred at the level of mRNA expression. Despite having a strong inhibitory effect on the NF-κB-dependent transcriptional activation, APC0576 does not inhibit the IL-1-induced DNA binding of NF-κB, degradation of I-κB-α, or phosphorylation of RelA (p65). Although its molecular mechanism of action is not yet clear, APC0576 is a promising therapeutic candidate for diverse diseases involved in the pathogenic endothelial activation. [Copyright &y& Elsevier]

Transport properties of C60 field-effect transistors (FETs) have been investigated in the temperature range between 160 and 300 K. Activation energy was estimated from temperature dependence of resistance at the linear region and of current at the saturation region for various channel lengths. Variation of activation energy values is attributed to carrier injection barrier at contact between source electrode and C60 channel, and barriers to carrier hopping between trap states in the channel of C60. [ABSTRACT FROM AUTHOR]

Introduction: Neural crest cells (NCCs) are cell populations that originate during the formation of neural crest in developmental stages. They are characterized by their multipotency, self-renewal and migration potential. Given their ability to differentiate into various types of cells such as neurons and Schwann cells, NCCs hold promise for cell therapy applications. The conventional method for obtaining NCCs involves inducing them from stem cells like induced pluripotent stem cells (iPSCs), followed by a long-term passage or purification using fluorescence-activated cell sorting (FACS). Although FACS allows high purity induced neural crest cells (iNCCs) to be obtained quickly, it is complex and costly. Therefore, there is a need for a simpler, cost-effective and less time-consuming method for cell therapy application., Methods: To select differentiated iNCCs from heterogeneous cell populations quickly without using FACS, we adopted the use of scaffold material full-length laminin 211 (LN211), a recombinant, xeno-free protein suitable for cell therapy. After fist passage on LN211, iNCCs characterization was performed using polymerase chain reaction and flow cytometry. Additionally, proliferation and multipotency to various cells were evaluated., Result: The iNCCs obtained using our new method expressed cranial NCC- related genes and exhibited stable proliferation ability for at least 57 days, while maintaining high expression level of the NCCs marker CD271. They demonstrated differentiation ability into several cell types: neurons, astrocytes, melanocytes, smooth muscle cells, osteoblasts, adipocytes and chondrocytes. Furthermore, they could be induced to differentiate into induced mesenchymal stem cells (iMSCs) which retain the essential functions of somatic MSCs., Conclusion: In this study, we have developed novel method for obtaining high purity iNCCs differentiated from iPSCs in a short time using LN211 under xeno-free condition. Compared with traditional methods, like FACS or long-term passage, this approach enables the acquisition of a large amount of cells at a lower cost and labor, and it is expected to contribute to stable supply of large scale iNCCs for future cell therapy applications., Competing Interests: We hereby declare that there are no conflicts of interest to report. We confirm that there have been no financial or personal relationships with other people or organizations that could inappropriately influence or bias our work., (© 2024 The Author(s).)

Despite recent advances in surgical techniques and perioperative management, the prognosis of pancreatic cancer (PCa) remains extremely poor. To provide optimal treatment for each patient with Pca, superior biomarkers are urgently needed in all phases of management from early detection to staging, treatment monitoring, and prognosis. In the blood of patients with cancer, circulating tumor cells (CTCs) and cell-free nucleic acids (cfNAs), such as DNA, mRNA, and noncoding RNA have been recognized. In the recent years, their presence in the blood has encouraged researchers to investigate their potential use as novel blood biomarkers, and numerous studies have demonstrated their potential clinical utility as a biomarker for certain types of cancer. This concept, called "liquid biopsy" has been focused on as a less invasive, alternative approach to cancer tissue biopsy for obtaining genetic and epigenetic aberrations that contribute to oncogenesis and cancer progression. In this article, we review the available literature on CTCs and cfNAs in patients with cancer, particularly focusing on PCa, and discuss future perspectives in this field.

Aim: To assess the clinical features of hepatoduodenal lymph node (HDLN) metastasis and to clarify the optimal indication of HDLN dissection., Methods: We investigated a total of 276 patients who underwent gastrectomy with extended lymphadenectomy, including HDLN dissection, for gastric cancer between 1999 and 2012. Of these, 26 patients (9.4%) had HDLN metastasis. First, we investigated the clinicopathological characteristics, their perioperative clinical outcomes, such as postoperative complications, and prognostic outcomes between patients with and without HDLN metastasis. Second, we detected the prognostic factors, particularly in patients with HDLN metastasis. Third, we assessed the therapeutic value of HDLN dissection to determine its optimal indication., Results: The five-year overall survival rate of the patients with HDLN metastasis was 29%. Univariate and multivariate logistic regression analyses revealed that the tumour location (the middle or lower stomach [P = 0.005, OR = 5.88 (95%CI: 1.61-38.1)] and pT category [T3 or T4, P = 0.017, OR = 4.45 (95%CI: 1.28-21.3)] were independent risk factors for HDLN metastasis. Cox proportional hazard analysis identified pN3 as an independent poor prognostic factor in the patients with HDLN metastasis [P = 0.021, HR = 5.17 (95%CI: 1.8-292)]. For patients who underwent radical HDLN dissection, HDLN metastasis was a prognostic indicator in pN3 gastric cancer (P < 0.0001), but not pN1-2 (P = 0.602). Furthermore, the index of therapeutic value of HDLN dissection for gastric cancer in the middle or lower stomach and the upper stomach was 3.4 and 0.0, respectively., Conclusion: We suggest that HDLN dissection should be indicated for pN1 or pN2 gastric cancers located at the middle or lower stomach.

