Tumor-dependent secretion of close homolog of L1 results in elevation of its circulating level in mouse model for human lung tumor

Close homolog of L1 (CHL1) and its truncated form mainly play crucial roles in mouse brain development and neural functions. Herein, we newly identified that truncated form of CHL1 is produced and released from lung tumor tissue in a mouse model expressing human EML4-ALK fusion gene. Both western blot and direct ELISA analysis revealed that mouse CHL1 level in serum (including serum extracellular vesicles) was significantly elevated in EML4-ALK transgenic mice. The correlation between the tumor size and the amount of CHL1 secretion could be examined in this study, and showed a significant positive correlation in a tumor size-dependent manner. Considering these results, the measurement of circulating CHL1 level may contribute to assess a tumor progression in human lung tumor patients

Proximity proteomics identifies cancer cell membrane cis‐molecular complex as a potential cancer target

Cancer-specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in the last 20 years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane-resident "cis-bimolecular complex" as a possible cancer target (cis-bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in the last 10 years. BiCAT were detected using a previously developed method termed the enzyme-mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCAT, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and alpha2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that CHL1 and alpha2 integrin were highly co-expressed in almost all cancer tissues compared with normal lung tissues. As an example of BiCAT application, in vitro simulation of effective drug combinations used for multiple drug treatment strategies was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCAT in cancer cells is useful for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the potential to contribute to several molecular targeted strategies in future

Dysbindin Regulates the Transcriptional Level of Myristoylated Alanine-Rich Protein Kinase C Substrate via the Interaction with NF-YB in Mice Brain

BACKGROUND: An accumulating body of evidence suggests that Dtnbp1 (Dysbindin) is a key susceptibility gene for schizophrenia. Using the yeast-two-hybrid screening system, we examined the candidate proteins interacting with Dysbindin and revealed one of these candidates to be the transcription factor NF-YB. METHODS: We employed an immunoprecipitation (IP) assay to demonstrate the Dysbindin-NF-YB interaction. DNA chips were used to screen for altered expression of genes in cells in which Dysbindin or NF-YB was down regulated, while Chromatin IP and Reporter assays were used to confirm the involvement of these genes in transcription of Myristoylated alanine-rich protein kinase C substrate (MARCKS). The sdy mutant mice with a deletion in Dysbindin, which exhibit behavioral abnormalities, and wild-type DBA2J mice were used to investigate MARCKS expression. RESULTS: We revealed an interaction between Dysbindin and NF-YB. DNA chips showed that MARCKS expression was increased in both Dysbindin knockdown cells and NF-YB knockdown cells, and Chromatin IP revealed interaction of these proteins at the MARCKS promoter region. Reporter assay results suggested functional involvement of the interaction between Dysbindin and NF-YB in MARCKS transcription levels, via the CCAAT motif which is a NF-YB binding sequence. MARCKS expression was increased in sdy mutant mice when compared to wild-type mice. CONCLUSIONS: These findings suggest that abnormal expression of MARCKS via dysfunction of Dysbindin might cause impairment of neural transmission and abnormal synaptogenesis. Our results should provide new insights into the mechanisms of neuronal development and the pathogenesis of schizophrenia

Lower In-Hospital Mortality With Beta-Blocker Use at Admission in Patients With Acute Decompensated Heart Failure

[Background] It remains unclear whether beta‐blocker use at hospital admission is associated with better in‐hospital outcomes in patients with acute decompensated heart failure. [Methods and Results] We evaluated the factors independently associated with beta‐blocker use at admission, and the effect of beta‐blocker use at admission on in‐hospital mortality in 3817 patients with acute decompensated heart failure enrolled in the Kyoto Congestive Heart Failure registry. There were 1512 patients (39.7%) receiving, and 2305 patients (60.3%) not receiving beta‐blockers at admission for the index acute decompensated heart failure hospitalization. Factors independently associated with beta‐blocker use at admission were previous heart failure hospitalization, history of myocardial infarction, atrial fibrillation, cardiomyopathy, and estimated glomerular filtration rate <30 mL/min per 1.73 m2. Factors independently associated with no beta‐blocker use were asthma, chronic obstructive pulmonary disease, lower body mass index, dementia, older age, and left ventricular ejection fraction <40%. Patients on beta‐blockers had significantly lower in‐hospital mortality rates (4.4% versus 7.6%, P<0.001). Even after adjusting for confounders, beta‐blocker use at admission remained significantly associated with lower in‐hospital mortality risk (odds ratio, 0.41; 95% CI, 0.27–0.60, P<0.001). Furthermore, beta‐blocker use at admission was significantly associated with both lower cardiovascular mortality risk and lower noncardiovascular mortality risk. The association of beta‐blocker use with lower in‐hospital mortality risk was relatively more prominent in patients receiving high dose beta‐blockers. The magnitude of the effect of beta‐blocker use was greater in patients with previous heart failure hospitalization than in patients without (P for interaction 0.04). [Conclusions] Beta‐blocker use at admission was associated with lower in‐hospital mortality in patients with acute decompensated heart failure

