A Case of Idiopathic Multicentric Castleman's Disease Diagnosed From Anemia and Renal Dysfunction on an Annual Check-Up.

A 34-year-old man was referred to our hospital because of mild renal dysfunction and anemia. He had no specific preexisting medical conditions; his complaint was fatigue. Physical examination revealed several mobile, pinky head-sized (no tenderness) palpable lymph nodes on the bilateral neck. Blood biochemistry tests revealed anemia, renal dysfunction, increased inflammation, and a protein-albumin discrepancy. Immunological examination revealed polyclonal elevation of immunoglobulins (no shift in κ/λ ratio). A cervical lymph node biopsy was performed, and the pathological results showed numerous clusters of mature plasma cells (plasmacytic type), leading to the definitive diagnosis of idiopathic multicentric Castleman's disease (iMCD).

Chondroitin sulfate modification of CSPG4 regulates the maintenance and differentiation of glioma-initiating cells via integrin-associated signaling.

Glioma stem cell/glioma-initiating cell (GIC) and their niches are considered responsible for the therapeutic resistance and recurrence of malignant glioma. To clarify the molecular mechanisms of GIC maintenance/differentiation, we performed a unique integrated proteogenomics utilizing GIC clones established from patient tumors having the potential to develop glioblastoma. After the integration and extraction of the transcriptomics/proteomics data, we found that chondroitin sulfate proteoglycan 4 (CSPG4) and its glycobiosynthetic enzymes were significantly upregulated in GICs. Glyco-quantitative PCR array revealed that chondroitin sulfate (CS) biosynthetic enzymes, such as xylosyltransferase 1 (XYLT1) and carbohydrate sulfotransferase 11, were significantly downregulated during serum-induced GIC differentiation. Simultaneously, the CS modification on CSPG4 was characteristically decreased during the differentiation and also downregulated by XYLT1 knockdown. Notably, the CS degradation on CSPG4 by ChondroitinaseABC treatment dramatically induced GIC differentiation, which was significantly inhibited by the addition of CS. GIC growth and differentiation ability were significantly suppressed by CSPG4 knockdown, suggesting that CS-CSPG4 is an important factor in GIC maintenance/differentiation. To understand the molecular function of CS-CSPG4, we analyzed its associating proteins in GICs and found that CSPG4, but not CS-CSPG4, interacts with integrin αV during GIC differentiation. This event sequentially upregulates integrin-extracellular signal-regulated kinase signaling, which can be inhibited by cyclic-RGD (Arg-Gly-Asp) integrin αV inhibitor. These results indicate that CS-CSPG4 regulates the GIC microenvironment for GIC maintenance/differentiation via the CS moiety, which controls integrin signaling. This study demonstrates a novel function of CS on CSPG4 as a niche factor, so-called "glyco-niche" for GICs, and suggests that CS-CSPG4 could be a potential target for malignant glioma.

Early mortality of emergency surgery for acute type A aortic dissection in octogenarians and nonagenarians: A multi-center retrospective study.

OBJECTIVES: The clinical data on postoperative mortality and central nervous system (CNS) complications in older adults who underwent acute type A aortic dissection are limited. Thus, in this study we aimed to evaluate the association between age and early postoperative mortality and occurrence of CNS complications. METHODS: This multicentric retrospective cohort study included 5 tertiary hospitals in Japan. All patients who underwent emergency surgery for acute type A aortic dissection between October 1998 and December 2019 were enrolled. The multilevel Cox proportional hazards model, which considered years as level 1, institutions as level 2, and surgeons as level 3, was used to evaluate the association between age and early postoperative hospital mortality and occurrence of CNS complications. RESULTS: Of the 1037 patients, 227 (21.9%) were ≥80 years old and 810 (78.1%) were <80 years old. Overall, 134 patients (12.9%) died within 30 days postoperatively; among them, 42/227 (18.5%) and 92/810 (11.4%) were aged ≥80 and <80 years, respectively (hazard ratio [HR], 1.63; P = .0046). CNS complications within 30 days postoperatively occurred in 140/1037 (13.5%) patients; among them, 42/227 (18.5%) and 98/810 (12.1%) were aged ≥80 and <80 years, respectively (HR, 1.63; P = .011). In multivariate analysis, age ≥80 years was associated with mortality within 30 days postoperatively (adjusted HR, 2.37; 95% CI, 1.23-4.57; P = .01) but not with CNS complications (adjusted HR, 1.58; 95% CI, 0.93-2.69; P = .091). CONCLUSIONS: The early postoperative mortality in older patients was approximately 50% higher than in the younger population. A thorough discussion regarding the surgical indications should be done.

Inverse agonism of lysophospholipids with cationic head groups at Gi-coupled receptor GPR82.

GPR82 is an orphan G protein-coupled receptor (GPCR) that has been implicated in lipid storage in mouse adipocytes. However, the intracellular signaling as well as the specific ligands of GPR82 remain unknown. GPR82 is closely related to GPR34, a GPCR for the bioactive lipid molecule lysophosphatidylserine. In this study, we screened a lipid library using GPR82-transfected cells to search for ligands that act on GPR82. By measuring cyclic adenosine monophosphate levels, we found that GPR82 is an apparently constitutively active GPCR that leads to Gi protein activation. In addition, edelfosine (1-O-octadecyl-2-O-methyl-sn-glycero-3-phosphocholine), an artificial lysophospholipid with a cationic head group that exerts antitumor activity, inhibited the Gi protein activation by GPR82. Two endogenous lysophospholipids with cationic head groups, lysophosphatidylcholine (1-oleoyl-sn-glycero-3-phosphocholine) and lysophosphatidylethanolamine (1-oleoyl-sn-glycero-3-phosphoethanolamine), also exhibited GPR82 inhibitory activity, albeit weaker than edelfosine. Förster resonance energy transfer imaging analysis consistently demonstrated that Gi protein-coupled GPR82 has an apparent constitutive activity that is edelfosine-sensitive. Consistent data were obtained from GPR82-mediated binding analysis of guanosine-5'-O-(3-thiotriphosphate) to cell membranes. Furthermore, in GPR82-transfected cells, edelfosine inhibited insulin-induced extracellular signal-regulated kinase activation, like compounds that function as inverse agonists at other GPCRs. Therefore, edelfosine is likely to act as an inverse agonist of GPR82. Finally, GPR82 expression inhibited adipocyte lipolysis, which was abrogated by edelfosine. Our findings suggested that the cationic lysophospholipids edelfosine, lysophosphatidylcholine and lysophosphatidylethanolamine are novel inverse agonists for Gi-coupled GPR82, which is apparently constitutively active, and has the potential to exert lipolytic effects through GPR82.

