CXCL12/CXCR4 activation by cancer‐associated fibroblasts promotes integrin β1 clustering and invasiveness in gastric cancer

Cancer‐associated fibroblasts (CAFs) are reportedly involved in invasion and metastasis in several types of cancer, including gastric cancer (GC), through the stimulation of CXCL12/CXCR4 signaling. However, the mechanisms underlying these tumor‐promoting effects are not well understood, which limits the potential to develop therapeutic targets against CAF‐mediated CXCL12/CXCR4 signaling. CXCL12 expression was analyzed in resected GC tissues from 110 patients by immunohistochemistry (IHC). We established primary cultures of normal fibroblasts (NFs) and CAFs from the GC tissues and examined the functional differences between these primary fibroblasts using co‐culture assays with GC cell lines. We evaluated the efficacy of a CXCR4 antagonist (AMD3100) and a FAK inhibitor (PF‐573,228) on the invasive ability of GC cells. High CXCL12 expression levels were significantly associated with larger tumor size, increased tumor depth, lymphatic invasion and poor prognosis in GC. CXCL12/CXCR4 activation by CAFs mediated integrin β1 clustering at the cell surface and promoted the invasive ability of GC cells. Notably, AMD3100 was more efficient than PF‐573,228 at inhibiting GC cell invasion through the suppression of integrin β1/FAK signaling. These results suggest that CXCL12 derived from CAFs promotes GC cell invasion by enhancing the clustering of integrin β1 in GC cells, resulting in GC progression. Taken together, the inhibition of CXCL12/CXCR4 signaling in GC cells may be a promising therapeutic strategy against GC cell invasion.     

Anti‐human SIRPα antibody is a new tool for cancer immunotherapy

Interaction of signal regulatory protein α (SIRPα) expressed on the surface of macrophages with its ligand CD47 expressed on target cells negatively regulates phagocytosis of the latter cells by the former. We recently showed that blocking Abs to mouse SIRPα enhanced both the Ab‐dependent cellular phagocytosis (ADCP) activity of mouse macrophages for Burkitt's lymphoma Raji cells opsonized with an Ab to CD20 (rituximab) in vitro as well as the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in nonobese diabetic (NOD)/SCID mice. However, the effects of blocking Abs to human SIRPα in preclinical cancer models have remained unclear given that such Abs have failed to interact with endogenous SIRPα expressed on macrophages of immunodeficient mice. With the use of Rag2^?/?γ_c^?/? mice harboring a transgene for human SIRPα under the control of human regulatory elements (hSIRPα‐DKO mice), we here show that a blocking Ab to human SIRPα significantly enhanced the ADCP activity of macrophages derived from these mice for human cancer cells. The anti‐human SIRPα Ab also markedly enhanced the inhibitory effect of rituximab on the growth of tumors formed by Raji cells in hSIRPα‐DKO mice. Our results thus suggest that the combination of Abs to human SIRPα with therapeutic Abs specific for tumor antigens warrants further investigation for potential application to cancer immunotherapy. In addition, humanized mice, such as hSIRPα‐DKO mice, should prove useful for validation of the antitumor effects of checkpoint inhibitors before testing in clinical trials.     

Association between low body temperature on admission and in-hospital mortality according to body mass index categories of patients with sepsis

Hypothermia has been shown to be associated with a high mortality rate among patients with sepsis. However, the relationship between hypothermia and body mass index (BMI) with respect to mortality remains to be elucidated. We conducted this study to assess the association between hypothermia and survival outcomes of patients with sepsis according to BMI categories. This secondary analysis of a prospective cohort study enrolled 1184 patients (aged ≥ 16 years) with sepsis hospitalized in 59 intensive care units in Japan. Patients were divided into 3 BMI categories (<18.5 [low], 18.5–24.9 [normal], >24.9 [high] kg/m²) and 2 body temperature (36 °C and ≥ 36 °C) groups. The primary outcome was in-hospital mortality rate. Associations between hypothermia and BMI categories with respect to in-hospital mortality were evaluated using multivariate logistic regression analysis. Of the 1089 patients, 223, 612, and 254 had low, normal, and high BMI values, respectively. Patients with body temperature < 36 °C (hypothermia) had a higher in-hospital mortality rate than that had by those without hypothermia in the normal BMI group (25/63, 39.7% vs. 107/549, 19.5%); however, this was not true for patients in the low or high BMI groups. A significant interaction was observed between hypothermia and normal BMI for in-hospital mortality (odds ratio, 1.56; 95% confidence interval, 1.00–3.41; P value for interaction = .04); however, such an interaction was not found between hypothermia and low or high BMIs. Patients with sepsis and hypothermia in the normal BMI subgroup may have a higher mortality risk than that of those in the low or high BMI subgroups and, therefore, require more attention.     