Association between Body Mass Index and Prognosis of Patients Hospitalized With Heart Failure

The prognostic implications of very low body mass index (BMI) values remain unclear in patients with acute decompensated heart failure (ADHF). This study aimed to investigate the prognostic impact of BMI classification based on the World Health Organization criteria in patients with ADHF. Among 3509 patients with ADHF and available BMI data at discharge in 19 participating hospitals in Japan between October 2014 and March 2016, the study population was divided into five groups; (1) Severely underweight: BMI < 16 kg/m², (2) Underweight: BMI ≥ 16 kg/m² and < 18.5 kg/m², (3) Normal weight: BMI ≥ 18.5 kg/m² and < 25 kg/m², (4) Overweight: BMI ≥ 25 kg/m² and < 30 kg/m² (5) Obese: BMI ≥ 30 kg/m². The primary outcome measure was all-cause death. The median follow-up duration was 471 days, with 96.4% follow up at 1-year. The cumulative 1-year incidence of all-cause death was higher in underweight groups, and lower in overweight groups (Severely underweight: 36.3%, Underweight: 23.9%, Normal weight: 14.4%, Overweight: 7.9%, and Obese: 9.0%, P < 0.001). After adjusting confounders, the excess mortality risk remained significant in the severely underweight group (HR, 2.32; 95%CI, 1.83–2.94; P < 0.001), and in the underweight group (HR, 1.31; 95%CI, 1.08–1.59; P = 0.005) relative to the normal weight group, while the lower mortality risk was no longer significant in the overweight group (HR, 0.82; 95%CI, 0.62–1.10; P = 0.18) and in the obese group (HR, 1.09; 95%CI, 0.65–1.85; P = 0.74). Very low BMI was associated with a higher risk for one-year mortality after discharge in patients with ADHF

Newly Diagnosed Infection After Admission for Acute Heart Failure: From the KCHF Registry

[Background] No studies have explored the association between newly diagnosed infections after admission and clinical outcomes in patients with acute heart failure. We aimed to explore the factors associated with newly diagnosed infection after admission for acute heart failure, and its association with in‐hospital and post‐discharge clinical outcomes. [Methods and Results] Among 4056 patients enrolled in the Kyoto Congestive Heart Failure registry, 2399 patients without any obvious infectious disease upon admission were analyzed. The major in‐hospital and post‐discharge outcome measures were all‐cause deaths. There were 215 patients (9.0%) with newly diagnosed infections during hospitalization, and 2184 patients (91.0%) without infection during hospitalization. The factors independently associated with a newly diagnosed infection were age ≥80 years, acute coronary syndrome, non‐ambulatory status, hyponatremia, anemia, intubation, and patients who were not on loop diuretics as outpatients. The newly diagnosed infection group was associated with a higher incidence of in‐hospital mortality (16.3% and 3.2%, P<0.001) and excess adjusted risk of in‐hospital mortality (odds ratio, 6.07 [95% CI, 3.61–10.19], P<0.001) compared with the non‐infection group. The newly diagnosed infection group was also associated with a higher 1‐year incidence of post‐discharge mortality (19.3% in the newly diagnosed infection group and 13.6% in the non‐infection group, P<0.001) and excess adjusted risk of post‐discharge mortality (hazard ratio, 1.49 [95% CI, 1.08–2.07], P=0.02) compared with the non‐infection group. [Conclusions] Elderly patients with multiple comorbidities were associated with the development of newly diagnosed infections after admission for acute heart failure. Newly diagnosed infections after admission were associated with higher in‐hospital and post‐discharge mortality in patients with acute heart failure

