Tumor-infiltrating immune cells, such as lymphocytes and macrophages, have been associated with tumor aggressiveness, prognosis and treatment response in colorectal cancer (CRC). An immune scoring ...system, Immunoscore (IS), based on tumor-infiltrating T cells in stage I-III CRC, was used to predict prognosis. An alternative immune scoring signature of immune activation (SIA) reflects the balance between anti- and pro-tumoral immune components. The present study aimed to evaluate the prognostic value of modifed IS (mIS) and modifed SIA (mSIA) in locally advanced pathological T4 (pT4) CRC, including stage IV CRC. Immunohistochemical staining for immune cell markers, such as CD3 (pan-T cell marker), CD8 (anti-tumoral cytotoxic T cell marker) and CD163 (tumor-supportive macrophage marker), in specimens from patients with radically resected pT4 CRC at stages II-IV was performed. mIS levels in the T4 CRC cohort were not associated with prognosis. However, low mSIA levels were associated with low survival. Furthermore, low mSIA was an independent predictor of recurrence in patients with radically resected pT4 CRC. In patients with CRC who did not receive postoperative adjuvant chemotherapy, low mSIA was a major poor prognostic factor; however, this was not observed in patients receiving adjuvant chemotherapy. Evaluation of the tumor-infiltrating immune cell population could serve as a valuable marker of recurrence and poor prognosis in patients with locally advanced CRC. mSIA assessment after radical CRC resection may be promising for identifying high-risk patients with pT4 CRC who require aggressive adjuvant chemotherapy. Key words: immune cell infiltration, tumor immunity, prognostic marker, colon cancer, locally advanced colon cancer, Immunoscore, signature of immune activation
Previous findings regarding the effects of living in urban environments on residents' subjective well-being have been inconsistent. The present study developed a scale to measure the multifaceted ...nature of urban living environments and investigated the aspects of urban environments that enhance or reduce residents' life satisfaction. We conducted two online surveys in which adults living in urban or rural areas in Japan (1,000 participants for each survey) completed the Multifaceted Urban Living Environment Scale and the Life Satisfaction Scale. Results indicated that urban living environments are characterized by quality of facilities, life convenience, life unpleasantness, and easy accessibility to public transportation. Of importance, each of these aspects affected residents' life satisfaction differently. Specifically, the quality of facilities was positively associated with life satisfaction, whereas life convenience was negatively associated. However, life unpleasantness and easy accessibility to public transportation had no effect on life satisfaction. These results suggest that it is important to measure the multifaceted nature of urban living environments to gain a deeper understanding of the effects of urbanization on residents' subjective well-being.
In π$\upi$‐conjugated polymers, a highly ordered backbone structure and solubility are always in a trade‐off relationship that must be overcome to realize highly efficient and solution‐processable ...organic photovoltaics (OPVs). Here, it is shown that a π$\upi$‐conjugated polymer based on a novel thiazole‐fused ring, thieno2′,3′:5,6benzo1,2‐d:4,3‐d′bisthiazole (TBTz) achieves both high backbone order and high solubility due to the structural feature of TBTz such as the noncovalent interlocking of the thiazole moiety, the rigid and bent‐shaped structure, and the fused alkylthiophene ring. Furthermore, based on the electron‐deficient nature of these thiazole‐fused rings, the polymer exhibits deep HOMO energy levels, which lead to high open‐circuit voltages (VOCs) in OPV cells, even without halogen substituents that are commonly introduced into high‐performance polymers. As a result, when the polymer is combined with a typical nonfullerene acceptor Y6, power conversion efficiencies of reaching 16% and VOCs of more than 0.84 V are observed, both of which are among the top values reported so far for “halogen‐free” polymers. This study will serve as an important reference for designing π$\upi$‐conjugated polymers to achieve highly efficient and solution‐processable OPVs.
A halogen‐free π$\upi$‐conjugated polymer based on a novel thiazole‐based fused ring, thieno2′,3′:5,6benzo1,2‐d:4,3‐d′bisthiazole (TBTz), is designed and synthesized to have high backbone order and high solubility. The polymer shows a high efficiency of approximately 16% in nonfullerene organic solar cells, which is among the highest values for halogen‐free π$\upi$‐conjugated polymers.
Fibroblast growth factor receptor 2 (FGFR2) genetic alterations lead to tumor cell proliferation in various types of cancer. We hypothesized that FGFR2 amplification is associated with FGFR2 ...expression, resulting in tumor growth and poorer outcome in esophagogastric junction (EGJ) adenocarcinoma.
