AXL signal mediates adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutant tumor cells.

Recently, novel Kirsten rat sarcoma viral oncogene homolog (KRAS) inhibitors have been clinically developed to treat KRAS G12C-mutated non-small cell lung cancer (NSCLC) patients. However, achieving complete tumor remission is challenging. Therefore, the optimal combined therapeutic intervention with KRAS G12C inhibitors has a potentially crucial role in the clinical outcomes of patients. We investigated the underlying molecular mechanisms of adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC cells to devise a strategy preventing drug-tolerant cell emergence. We demonstrate that AXL signaling led to the adaptive resistance to KRAS G12C inhibitors in KRAS G12C-mutated NSCLC, activation of which is induced by GAS6 production via YAP. AXL inhibition reduced the viability of AXL-overexpressing KRAS G12C-mutated lung cancer cells by enhancing KRAS G12C inhibition-induced apoptosis. In xenograft models of AXL-overexpressing KRAS G12C-mutated lung cancer treated with KRAS G12C inhibitors, initial combination therapy with AXL inhibitor markedly delayed tumor regrowth compared with KRAS G12C inhibitor alone or with the combination after acquired resistance to KRAS G12C inhibitor. These results indicated pivotal roles for the YAP-GAS6-AXL axis and its inhibition in the intrinsic resistance to KRAS G12C inhibitor.

Living Arrangements Predict Frequent Alcohol Consumption Among University Students: A Retrospective Cohort Study.

PURPOSE: This study aimed to confirm the clinical impact of living arrangements on incidence of frequent alcohol consumption in university students. DESIGN: A retrospective cohort study. SETTING: A national university in Japan. SUBJECTS: 17,774 university students. MEASURES: The association between living arrangements on admission and the incidence of frequent alcohol consumption (≥4 days/week) was assessed using multivariable-adjusted Cox proportional-hazards models. RESULTS: Among 5,685, 692, and 5,151 male students living with family, living in the dormitory, and living alone, 5.0%, 6.2%, and 5.8% reported frequent alcohol consumption during the median observational period of 3.0 years, respectively. Living in the dormitory and living alone were identified as significant predictors of frequent alcohol consumption (multivariable-adjusted hazard ratios: 1.00 [reference], 1.39 [1.01-1.92], and 1.21 [1.03-1.42], respectively). On the contrary, living arrangements were not associated with the incidence of frequent alcohol consumption among of 6,091 female students, partly because of low incidence of frequent alcohol consumption (2.3%, 1.4%, and 2.6%, respectively). CONCLUSIONS: Living arrangements predicted frequent alcohol consumption among male university students, whereas not among female university students.

High efficacy of brigatinib for brain metastases in ALK fusion gene-positive non-small cell lung cancer: A case series.

Anaplastic lymphoma kinase (ALK) fusion gene-positive lung cancer often shows brain metastasis at initial diagnosis or during the course of treatment. However, molecular-targeted drugs are known to pass through the blood-brain barrier and present positive effects for central nervous system lesions. There are few reports suggesting how effective molecular-targeted drug therapy alone is for brain metastasis lesions of ALK fusion-positive lung cancer, especially after the first use of ALK-tyrosine kinase inhibitor (TKI) or for bulky brain metastases. A patient in his mid-fifties with stage IV pleural dissemination developed brain metastases after 10 years of crizotinib use, but showed a complete response after switching to brigatinib. Moreover, a patient in her early sixties with stage III recurrent large brain metastases 5 years after chemoradiation therapy experienced dramatic tumor shrinkage with brigatinib. In each case of ALK fusion gene-positive lung cancer with brain metastases, brigatinib showed a high efficacy and was well-tolerated after previous ALK-TKI and for bulky lesions.

Hysterectomy through Minimally Invasive Surgery for Cervical High-grade Intraepithelial Neoplasia: Reassessment of the Specimens' Eligibility for Histological Examination.