Abdominal aortic calcification is associated with Fibrosis‐4 index and low body mass index in type 2 diabetes patients: A retrospective cross‐sectional study

Aims/IntroductionThis study aimed to clarify the nature of the relationship between the abdominal aortic calcification (AAC) grade and the presence of cardiovascular diseases, and determine factors related to AAC grade in people with type 2 diabetes mellitus.Materials and MethodsThis retrospective cross‐sectional study enrolled 264 inpatients with type 2 diabetes mellitus. The AAC score and length were measured using the lateral abdominal radiographs. Logistic regression models were used to assess the associations between AAC scores/lengths and the presence of coronary artery disease (CAD), cerebral infarction (CI) and peripheral artery disease (PAD). The correlation between AAC scores/lengths and other clinical factors were evaluated using linear regression models.ResultsThe AAC score was significantly correlated with prevalent CAD and CI independent of age and smoking, but not with the prevalence of PAD. AAC length was not significantly correlated with the presence of CAD, CI or PAD; however, the sample size was insufficient to conclude, probably due to low prevalence. Both the AAC score and length were correlated inversely with body mass index (BMI) and, with the Fibrosis‐4 (Fib‐4) index >2.67; these correlations were significant after adjusting for cardiovascular risk factors and BMI, although AAC was not associated with ultrasonography‐diagnosed fatty liver. There was a significant interaction between BMI and Fib‐4 index; lower BMI and Fib‐4 index >2.67 showed a synergistic association with high AAC grade.ConclusionsAAC score is associated with CAD and CI morbidity in participants with type 2 diabetes mellitus. Low BMI and Fib‐4 index >2.67 can be valuable indicators of AAC in people with type 2 diabetes mellitus.     

Inter-prefectural Travel and Network Connectedness During the COVID-19 Pandemic in Japan

BackgroundIncreases in human mobility have been linked to rises in novel coronavirus disease 2019 (COVID-19) transmission. The pandemic era in Japan has been characterized by changes in inter-prefectural mobility across state of emergency (SOE) declarations and travel campaigns, but they have yet to be characterized.MethodsUsing Yahoo Japan mobility data extracted from the smartphones of more than 10 million Japanese residents, we calculated the monthly number of inter-prefectural travel instances, stratified by residential prefecture and destination prefecture. We then used this adjacency matrix to calculate two network connectedness metrics, closeness centrality and effective distance, that reliably predict disease transmission.ResultsInter-prefectural mobility and network connectedness decreased most considerably during the first SOE, but this decrease dampened with each successive SOE. Mobility and network connectedness increased during the Go To Travel campaign. Travel volume between distant prefectures decreased more than travel between prefectures with geographic proximity. Closeness centrality was found to be negatively correlated with the rate of COVID-19 infection across prefectures, with the strength of this association increasing in tandem with the infection rate. Changes in effective distance were more visible among geographically isolated prefectures (Hokkaido and Okinawa) than among metropolitan, central prefectures (Tokyo, Aichi, Osaka, and Fukuoka).ConclusionThe magnitude of reductions in human mobility decreased with each subsequent state of emergency, consistent with pandemic fatigue. The association between network connectedness and rates of COVID-19 infection remained visible throughout the entirety of the pandemic period, suggesting that inter-prefectural mobility may have contributed to disease spread.Key words: Japan, human mobility, domestic travel, COVID-19, travel campaign     