Aim: To evaluate discrepancies between biopsy and resected specimens using the Japanese Classification of Gastric Carcinoma (JCGC) and tumor-node-metastasis (TNM) classification., Methods: A total of 376 consecutive paired samples from biopsy and resected gastric specimens, which were derived from curative gastrectomy for gastric cancer between 2008 and 2011, were retrospectively analyzed., Results: (1) Discrepancies in the histologic type were observed between biopsy and resected specimens; 11.7% (44/376) in the JCGC and 18.1% (68/376) in TNM. In specimens diagnosed as the differentiated type from biopsy specimens, 14.4% (28/195) in the JCGC and 41.1% (67/163) in TNM were finally diagnosed as the undifferentiated type from resected specimens; and (2) the incidence of mixed-type gastric cancer was significantly higher in specimens with discrepancies than in those without in both the JCGC and TNM (both P < 0.0001); 93.2% (41/44) of specimens with discrepancies in the JCGC and 97.1% (66/68) of specimens with discrepancies in TNM were mixed-type gastric cancers., Conclusion: Mixed-type gastric cancer was associated with a high incidence of histologic discrepancies between biopsy and resected specimens in both the JCGC and TNM definitions. Care should be taken in deciding treatments based on diagnosis of the histologic type for mixed-type gastric cancer from biopsy specimens.

Aim: To evaluate the clinicopathological features of mixed-type gastric cancer and their influence on prognosis of mixed-type stage I gastric cancer., Methods: We analyzed 446 patients who underwent curative gastrectomy for stage I gastric cancer between 1999 and 2009. The patients were divided into two groups: those with differentiated or undifferentiated cancer (non-mixed-type, n = 333) and those with a mixture of differentiated and undifferentiated cancers (mixed-type, n = 113)., Results: The overall prevalence of mixed-type gastric cancer was 25.3% (113/446). Compared with patients with non-mixed-type gastric cancer, those with mixed-type gastric cancer tended to be older at onset (P = 0.1252) and have a higher incidence of lymph node metastasis (P = 0.1476). They also had significantly larger tumors (P < 0.0001), more aggressive lymphatic invasion (P = 0.0011), and deeper tumor invasion (P < 0.0001). In addition, they exhibited significantly worse overall survival rates than did patients with non-mixed-type gastric cancer (P = 0.0026). Furthermore, mixed-type gastric cancer was independently associated with a worse outcome in multivariate analysis [P = 0.0300, hazard ratio = 11.4 (1.265-102.7)]., Conclusion: Histological mixed-type of gastric cancer contributes to malignant outcomes and highlight its usefulness as a prognostic indicator in stage I gastric cancer.

Aim: To allow the identification of high-risk postoperative pancreatic fistula (POPF) patients with special reference to the International Study Group on Pancreatic Fistula (ISGPF) classification., Methods: Between 1997 and 2010, 1341 consecutive patients underwent gastrectomy for gastric cancer at the Department of Digestive Surgery, Kyoto Prefectural University of Medicine, Japan. Based on the preoperative diagnosis, total or distal gastrectomy and sufficient lymphadenectomy was performed, mainly according to the Japanese guidelines for the treatment of gastric cancer. Of these, 35 patients (2.6%) were diagnosed with Grade B or C POPF according to the ISGPF classification and were treated intensively. The hospital records of these patients were reviewed retrospectively., Results: Of 35 patients with severe POPF, 17 (49%) and 18 (51%) patients were classified as Grade B and C POPF, respectively. From several clinical factors, the severity of POPF according to the ISGPF classification was significantly correlated with the duration of intensive POPF treatments (P = 0.035). Regarding the clinical factors to distinguish extremely severe POPF, older patients (P = 0.035, 65 years ≤ vs < 65 years old) and those with lower lymphocyte counts at the diagnosis of POPF (P = 0.007, < 1400/mm(3) vs 1400/mm(3) ≤) were significantly correlated with Grade C POPF, and a low lymphocyte count was an independent risk factor by multivariate analysis [P = 0.045, OR = 10.45 (95%CI: 1.050-104.1)]., Conclusion: Caution and intensive care are required for older POPF patients and those with lower lymphocyte counts at the diagnosis of POPF.