Objectives: The objective was to investigate the microscopic artifacts made in the uterus of cervical high-grade squamous intraepithelial lesion (HSIL) resected by hysterectomy through minimally invasive (H-MI) procedures and to verify whether these specimens are suitable for histopathological assessment. Materials and Methods: This single-center retrospective study analyzed 28 patients with cervical HSIL, consisting of 21 premenopausal and seven postmenopausal women, who underwent H-MI. The proportion of the cervical mucosa covered by intact surface epithelium (residual ratio [RR]) was measured on microscopically. Surgical margin's status was also verified. Results: All cases developed detachment of the cervical surface epithelium to a varying extent. The RR was significantly higher in the premenopausal patients (median: 75.5%) than in the postmenopausal patients (median: 37.6%). Among the premenopausal patients, the RR was lower in the cases on whom uterine manipulator (UM) was used (median: 70.5%) than in the cases without UM use (median 92.7%). Among the 21 cases whose resected uterus contained HSIL, the vaginal resection margin was not assessable in three (14.2%) of the seven postmenopausal cases due to the artifact. Conclusion: Although transvaginal manipulation of the uterus causes detachment of the cervical surface epithelium, H-MI for cervical HSIL provides an acceptable specimen for histological assessment in premenopausal patients, even if UM is used. In postmenopausal women, H-MI easily develops artifactual loss of cervical surface epithelium, sometimes providing an unfavorable specimen for microscopic assessment.

Association of secondhand smoke exposure and health-related lifestyle behaviors among male university employees in Japan.

Secondhand smoke (SHS) exposure causes various health problems associated with an unhealthy lifestyle. However, the lifestyles of individuals exposed to SHS have not been characterized extensively. Therefore, this cross-sectional study aimed to investigate the association between SHS exposure and lifestyle behaviors. The participants were 2379 healthy male employees at Osaka University who underwent health examinations. Physical and biochemical parameters and lifestyle behavior data were obtained from all the participants. Participants with SHS exposure had significantly higher body mass index, waist circumference, and serum levels of triglycerides and uric acid than that of those without SHS exposure. SHS exposure was significantly correlated with several lifestyle behaviors, including TV time, frequency of breakfast consumption and fried food consumption, vegetable and fruit intake, alcohol consumption frequency and daily alcohol intake, and smoking status. Thus, SHS exposure may be associated with an unhealthy lifestyle. The lifestyle behaviors of the smoke-excluded population were assessed further; however, SHS exposure was still associated with dietary and drinking habits. Since participants with SHS exposure are likely to have an unhealthy life and combined unhealthy lifestyle behaviors, the confounding effect of these factors should be considered when assessing the impact of SHS exposure on health.

XCR1+ conventional dendritic cell-induced CD4+ T helper 1 cell activation exacerbates cardiac remodeling after ischemic myocardial injury.

Cardiac remodeling has no established therapies targeting inflammation. CD4+ T-cell subsets have been reported to play significant roles in healing process after ischemic myocardial injury, but their detailed mechanisms of activation remain unknown. To explore immune reactions during cardiac remodeling, we applied a non-surgical model of coronary heart disease (CHD) induced by a high-fat diet (HFD-CHD) in SR-BI-/-/ApoeR61h/h mice. Flow cytometry analyses throughout the period of progressive cardiac dysfunction revealed that CD4+ T Helper 1 (Th1) cells were predominantly activated in T-cell subsets. Probucol was reported to attenuate cardiac dysfunction after coronary artery ligation model (ligation-MI) in rats. To determine whether probucol suppress cardiac remodeling after HFD-CHD, we treated SR-BI-/-/ApoeR61h/h mice with probucol. We found treatment with probucol in HFD-CHD mice reduced cardiac dysfunction, with attenuated activation of Th1 cells. RNA-seq analyses revealed that probucol suppressed the expression of CXCR3, a Th1-related chemokine receptor, in the heart. XCR1+ cDC1 cells, which highly expresses the CXCR3 ligands CXCL9 and CXCL10, were predominantly activated after HFD-CHD. XCR1+ cDC1 lineage skewing of pre-DC progenitors was observed in bone marrow, with subsequent systemic expansion of XCR1+ cDC1 cells after HFD-CHD. Activation of CXCR3+ Th1 cell and XCR1+ cDC1 cells was also observed in ligation-MI. Notably, post-MI depletion of XCR1+ cDC1 cells suppressed CXCR3+ Th1 cell activation and prevented cardiac dysfunction. In patient autopsy samples, CXCR3+ Th1 and XCR1+ cDC1 cells infiltrated the infarcted area. In this study, we identified a critical role of XCR1+ cDC1-activated CXCR3+ Th1 cells in ischemic cardiac remodeling.

