Macrophages are an essential component of antitumor activity; however, the role of tumor‐associated macrophages (TAMs) in colorectal cancer (CRC) remains controversial. Here, we elucidated the role ...of TAMs in CRC progression, especially at the early stage. We assessed the TAM number, phenotype, and distribution in 53 patients with colorectal neoplasia, including intramucosal neoplasia, submucosal invasive colorectal cancer (SM‐CRC), and advanced cancer, using double immunofluorescence for CD68 and CD163. Next, we focused on the invasive front in SM‐CRC and association between TAMs and clinicopathological features including lymph node metastasis, which were evaluated in 87 SM‐CRC clinical specimens. The number of M2 macrophages increased with tumor progression and dynamic changes were observed with respect to the number and phenotype of TAMs at the invasive front, especially at the stage of submucosal invasion. A high M2 macrophage count at the invasive front was correlated with lymphovascular invasion, low histological differentiation, and lymph node metastasis; a low M1 macrophage count at the invasive front was correlated with lymph node metastasis. Furthermore, receiver operating characteristic curve analysis revealed that the M2/M1 ratio was a better predictor of the risk of lymph node metastasis than the pan‐, M1, or M2 macrophage counts at the invasive front. These results suggested that TAMs at the invasive front might play a role in CRC progression, especially at the early stages. Therefore, evaluating the TAM phenotype, number, and distribution may be a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential CRC therapeutic target.
We identified dynamic changes in the number and phenotype of tumor‐associated macrophages (TAMs) at the invasive front in colorectal cancer (CRC), especially at the stage of submucosal invasion. Furthermore, TAMs at the invasive front may play a role in CRC progression, especially in early stage CRC, ie, M1 macrophages at the invasive front may inhibit CRC progression, while M2 macrophages may promote CRC progression via EMT. Therefore, a marker comprising the phenotype, number, and distribution of TAMs may serve as a potential predictor of metastasis, including lymph node metastasis, and TAMs may be a potential therapeutic target in CRC.
Prolyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal ...anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected to have other effects in addition to erythropoiesis, such as protection against metabolic disorders. However, whether such beneficial effects would extend to metabolic disorder-related kidney disease is largely unknown.
We administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR)
mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and
experiments using murine mesangial cells.
Compared with BTBR
mice that received only vehicle, BTBR
mice treated with enarodustat displayed lower body weight, reduced blood glucose levels with improved insulin sensitivity, lower total cholesterol levels, higher adiponectin levels, and less adipose tissue, as well as a tendency for lower macrophage infiltration. Enarodustat-treated mice also exhibited reduced albuminuria and amelioration of glomerular epithelial and endothelial damage. Transcriptome analysis of isolated glomeruli revealed reduced expression of C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) in enarodustat-treated mice compared with the vehicle-only group, accompanied by reduced glomerular macrophage infiltration.
experiments demonstrated that both local HIF-1 activation and restoration of adiponectin by enarodustat contributed to CCL2/MCP-1 reduction in mesangial cells.
These results indicate that the PHD inhibitor enarodustat has potential renoprotective effects in addition to its potential to protect against metabolic disorders.
Protruding lesions of the small bowel vary in wireless capsule endoscopy (WCE) images, and their automatic detection may be difficult. We aimed to develop and test a deep learning–based system to ...automatically detect protruding lesions of various types in WCE images.
We trained a deep convolutional neural network (CNN), using 30,584 WCE images of protruding lesions from 292 patients. We evaluated CNN performance by calculating the area under the receiver operating characteristic curve (AUC), sensitivity, and specificity, using an independent set of 17,507 test images from 93 patients, including 7507 images of protruding lesions from 73 patients.