A total of 176 consecutive chemo-naive patients with EGJ adenocarcinoma were enrolled from two academic institutions. FGFR2 amplification was examined by real-time PCR (N = 140) and FGFR2 expression with immunohistochemical staining (N = 176), and compared against clinicopathological factors and patient outcomes. The effects of FGFR2 inhibition or overexpression on cell proliferation, cell cycle, and apoptosis assays were investigated in EGJ adenocarcinoma cell lines. Downstream FGFR2, AKT and ERK were also examined.
Based on the correlation between FGFR2 levels and FGFR2 overexpression in vitro, FGFR2 amplification was defined as copy number > 3.0. In clinical samples, FGFR2 amplification and FGFR2 IHC expression were 15% and 61%, respectively. Although these two statuses were significantly correlated (P < 0.05), only FGFR2 IHC expression was significantly associated with tumor depth (multivariate P < 0.001) and overall survival of patients (univariate P = 0.007). Supporting these findings, FGFR2 overexpression was associated with tumor cell proliferation, cell cycle progression, and anti-apoptosis. Selective inhibition of FGFR2 sufficiently suppressed tumor cell proliferation through de-phosphorylation of AKT and ERK.
FGFR2 amplification was significantly associated with FGFR2 expression. FGFR2 expression (but not FGFR2 amplification) was associated with tumor growth and patient outcomes. Our findings support FGFR2 as a novel therapeutic target for EGJ adenocarcinoma.
To assess the relevance and availability of subtotal nephrectomized common marmoset monkeys as a chronic renal failure (CRF) model, we observed for 26 weeks the pathophysiological condition of female ...marmosets subjected to five-sixth surgical nephrectomy (5/6Nx) by a two-step surgical method. The 5/6Nx marmosets showed a significant increase in serum levels of urea nitrogen, creatinine and cystatin-C immediately after 5/6Nx surgery. These renal disorder parameters subsequently tended to decrease with the passage of time but remained higher than the control levels by the end of the study. Hyperplastic parathyroid glands, a high turnover state of osteodystrophy in the femoral bone with higher serum ALP activity and anemia with hypocellularity of bone marrow were evident. The 5/6Nx marmosets showed a stable CRF condition for a long time and some characteristic disorders similar to those observed in CRF patients. These diagnostic aspects might be a species-specific anatomical and physiological signature, reflecting the nutritional condition. The CRF model using 5/6Nx marmosets might become a useful method of evaluating the unique mechanism of CRF development.
The incidence rate of esophagogastric junction (EGJ) adenocarcinoma has been rapidly increasing worldwide. Carcinoembryonic antigen (CEA) and carbohydrate antigen 19‐9 (CA19‐9) are major serum tumor ...markers in gastrointestinal cancers. However, the role of these markers in EGJ adenocarcinoma has not been thoroughly investigated. A total of 211 patients with EGJ adenocarcinoma who underwent surgery or endoscopic submucosal dissection at two academic institutions, Kumamoto University Hospital or Kyushu University Hospital between January 1996 and March 2014, were eligible for this study. Serum CEA and CA19‐9 were examined within 1 month before resection. The cut‐off values for CEA and CA19‐9 were set at 5.0 ng/mL and 37 U/mL, respectively. The clinicopathological features and prognostic roles of the markers were examined using univariate and multivariate analyses. The positive ratios for preoperative CEA (>5.0 ng/mL) and CA19‐9 (>37 U/mL) were 20.3% and 12.9%, respectively. The positive ratio of CEA and CA19‐9 was significantly higher in patients with tumors invading muscular or deeper layers (P = 0.002 and <0.001, respectively). Cox proportional hazards model revealed that CA19‐9 positivity, but not CEA positivity, was an independent prognostic factor in patients with EGJ adenocarcinoma for cancer‐specific survival (multivariate hazard ratio HR = 3.89, 95% confidence interval CI 1.41–10.33; P = 0.010) and overall survival (multivariate HR = 2.43, 95% CI 1.03–5.35; P = 0.043). Preoperative serum CA19‐9 is a useful prognostic marker in patients with EGJ adenocarcinoma.
Preoperative serum carbohydrate antigen 19‐9, which was significantly correlated with depth of tumor invasion, is a useful prognostic marker in patients with esophagogastric junction adenocarcinoma.
This study investigated the determinants of exchange anxiety in close relationships—generalized worries that one’s partner will replace him/her with a more suitable person. We hypothesized that ...exchange anxiety would increase when individuals compare themselves with others who are more competent (experiencing upward social comparisons), especially in environments where they cannot easily find alternative relationships (environments with low relational mobility). By experimentally manipulating the type of social comparison, the results from Study 1 revealed that undergraduates (n＝299) living in environments with low relational mobility felt stronger exchange anxiety when they experienced upward social comparison than downward social comparison. In Study 2, an online survey was conducted with a sample of adults living in either urban or rural areas (n＝1000). The results showed that the frequency of upward social comparison was positively associated with exchange anxiety and that this tendency was moderated by the combined effect of relational mobility and trait self-esteem. These results suggest that the characteristics of one’s interpersonal environments affect the impact of the perceived risk of being replaced on exchange anxiety in one’s close relationships.