Anti-GPIHBP1 Antibody-Positive Autoimmune Hyperchylomicronemia and Immune Thrombocytopenia.

Primary hyperchylomicronemia is characterized by marked hypertriglyceridemia exceeding 1,000 mg/dL. It is caused by dysfunctional mutations in specific genes, namely those for lipoprotein lipase (LPL), glycosylphosphatidylinositol-anchored high-density lipoprotein binding protein 1 (GPIHBP1), apolipoprotein C2 (ApoC-II), lipase maturation factor 1 (LMF1), or apolipoprotein A5 (ApoA-V). Importantly, antibodies against LPL or GPIHBP1 have also been reported to induce autoimmune hyperchylomicronemia. The patient was a 46-year-old man diagnosed with immune thrombocytopenia (ITP) at 41 years. At the time, he was administered prednisolone (PSL) and eltrombopag, a thrombopoietin receptor agonist. At 44 years, he suffered from acute myocardial infarction, and PSL was discontinued to avoid enhancing atherogenic risks. He was maintained on eltrombopag monotherapy. After discontinuing PSL, marked hypertriglyceridemia (＞3,000 mg/dL) was observed, which did not improve even after a few years of pemafibrate therapy. Upon referral to our clinic, the triglyceride (TG) level was 2,251 mg/dL, ApoC-II was 19.8 mg/dL, LPL was 11.1 ng/mL (0.02-1.5 ng/mL), GPIHBP1 was 47.7 pg/mL (740.0-1,014.0 pg/mL), and anti-GPIHBP1 antibody was detected. The patient was diagnosed to have anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia. He was administered PSL 15 mg/day, and TG levels were controlled at approximately 200 mg/dL. Recent studies have reported that patients with anti-GPIHBP1 antibody-induced autoimmune hyperchylomicronemia had concomitant rheumatoid arthritis, systemic lupus erythematosus, Sjogren's syndrome, Hashimoto's disease, and Graves' disease. We report a rare case of anti-GPIHBP1 antibody-positive autoimmune hyperchylomicronemia with concomitant ITP, which became apparent when PSL was discontinued due to the onset of steroid-induced acute myocardial infarction.

Living alone and prediction of weight gain and overweight/obesity in university students: a retrospective cohort study.

Objective:  To assess the clinical impact of living alone on weight gain in university students. Participants: This retrospective cohort study included 17540 male and 8854 female university students admitted to a national university in Japan. Methods: An association between living arrangement and the incidence of weight gain ≥10% and overweight/obesity (body mass index (BMI) ≥25 kg/m2) was assessed using multivariable-adjusted Poisson regression models. Results: Weight gain was observed in 1889 (10.8%) male and 1516 (17.1%) female students during 3.0 and 2.9 years of the mean observational period, respectively. Living alone was identified as a significant predictor of weight gain (adjusted incidence rate ratio of living alone vs. living with family: 1.24 [1.13-1.36] and 1.76 [1.58-1.95] in male and female students, respectively) and was also as a predictor of overweight/obesity. Conclusions: University students living alone were at a significantly higher risk of weight gain and overweight/obesity than those living with family.

A Dietary Oxysterol, 7-Ketocholesterol, Exacerbates Imiquimod-Induced Psoriasis-like Dermatitis in Steatohepatitic Mice.