The developed CNN analyzed 17,507 images in 530.462 seconds. The AUC for detection of protruding lesions was 0.911 (95% confidence interval Cl, 0.9069–0.9155). The sensitivity and specificity of the CNN were 90.7% (95% CI, 90.0%–91.4%) and 79.8% (95% CI, 79.0%–80.6%), respectively, at the optimal cut-off value of 0.317 for probability score. In a subgroup analysis of the category of protruding lesions, the sensitivities were 86.5%, 92.0%, 95.8%, 77.0%, and 94.4% for the detection of polyps, nodules, epithelial tumors, submucosal tumors, and venous structures, respectively. In individual patient analyses (n = 73), the detection rate of protruding lesions was 98.6%.
We developed and tested a new computer-aided system based on a CNN to automatically detect various protruding lesions in WCE images. Patient-level analyses with larger cohorts and efforts to achieve better diagnostic performance are necessary in further studies.
Abstract
α-Alkylation of a β-keto ester is a frequently used reaction for carbon–carbon bond formation. However, extension to a stereoselective reaction remains a significant challenge, because the ...product easily racemizes under acidic or basic conditions. Here, we report a hybrid system consisting of Pd and Ru complexes that catalyzes the asymmetric dehydrative condensation between cinnamyl-type allylic alcohols and β-keto esters. α-Non-substituted β-keto ester can be allylated to afford an α-mono-substituted product with high regio-, diastereo-, and enantioselectivity. No epimerization occurs owing to the nearly neutral conditions, which is achieved by a rapid proton transfer from Pd-enolate formation to Ru π-allyl complex formation. Four diastereomers can be synthesized on demand by changing the stereochemistry of the Pd or Ru complex. Eight stereoisomers with three adjacent stereogenic centers can be synthesized by employing diastereoselective reduction of the ketone in the products. The formal synthesis of (+)-pancratistatin demonstrates the utility of the reaction.
The Colonoscopy Screening and Surveillance Guidelines were developed by the Japan Gastroenterological Endoscopy Society as basic guidelines based on the scientific methods. The importance of ...endoscopic screening and surveillance for both detection and post‐treatment follow‐up of colorectal cancer has been recognized as essential to reduce disease mortality. There is limited high‐level evidence in this field; therefore, we had to focus on the consensus of experts. These clinical practice guidelines consist of 20 clinical questions and eight background knowledge topics that have been determined as the current guiding principles.
Background & Aims Almost all colorectal polyps ≤5 mm are benign, yet current practice requires costly pathologic analysis. We aimed to develop and evaluate the validity of a simple narrow-band ...imaging (NBI)-based classification system for differentiating hyperplastic from adenomatous polyps. Methods The study was conducted in 4 phases: (1) evaluation of accuracy and reliability of histologic prediction by NBI-experienced colonoscopists; (2) development of a classification based on color, vessels, and surface pattern criteria, using a modified Delphi method; (3) validation of the component criteria by people not experienced in endoscopy or NBI analysis (25 medical students, 19 gastroenterology fellows) using 118 high-definition colorectal polyp images of known histology; and (4) validation of the classification system by NBI-trained gastroenterology fellows, using still images. We performed a pilot evaluation during real-time colonoscopy. Results We developed a classification system for the endoscopic diagnosis of colorectal polyp histology and established its predictive validity. When all 3 criteria were used, the specificity ranged from 94.9% to 100% and the combined sensitivity ranged from 8.5% to 61.0%. The specificities of the individual criteria were lower although the sensitivities were higher. During real-time colonoscopy, endoscopists made diagnoses with high confidence for 75% of consecutive small colorectal polyps, with 89% accuracy, 98% sensitivity, and 95% negative predictive values. Conclusions We developed and established the validity of an NBI classification system that can be used to diagnose colorectal polyps. In preliminary real-time evaluation, the system allowed endoscopic diagnoses of colorectal polyp histology.