Association between changes in loop diuretic dose and outcomes in acute heart failure

AIMS: Little is known about the association between the starting of or dose changes in loop diuretics during acute heart failure (AHF) hospitalization and post-discharge outcomes. We investigated the clinical impact of starting loop diuretics and changing the loop diuretics dose during hospitalization on post-discharge outcomes. METHODS AND RESULTS: From the Kyoto Congestive Heart Failure registry, 3665 consecutive patients hospitalized for HF and discharged alive were included in this study. We analysed 1906 patients without loop diuretics on admission and were discharged alive and 1759 patients who received loop diuretics on admission and were discharged alive. The primary outcome measure was all-cause death. Of the 1906 patients without loop diuretics on admission, 1366 (71.7%) patients started loop diuretics during the index AHF hospitalization. Starting loop diuretics was not associated with lower post-discharge mortality [adjusted hazard ratio (HR) 0.92, 95% confidence interval (CI) 0.68-1.25]. Of the 1759 patients who received loop diuretics on admission, loop diuretic dose was decreased in 23.8%, unchanged in 44.6%, and increased in 31.6% of the patients. Changes in the dose at discharge compared with no change in dose were not associated with lower risk of post-discharge mortality (decrease relative to no change: adjusted HR 0.98, 95% CI 0.76-1.28; increase relative to no change: adjusted HR 1.00, 95% CI 0.78-1.27). Compared with no loop diuretics at discharge, a loop diuretics dose of ≥80 mg at discharge was associated with higher post-discharge mortality risk. CONCLUSIONS: In patients with AHF, we found no association between the starting of loop diuretics and post-discharge outcomes and between dose changes and post-discharge outcomes

Coronary angiography in patients with acute heart failure: from the KCHF registry

[Aims] Little is known about the characteristics and outcomes of patients who undergo coronary angiography during heart failure (HF) hospitalization, as well as those with coronary stenosis, and those who underwent coronary revascularization. [Methods and results] We analysed 2163 patients who were hospitalized for HF without acute coronary syndrome or prior HF hospitalization. We compared patient characteristics and 1 year clinical outcomes according to (i) patients with versus without coronary angiography, (ii) patients with versus without coronary stenosis, and (iii) patients with versus without coronary revascularization. The primary outcome measure was the composite of all-cause death or HF hospitalization. Coronary angiography was performed in 37.0% of patients. In the multivariable logistic regression analysis, factors independently associated with coronary angiography were age < 80 years [adjusted odds ratio (OR) = 1.76, 95% confidence interval (CI) = 1.41–2.20, P < 0.001], men (adjusted OR = 1.28, 95% CI = 1.03–1.59, P = 0.02), diabetes (adjusted OR = 1.27, 95% CI = 1.02–1.60, P = 0.04), no atrial fibrillation or flutter (adjusted OR = 1.45, 95% CI = 1.17–1.82, P < 0.001), no prior device implantation (adjusted OR = 1.81, 95% CI = 1.13–2.91, P = 0.01), current smoking (adjusted OR = 1.40, 95% CI = 1.05–1.87, P = 0.02), no cognitive dysfunction (adjusted OR = 1.90, 95% CI = 1.34–2.69, P < 0.001), ambulatory status (adjusted OR = 2.89, 95% CI = 2.03–4.10, P < 0.001), HF with reduced ejection fraction (adjusted OR = 1.55, 95% CI = 1.24–1.93, P < 0.001), estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 (adjusted OR = 1.93, 95% CI = 1.45–2.58, P < 0.001), no anaemia (adjusted OR = 1.27, 95% CI = 1.02–1.59, P = 0.04), and no prescription of β-blockers prior to admission (adjusted OR = 1.32, 95% CI = 1.03–1.68, P = 0.03). Patients who underwent coronary angiography had a lower risk of the primary outcome [adjusted hazard ratio (HR) = 0.70, 95% CI = 0.58–0.85, P < 0.001]. Among the patients who underwent coronary angiography, those with coronary stenosis (38.9%) did not have lower risk of the primary outcome measure than those without coronary stenosis (adjusted HR = 0.93, 95% CI = 0.65–1.32, P = 0.68). Among the patients with coronary stenosis, those with coronary revascularization (54.3%) did not have higher risk of the primary outcome measure than those without coronary revascularization (adjusted HR = 1.36, 95% CI = 0.84–2.21, P = 0.22). [Conclusions] In patients with acute HF, patients who underwent coronary angiography had a lower risk of clinical outcomes and were significantly different from those who did not undergo coronary angiography