Patients with psoriasis are at a higher risk of developing nonalcoholic fatty liver disease. We previously identified an oxidized derivative of cholesterol, 7-ketocholesterol (7KC), in diet-induced steatohepatitic mice. Here, we investigated whether 7KC exacerbates psoriasis-like dermatitis by accelerating steatohepatitis in mice. A high-fat/high-cholesterol/high-sucrose/bile salt diet (nonalcoholic steatohepatitis (NASH) diet) with or without 0.0125% 7KC was fed to C57BL/6 mice (7KC or control group) for three weeks to induce steatohepatitis. A 5% imiquimod cream was then applied to the ears and dorsal skin for four days to induce psoriasis-like dermatitis. Hepatic lipid accumulation and inflammatory cell infiltration were exacerbated in the 7KC group compared with the control group after three weeks. Serum tumor necrosis factor-α (TNF-α) levels were also elevated in the 7KC group (108.5 ± 9.8 vs. 83.1 ± 13.1 pg/mL, p < 0.005). Imiquimod cream increased the psoriasis area severity index (PASI) score in mice in the 7KC group (9.14 ± 0.75 vs. 5.17 ± 1.17, p < 0.0001). Additionally, Tnfa, Il23a, Il17a, and Il22 mRNA levels in the dorsal lesion were significantly upregulated. Finally, Th17 cell differentiation and the TNF signaling pathway were enhanced in the dorsal lesions and liver of mice in the 7KC group. These data suggest that steatohepatitis and psoriasis are linked by a potent, diet-related factor.

Skipping Breakfast and Incidence of Frequent Alcohol Drinking in University Students in Japan: A Retrospective Cohort Study.

Frequency of alcohol drinking is a potential predictor of binge drinking of alcohol, a serious social problem for university students. Although previous studies have identified skipping breakfast as a predictor of various health-compromising behaviors and cardiometabolic diseases, few studies have assessed the association between skipping breakfast and the incidence of frequent alcohol drinking. This retrospective cohort study included 17,380 male and 8799 female university students aged 18-22 years admitted to Osaka universities between 2004 and 2015. The association between breakfast frequency (eating every day, skipping occasionally, and skipping often/usually) and the incidence of frequent alcohol drinking, defined as drinking ≥4 days/week, was assessed using multivariable-adjusted Cox proportional hazards models. During the median observational period of 3.0 years, 878 (5.1%) men and 190 (2.2%) women engaged in frequent alcohol drinking. Skipping breakfast was significantly associated with the incidence of frequent alcohol drinking (adjusted hazard ratios [95% confidence interval] of eating every day, skipping occasionally, and skipping often/usually: 1.00 [reference], 1.02 [0.84-1.25], and 1.48 [1.17-1.88] in men; 1.00 [reference], 1.60 [1.03-2.49], and 3.14 [1.88-5.24] in women, respectively). University students who skipped breakfast were at a higher risk of frequent alcohol drinking than those who ate breakfast every day.

Pemafibrate suppresses NLRP3 inflammasome activation in the liver and heart in a novel mouse model of steatohepatitis-related cardiomyopathy.

Although patients with nonalcoholic fatty liver disease have been reported to have cardiac dysfunction, and appropriate model has not been reported. We established a novel mouse model of diet-induced steatohepatitis-related cardiomyopathy and evaluated the effect of pemafibrate. C57Bl/6 male mice were fed a (1) chow diet (C), (2) high-fat, high-cholesterol, high-sucrose, bile acid diet (NASH diet; N), or (3) N with pemafibrate 0.1 mg/kg (NP) for 8 weeks. In the liver, macrophage infiltration and fibrosis in the liver was observed in the N group compared to the C group, suggesting steatohepatitis. Free cholesterol accumulated, and cholesterol crystals were observed. In the heart, free cholesterol similarly accumulated and concentric hypertrophy was observed. Ultrahigh magnetic field magnetic resonance imaging revealed that the left ventricular (LV) ejection fraction (EF) was attenuated and LV strain was focally impaired. RNA sequencing demonstrated that the NOD-like receptor and PI3 kinase-Akt pathways were enhanced. mRNA and protein expression of inflammasome-related genes, such as Caspase-1, NLRP3, and IL-1ß, were upregulated in both the liver and heart. In the NP compared to the N group, steatohepatitis, hepatic steatosis, and cardiac dysfunction were suppressed. Sequential administration of pemafibrate after the development of steatohepatitis-related cardiomyopathy recovered hepatic fibrosis and cardiac dysfunction.

Serum FGF21 levels are altered by various factors including lifestyle behaviors in male subjects.