Water has significant influence on human body due to physiological carrier media. In addition, rheological behavior of interstitial fluid in epidermal and dermal tissue, including blood ...micro-circulation, can vary skin mechanics in micro scale, i.e. vis. Therefore, an in vivo measurement of moisture content and capillary blood flow velocity is necessary to clarify skin mechanics. In this paper, we propose 2C-OCM (2-Color Optical Coherence Moisturegraphy), which was composed of two-band light sources having different optical absorption properties of water respectively. These are capable of tomographically in vivo diagnosing the moisture content. Furthermore, OCDV (Optical Coherence Doppler Velocigraphy) algorithm can visualize the tomographic flow velocity of red blood cell in capillaries of human epidermal skin. In this experiment, 2C-OCM & OCDV were in vivo applied to human finger skin. Consequently, it was concluded that 2C-OCM & OCDV can provide micro tomography of moisture content and capillary blood velocity inside skin tissue.
Clenbuterol (CB), a selective β2‐adrenergic receptor (AR) agonist, induces muscle hypertrophy and counteracts muscle atrophy. However, it is paradoxically less effective in slow‐twitch muscle than in ...fast‐twitch muscle, though slow‐twitch muscle has a greater density of β‐AR. We recently demonstrated that Epac1 (exchange protein activated by cyclic AMP cAMP1) plays a pivotal role in β2‐AR‐mediated masseter muscle hypertrophy through activation of the Akt and calmodulin kinase II (CaMKII)/histone deacetylase 4 (HDAC4) signaling pathways. Here, we investigated the role of Epac1 in the differential hypertrophic effect of CB using tibialis anterior muscle (TA; typical fast‐twitch muscle) and soleus muscle (SOL; typical slow‐twitch muscle) of wild‐type (WT) and Epac1‐null mice (Epac1KO). The TA mass to tibial length (TL) ratio was similar in WT and Epac1KO at baseline and was significantly increased after CB infusion in WT, but not in Epac1KO. The SOL mass to TL ratio was also similar in WT and Epac1KO at baseline, but CB‐induced hypertrophy was suppressed in both mice. In order to understand the mechanism involved, we measured the protein expression levels of β‐AR signaling‐related molecules, and found that phosphodiesterase 4 (PDE4) expression was 12‐fold greater in SOL than in TA. These results are consistent with the idea that increased PDE4‐mediated cAMP hydrolysis occurs in SOL compared to TA, resulting in a reduced cAMP concentration that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 hypertrophic signaling pathways in SOL of WT. This scenario can account for the differential effects of CB on fast‐ and slow‐twitch muscles.
Chronic infusion of CB, a selective β2‐adrenergic receptor (β2‐AR) agonist, induced hypertrophy of tibialis anterior muscle (TA; typical fast‐twitch muscle) through activation of Akt/mTOR and CaMKII/HDAC4 signaling, in wild‐type (WT), but not in Epac1 (exchange protein directly activated by cAMP 1)‐null mice (Epac1KO).
In contrast, chronic CB infusion did not induce hypertrophy of soleus muscle (SOL; typical slow‐twitch muscle) in either WT or Epac1KO, and did not activate Akt/mTOR and CaMKII/HDAC4 signaling pathways in SOL of WT.
Expression of phosphodiesterase 4 (PDE4), whose activity negatively regulates cAMP level in skeletal muscle cells, was about 12‐fold greater in SOL than in TA.
Our results indicate that compared to TA, increased PDE4‐mediated cAMP hydrolysis occurs in SOL, resulting in a level of cAMP that is insufficient to activate Epac1 and its downstream Akt and CaMKII/HDAC4 signaling pathways, which are the major signaling pathways in CB‐induced skeletal muscle hypertrophy.
A 15-month-old male beagle dog used in a toxicity study had a primary renal mesenchymal tumor. Macroscopically, the tumor was a gray-white mass which was found in the right kidney, and extended from ...the capsule to a position slightly compressing the medulla. Microscopically, most of the tumor cells showed a myxoid pattern, in which the matrix was positive for alcian blue staining. In the other parts of the tumor, a fascicular and wavy pattern was observed, and the matrix was full of collagen fibrils. Immunohistochemically, tumor cells were positive for vimentin and fibronectin, and negative for cytokeratin, desmin, á-smooth muscle actin, Von Willebrand factor, cyclooxigenase-2 and myelin basic protein. As a result, we diagnosed this case to be a renal mesenchymal tumor. Based on the microscopic findings, interstitial characteristics and immunohistochemical features, the present case was classified as a congenital mesoblastic tumor.
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