Dipeptidyl peptidase (DPP)-4 is an enzyme that cleaves and inactivates incretin hormones capable of stimulating insulin secretion from pancreatic β-cells. DPP-4 inhibitors are now widely used for the ...treatment of type 2 diabetes. Experimental studies have suggested a renoprotective role of DPP-4 inhibitors in various models of diabetic kidney disease, which may be independent of lowering blood glucose levels. In the present study, we examined the effect of DPP-4 inhibitors in the rat Thy-1 glomerulonephritis model, a nondiabetic glomerular injury model. Rats were injected with OX-7 (1.2 mg/kg iv) and treated with the DPP-4 inhibitor alogliptin (20 mg·kg(-1)·day(-1)) or vehicle for 7 days orally by gavage. Alogliptin significantly reduced the number of CD68-positive inflammatory macrophages in the kidney, which was associated with a nonsignificant tendency to ameliorate glomerular injury and reduce proteinuria. Another DPP-4 inhibitor, anagliptin (300 mg·kg(-1)·day(-1) mixed with food) and a glucagon-like peptide-1 receptor agonist, exendin-4 (10 mg/kg sc), similarly reduced CD68-positive macrophage infiltration to the kidney. Furthermore, ex vivo transmigration assays using peritoneal macrophages revealed that exendin-4, but not alogliptin, dose dependently reduced monocyte chemotactic protein-1-stimulated macrophage infiltration. These data suggest that DPP-4 inhibitors reduced macrophage infiltration directly via glucagon-like peptide-1-dependent signaling in the rat Thy-1 nephritis model and indicate that the control of inflammation by DPP-4 inhibitors is useful for the treatment of nondiabetic kidney disease models.
Recently, mesenchymal stem cells (MSCs) were reported to migrate to tumor stroma as well as injured tissue. We examined the role of human MSCs in tumor stroma using an orthotopic nude mice model of ...KM12SM colon cancer. In in vivo experiments, systemically injected MSCs migrated to the stroma of orthotopic colon tumors and metastatic liver tumors. Orthotopic transplantation of KM12SM cells mixed with MSCs resulted in greater tumor weight than did transplantation of KM12SM cells alone. The survival rate was significantly lower in the mixed‐cell group, and liver metastasis was seen only in this group. Moreover, tumors resulting from transplantation of mixed cells had a significantly higher proliferating cell nuclear antigen labeling index, significantly greater microvessel area and significantly lower apoptotic index. Splenic injection of KM12SM cells mixed with MSCs, in comparison to splenic injection of KM12SM cells alone, resulted in a significantly greater number of liver metastases. MSCs incorporated into the stroma of primary and metastatic tumors expressed α‐smooth muscle actin and platelet‐derived growth factor receptor‐β as carcinoma‐associated fibroblast (CAF) markers. In in vitro experiments, KM12SM cells recruited MSCs, and MSCs stimulated migration and invasion of tumor cells through the release of soluble factors. Collectively, MSCs migrate and differentiate into CAFs in tumor stroma, and they promote growth and metastasis of colon cancer by enhancing angiogenesis, migration and invasion and by inhibiting apoptosis of tumor cells.
•Neonatal social isolation in mice increased PSD-95-negative immature spines of the layer 2/3 pyramidal neuron in the somatosensory cortex (SSC).•Neonatal social isolation in mice didn’t alter spine ...dynamics of the layer 2/3 pyramidal neurons in the SSC.•Socially isolated mice showed modest change in dendritic morphology and spine structure of the layer 2/3 pyramidal neurons in the SSC.
Social isolation during the juvenile period is postulated to leave specific sequelae, such as attention deficits and emotion recognition. Miswiring of the cortical neuronal circuit during postnatal development may underlie such behavioral impairments, but the details of the circuit-level impairment associated with social isolation have not yet been clarified. In this study, we evaluated the possibility that environmental factors may induce alternation in spine characteristics and dynamics. We isolated mice from the mother and siblings from postnatal day 7 to 11 for 6 h per day. Both dynamics and structural properties of spines in the layer 2/3 pyramidal neurons of the somatosensory cortex were measured at postnatal 3 weeks by in vivo two-photon microscopy. We found decrease in the ratio of PSD-95-positive dendritic spines in the mice after social isolation. These mice did not show alteration in spine dynamics. Those results suggest that the neonatal social isolation results in less mature spines, with normal rate of their turnover, which is distinct from spine phenotype seen in multiple models of autism spectrum disorders.
PDF