Fibroblast growth factor (FGF) 21 has various functions, including glucose and lipid metabolism. This cross-sectional study aimed to investigate specific conditions that might influence the functions of FGF21. 398 men who underwent a health examination were enrolled in this study. Physical and biochemical parameters and information on several lifestyle behaviors were obtained from all subjects. FGF21 levels correlated with age, body mass index (BMI), waist circumference (WC), systolic blood pressure (SBP), diastolic blood pressure (DBP), aspartate aminotransferase (AST), alanine aminotransferase (ALT), gamma-glutamyl transpeptidase (γ-GTP), uric acid, total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDLC), fasting plasma glucose (FPG), and HbA1c. Moreover, FGF21 levels were significantly associated with lifestyle behaviors, including smoking status and breakfast and alcohol consumption frequency. Multivariable regression analysis showed that age, ALT, γ-GTP, smoking status, and breakfast and alcohol consumption frequency were independent variables for FGF21 levels. Assessment among the non-obese and obese groups showed that FGF21 levels correlated with WC, SBP, and TC only in the non-obese group. Thus, serum FGF21 levels were affected by several factors, including lifestyle behaviors, age, and liver function. To assess the functions of FGF21 in individuals, considering these factors would be essential.

Vegetable Preference and Prediction of Proteinuria: A Retrospective Cohort Study.

INTRODUCTION: Little information is available about the association between vegetable preference and chronic kidney disease. METHODS: This retrospective cohort study included 10,819 university workers in Japan who underwent their annual health checkups between January 2005 and March 2013. According to a question "Do you like vegetables"? with 3 possible answers of "I like vegetables," "I like vegetables somewhat," or "I dislike vegetables," 2,831, 2,249, and 104 male workers and 3,902, 1,648, and 85 female workers were classified into the "like," "somewhat," and "dislike" groups, respectively. An association between vegetable preference and incidence of proteinuria (dipstick urinary protein ≥1+) was assessed using Cox proportional-hazards models adjusted for clinically relevant factors. RESULTS: During the median observational period of 5.0 years, the incidence of proteinuria was observed in 650 (12.7%) male and 789 (14.1%) female workers. Among male workers, the "dislike" group had a significantly higher risk of proteinuria (multivariable-adjusted hazard ratio of "like," "somewhat," and "dislike" groups: 1.00 [reference], 1.05 [0.90-1.23], and 1.59 [1.01-2.50], respectively). Among female workers, vegetable preference was associated with the incidence of proteinuria in a dose-dependent manner (1.00 [reference], 1.20 [1.04-1.40], 1.95 [1.26-3.02], respectively). CONCLUSION: "Do you like vegetables"? was a clinically useful tool to identify subjects vulnerable to proteinuria.

Serum Klotho Levels Contribute to the Prevention of Disease Progression.

BACKGROUND: Assessing the progression of a disorder from its pre-clinical state is important in the prevention of various diseases. In the present study, we evaluated the role of serum levels of αKlotho (αKl) in the progression of several pre-clinical disorders. METHODS: This cohort study included 80 males who underwent their annual health checkup during the entry period between April 2005 and March 2008. Physical and biochemical parameters were obtained from all subjects. The associations of baseline serum levels of soluble αKl (sαKl) with the progression of the disorders were assessed in the study. RESULTS: Baseline serum levels of sαKl were significantly lower in subjects developing a high fasting plasma glucose (FPG) level than in subjects not developing a high FPG level. Logistic multivariable analysis showed that baseline serum levels of sαKl and FPG levels significantly associated with a high FPG level progression. It is suggested that low sαKl levels are associated with the progression of hyperglycemia. Evaluation of serum levels of sαKl in subjects with multiple disorders revealed that those with more pre-clinical disorders progression tended to show lower sαKl levels. CONCLUSION: A decrease in serum levels of sαKl could be associated with the progression of pre-clinical disorders.

Associations of Skipping Breakfast, Lunch, and Dinner with Weight Gain and Overweight/Obesity in University Students: A Retrospective Cohort Study.