Sex differences in patients with acute decompensated heart failure in Japan: observation from the KCHF registry

Aims: The association between sex and long‐term outcome in patients hospitalized for acute decompensated heart failure (ADHF) has not been fully studied yet in Japanese population. The aim of this study was to determine differences in baseline characteristics and management of patients with ADHF between women and men and to compare 1‐year outcomes between the sexes in a large‐scale database representing the current real‐world clinical practice in Japan. Methods and results: Kyoto Congestive Heart Failure registry is a prospective cohort study enrolling consecutive patients hospitalized for ADHF in Japan among 19 centres. Baseline characteristics, clinical presentation, management, and 1‐year outcomes were compared between men and women. A total of 3728 patients who were alive at discharge constituted the current study population. There were 1671 women (44.8%) and 2057 men. Women were older than men [median (IQR): 83 (76–88) years vs. 77 (68–84) years, P < 0.0001]. Hypertensive and valvular heart diseases were more prevalent in women than in men (28.0% vs. 22.5%, P = 0.0001; and 26.9% vs. 14.0%, P < 0.0001, respectively), whereas ischaemic aetiology was less prevalent in women than in men (20.0% vs. 32.5%, P < 0.0001). Women less often had reduced left ventricular ejection fraction (<40%) than men (27.5% vs. 45.1%, P < 0.0001). The cumulative incidence of all‐cause death or hospitalization for heart failure was not significantly different between women and men (33.6% vs. 34.3%, P = 0.71), although women were substantially older than men. After multivariable adjustment, the risk of all‐cause death or hospitalization for heart failure was significantly lower among women (adjusted hazard ratio: 0.84, 95% confidence interval: 0.74–0.96, P = 0.01). Conclusions: Women with heart failure were older and more often presented with preserved EF with a non‐ischaemic aetiology and were associated with a reduced adjusted risk of 1‐year mortality compared with men in the Japanese population

Appetite loss at discharge from acute decompensated heart failure: Observation from KCHF registry

OBJECTIVE: The complex link between nutritional status, protein and lipid synthesis, and immunity plays an important prognostic role in patients with heart failure. However, the association between appetite loss at discharge and long-term outcome remains unclear. METHODS: The Kyoto Congestive Heart Failure registry is a prospective cohort study that enrolled consecutive patients hospitalized for acute decompensated heart failure (ADHF) in Japan. We assessed 3528 patients alive at discharge, and for whom appetite and follow-up data were available. We compared one-year clinical outcomes in patients with and without appetite loss at discharge. RESULTS: In the multivariable logistic regression analysis using 19 clinical and laboratory factors with P value 1.0mg/dL (OR: 1.49, 95%CI: 1.04-2.14, P = 0.03), and presence of edema at discharge (OR: 4.30, 95%CI: 2.99-6.22, P<0.001) were associated with an increased risk of appetite loss at discharge, whereas ambulatory status (OR: 0.57, 95%CI: 0.39-0.83, P = 0.004) and the use of ACE-I/ARB (OR: 0.70, 95% CI: 0.50-0.98, P = 0.04) were related to a decreased risk in the presence of appetite loss. The cumulative 1-year incidence of all-cause death (primary outcome measure) was significantly higher in patients with appetite loss than in those without appetite loss (31.0% vs. 15.0%, P<0.001). The excess adjusted risk of appetite loss relative to no appetite loss remained significant for all-cause death (hazard ratio (HR): 1.63, 95%CI: 1.29-2.07, P<0.001). CONCLUSIONS: Loss of appetite at discharge was associated with worse 1-year mortality in patients with ADHF. Appetite is a simple, reliable, and useful subjective marker for risk stratification of patients with ADHF