Relationships between Food Production Experience and the Behavior,Attitude, and Knowledge of Dietary Recommendations among Japanese Adults: A Cross-Sectional Study

The Japanese Ministry of Agriculture, Forestry, and Fisheries proposed to educate more people in food production as one of the objectives of the Basic Plan for Food and Nutrition Education Promotion. This cross-sectional study aims to elucidate the relationship between food production experience (agricultural, forestry, and fishery experiences) and the behavior, attitude, and knowledge of dietary recommendations among Japanese adults. This study was conducted using data obtained from the “Survey on Dietary Habits and Agriculture, Forestry, and Fishery Experiences (2019)”. This survey was conducted by mailing paper questionnaires to respondents aged 20–69 years living in 17 regions across Japan. The independent variable was food production experience. The dependent variables were each of the 13 goals of the dietary guidelines in Japan, the total score for adherence to the 13 items (low scores indicate good adherence), adherence to a Japanese-style diet, and four items on the attitude and knowledge of dietary recommendations. I also examined the association between the point in life the food production experience occurred and the above outcomes. The data obtained from 3461 participants aged 20 to 69 years were used for multivariate logistic and linear regression analyses. Food production experience was positively associated with an improved behavior, attitude, and knowledge of dietary recommendations among adults in Japan. The study found a strong relationship with food production experiences in adulthood.     

Endoscopic Treatment of Superficial Gastric Cancer: Present Status and Future

Although the mortality rates of gastric cancer (GC) are gradually declining, gastric cancer is still the fourth leading cause of cancer-related death worldwide. This may be due to the high rate of patients who are diagnosed with GC at advanced stages. However, in countries such as Japan with endoscopic screening systems, more than half of GCs are discovered at an early stage, enabling endoscopic resection (ER). Especially after the introduction of endoscopic submucosal dissection (ESD) in Japan around 2000, a high en bloc resection rate allowing pathological assessment of margin and depth has become possible. While ER is a diagnostic method of treatment and may not always be curative, it is widely accepted as standard treatment because it is less invasive than surgery and can provide an accurate diagnosis for deciding whether additional surgery is necessary. The curability of ER is currently assessed by the completeness of primary tumor removal and the possibility of lymph node metastasis. This review introduces methods, indications, and curability criteria for ER of EGC. Despite recent advances, several problems remain unsolved. This review will also outline the latest evidence concerning future issues.     

Correlation between echocardiographic superior vena cava flow and short-term outcome in infants with asphyxia

Objectives

To assess the relationship between superior vena cava (SVC) flow and short-term outcome in infants with perinatal asphyxia.

Methods

Infants in sequence born after more than 35 weeks of gestation who had been hospitalized at the NICU and normal neonatal wards of Wakayama Medical University between May 2005 and September 2010 were recruited for this observational cohort study. The study eligibility criterion was the presence of perinatal asphyxia, as evidenced by abnormal fetal heart rate monitoring and an Apgar score of 7 or less at 1 min or need for resuscitation using positive pressure ventilation. SVC flow was measured in the first three days of life by Doppler echocardiography as described by Kluckow and Evans. Short-term outcome was defined as poor if MRI demonstrated bilateral lesions of the basal ganglia and thalamus and/or multicystic encephalomalacia due to hypoxic ischemia.

Results

In the head cooling group, SVC flow in infants with a good outcome was lower than that in infants with a poor outcome at 12 h (36.9 ± 7.7 vs 113.4 ± 42.4 ml/kg/min (p = 0.01)), 24 h (75.2 ± 25.3 vs 155.6 ± 45.7 ml/kg/min (p = 0.03)), and 48 h (92.5 ± 34.2 vs 161.1 ± 46.7 ml/kg/min (p = 0.04)) after birth. SVC flow decreased promptly after introduction of head cooling in infants who had a good outcome, whereas it increased gradually after head cooling in those who had a poor outcome.

Conclusion

We speculate that regulation of brain circulation is disrupted in infants with asphyxia who show a poor outcome.