Although multiple studies have identified skipping breakfast as a risk factor for weight gain, there is limited evidence on the clinical impact of skipping lunch and dinner on weight gain. This retrospective cohort study including 17,573 male and 8860 female university students at a national university in Japan, assessed the association of the frequency of breakfast, lunch, and dinner with the incidence of weight gain (≥10%) and overweight/obesity (body mass index ≥ 25 kg/m2), using annual participant health checkup data. Within the observation period of 3.0 ± 0.9 years, the incidence of ≥10% weight gain was observed in 1896 (10.8%) men and 1518 (17.1%) women, respectively. Skipping dinner was identified as a significant predictor of weight gain in multivariable-adjusted Poisson regression models for both men and women (skipping ≥ occasionally vs. eating every day, adjusted incidence rate ratios, 1.45 (95% confidence interval: 1.04-2.01) and 1.67 (1.33-2.09) in male and female students, respectively), whereas skipping breakfast and lunch were not. Similarly, skipping dinner, not breakfast or lunch, was associated with overweight/obesity (1.74 (1.07-2.84) and 1.68 (1.02-2.78) in men and women, respectively). In conclusion, skipping dinner predicted the incidence of weight gain and overweight/obesity in university students.

Alpha-Klotho is a novel predictor of treatment responsiveness in patients with heart failure.

Heart failure is a major cause of death with an increasing population of elderly individuals. Several studies have demonstrated the involvement of soluble alpha-Klotho (sαKl) in various diseases. However, the correlation between sαKl and heart failure remains to be understood. The aim of this study is to investigate the levels and role of sαKl in patients with heart failure. Twenty-eight consecutive patients with acute heart failure (19 male, 9 female), admitted to the Osaka University Hospital from 2010 to 2018, were enrolled in this study. Mean NYHA score, left ventricular ejection fraction and BNP were 3.3, 17.0% and 588 pg/mL, respectively. SαKl significantly increased in heart failure patients. SαKl on admission were significantly higher in patients with heart failure who showed improvement after intensive treatment than that in patients who did not show improvement after the treatment. SαKl levels decreased significantly in patients who showed improvement. Interestingly, sαKl levels increased in male patients with heart failure, but not in female patients. Our data suggest that soluble αKl may be a novel biomarker for the responsiveness against treatment in patients with heart failure with reduced ejection fraction. Our findings may help developing a personalized therapy for different patients with heart failure.

Development and Clinical Application of an Enzyme-Linked Immunosorbent Assay for Oxidized High-Density Lipoprotein.

AIMS: HDL particles have various anti-atherogenic functions, whereas HDL from atherosclerotic patients was demonstrated to be dysfunctional. One possible mechanism for the formation of dysfunctional HDL is the oxidation of its components. However, oxidized HDLs (Ox-HDLs) remain to be well investigated due to lack of reliable assay systems. METHODS: We have developed a novel sandwich enzyme-linked immunosorbent assay (ELISA) for Ox-HDL by using the FOH1a/DLH3 antibody, which can specifically recognize oxidized phosphatidylcholine, a major component of HDL phospholipid (HDL-PL). We defined forced oxidation of 1 mg/L HDL-PL as 1 U/L Ox-HDL. We assessed serum Ox-HDL levels of normolipidemic healthy subjects ( n=94) and dyslipidemic patients (n=177). RESULTS: The coefficients of variation of within-run and between-run assays were 12.5% and 13.5%. In healthy subjects, serum Ox-HDL levels were 28.5±5.0 (mean±SD) U/L. As Ox-HDL levels were moderately correlated with HDL-PL (r=0.59), we also evaluated the Ox-HDL/HDL-PL ratio, which represents the proportion of oxidized phospholipids in HDL particles. In dyslipidemic patients, Ox-HDL levels were highly variable and ranged from 7.2 to 62.1U/L, and were extremely high (50.4±13.3U/L) especially in patients with hyperalphalipoproteinemia due to cholesteryl ester transfer protein deficiency. Regarding patients with familial hypercholesterolemia, those treated with probucol, which is a potent anti-oxidative and anti-hyperlipidemic drug, showed significantly lower Ox-HDL (16.2±5.8 vs. 30.2±5.4, p＜0.001) and Ox-HDL/HDL-PL ratios (0.200±0.035 vs. 0.229±0.031, p=0.015) than those without probucol. CONCLUSION: We have established a novel sandwich ELISA for Ox-HDL, which might be a useful and easy strategy to evaluate HDL functionality, although the comparison study between this Ox-HDL ELISA and the assay of HDL cholesterol efflux capacity remains to be done. Our results indicated that probucol treatment may be associated with lower Ox-HDL levels.

Occupational sedentary behavior and prediction of proteinuria in young to middle-aged adults: a retrospective cohort study.

BACKGROUND: Although sedentary behavior is a risk factor of cardiometabolic diseases and mortality, little information is available about a clinical impact of occupational sedentary behavior on chronic kidney disease (CKD). METHODS: The present retrospective cohort study included 10,212 workers of a national university in Japan who underwent annual health checkups between April 2006 and March 2013. Main exposure of interest was self-reported occupational sedentary behavior at the baseline visit. The outcome was the incidence of proteinuria defined as dipstick urinary protein of 1 + or more. The association between sedentary workers and the incidence of proteinuria was assessed using Cox proportional hazards models adjusting for clinically relevant factors, including television viewing time, the major home sedentary behavior. RESULTS: During median 4.8 years (interquartile range 2.1-7.9) of the observational period, the incidence of proteinuria was observed in 597 (12.0%) males and 697 (13.3%) females. In males, sedentary workers were identified as a significant predictor of proteinuria (multivariable-adjusted hazard ratio of non-sedentary and sedentary workers: 1.00 [reference] and 1.35 [1.11-1.63]), along with longer television viewing time (< 30 min, 30-60 min, 1-2 h, 2-3 h, and > 3 h/day: 1.15 [0.93-1.42], 1.00 [reference], 1.24 [1.00-1.53], 1.41 [1.03-1.93], and 1.77 [1.13-2.76]), whereas not daily exercise time. In females, neither sedentary workers nor television viewing time was associated with the incidence of proteinuria. CONCLUSIONS: In conclusion, male sedentary workers were at high risk of proteinuria. Occupational sedentary behavior may be a potentially modifiable target for the prevention of CKD.

Malignant lymphoma of the cervix in a bicollis uterus considered to be a post-transplant lymphoproliferative disorder in a patient after renal transplantation: A case report.

Post-transplant lymphoproliferative disorder (PTLD) refers to a group of diseases, characterized by abnormal proliferation of lymphocytes, that develop after organ transplantation. PTLD is associated with poor prognosis, and has become a major problem for transplant patients. In this report, we described a case of malignant lymphoma of the cervix in a bicollis uterus considered to be a PTLD in a patient after renal transplantation. The incidence of this disease is expected to increase as the survival rate of transplant patients improves. Hence, it is very important for gynecological oncologists to consider the presence of PTLD when examining such patients.

Frequency of Breakfast, Lunch, and Dinner and Incidence of Proteinuria: A Retrospective Cohort Study.

Although multiple studies have revealed a close association of skipping breakfast with cardiometabolic diseases, few studies have reported its association with chronic kidney disease (CKD). Furthermore, there is scant reporting on the clinical impacts that skipping lunch and dinner has on cardiometabolic diseases and CKD. This retrospective cohort study, including 5439 female and 4674 male workers of a national university in Japan who underwent annual health checkups between January 2005 and March 2013, aimed to assess an association of frequencies of breakfast, lunch, and dinner with incidence of proteinuria (dipstick urinary protein ≥1+). The incidence of proteinuria was observed in 763 (14.0%) females and 617 (13.2%) males during the median 4.3 and 5.9 years of the observational period, respectively. In females, skipping breakfast as well as skipping dinner, but not lunch, were associated with the incidence of proteinuria (adjusted hazard ratios of breakfast frequency of "every day", "sometimes", and "rarely": 1.00 (reference), 1.35 (1.09-1.66), and 1.54 (1.22-1.94), respectively; those of dinner frequency of "every day" and "≤sometimes": 1.00 (reference) and 1.31 (1.00-1.72), respectively). However, no association was observed in male workers. Skipping breakfast and skipping dinner were identified as risk factors of proteinuria in females, but not in males.