Bioinformatic Identification of Potential RNA Alterations on the Atrial Fibrillation Remodeling from Human Pulmonary Veins.

Atrial fibrillation (AF) is the most frequent persistent arrhythmia. Many genes have been reported as a genetic background for AF. However, most transcriptome analyses of AF are limited to the atrial samples and have not been evaluated by multiple cardiac regions. In this study, we analyzed the expression levels of protein-coding and long noncoding RNAs (lncRNAs) in six cardiac regions by RNA-seq. Samples were donated from six subjects with or without persistent AF for left atria, left atrial appendages, right atria, sinoatrial nodes, left ventricles, right ventricles, and pulmonary veins (PVs), and additional four right atrial appendages samples were collected from patients undergoing mitral valve replacement. In total, 23 AF samples were compared to 23 non-AF samples. Surprisingly, the most influenced heart region in gene expression by AF was the PV, not the atria. The ion channel-related gene set was significantly enriched upon analysis of these significant genes. In addition, some significant genes are cancer-related lncRNAs in PV in AF. A co-expression network analysis could detect the functional gene clusters. In particular, the cancer-related lncRNA, such as SAMMSON and FOXCUT, belong to the gene network with the cancer-related transcription factor FOXC1. Thus, they may also play an aggravating role in the pathogenesis of AF, similar to carcinogenesis. In the least, this study suggests that (1) RNA alteration is most intense in PVs and (2) post-transcriptional gene regulation by lncRNA may contribute to the progression of AF. Through the screening analysis across the six cardiac regions, the possibility that the PV region can play a role other than paroxysmal triggering in the pathogenesis of AF was demonstrated for the first time. Future research with an increase in the number of PV samples will lead to a novel understanding of the pathophysiology of AF.

Radiation-induced angiosarcoma of the breast: individual participant meta-analysis of Japanese population.

BACKGROUND: Radiation-induced angiosarcoma (RIAS) of the breast is a very rare and poor prognostic disease. According to previous studies, the efficacy of chemotherapy for RIAS is still controversial. However, no study has assessed the prognosis of RIAS and the prognostic impact of preoperative or postoperative chemotherapy in Japanese patients. Our study aimed to assess them in Japanese people using publication data with our three patients. METHODS: Thirty-nine patients diagnosed with RIAS, including 36 patients from 34 published case series, and three patients from our hospital were used for analysis. Disease-free survival (DFS), distant disease-free survival (DDFS), and overall survival (OS) were assessed. RESULTS: Among the 39 patients, 36 patients (92.3%) underwent surgery. The median DFS and OS periods were 14 months (range 1-75 months) and 23 months (range 4-84 months), respectively. Chemotherapy with taxane-based regimen was administered in 13 cases (33.2%) pre- or post-operatively. DFS was significantly improved with chemotherapy in addition to surgery (p = 0.037). However, addition of chemotherapy to surgery did not improve DDFS (p = 0.09) and OS (p = 0.878). In multivariate analysis, age ≥ 70 years was an independent but poor prognostic factor of DFS. Additionally, a lack of chemotherapy showed a trend to be associated with worse DFS. There was no independent variable contributing to DDFS and OS. CONCLUSIONS: Chemotherapy may have reduced the recurrence rate of RIAS in Japanese patients but did not improve OS. Further data are needed to confirm the efficacy and proper regimen of chemotherapy.

Liver injury indicators and subsequent cancer development among non-fatty liver population.

BACKGROUND: Little is known about the association between liver indicators (The FIB-4 index, nonalcoholic fatty liver disease fibrosis score (NFS), and fatty liver index (FLI)) and cancer development in patients without preexisting liver disease. METHODS: We conducted a retrospective cohort study with participants who underwent voluntary health checkups and without fatty liver between 2005 and 2018. Our primary outcome was the development of any type of cancer, and its association with each liver indicator was evaluated. RESULTS: A total of 69,592 participants (mean age: 43.9 years, 29,984 (43.1%) were men) were included. During a median follow-up of 5.1 years, 3779 (5.4%) patients developed cancer. Compared to participants with a low NFS, those with a medium NFS had a higher risk of developing any type of cancer (adjusted hazard ratio [HR]: 1.18, 95% confidence interval [CI]: 1.07-1.31), whereas those with a medium FIB-4 index had a decreased risk of developing any type of cancer compared to those with a low FIB-4 index (adjusted HR: 0.91, 95% CI: 0.83-0.99). Patients with higher scores tended to have a higher risk of digestive organ cancer, regardless of the indicator. A high FLI was also associated with an increased risk of breast cancer (adjusted HR: 2.42, 95% CI: 1.24-4.71); however, those with a medium FIB-4 index (adjusted HR: 0.65, 95% CI: 0.52-0.81) and NFS (adjusted HR: 0.50, 95% CI: 0.35-0.72) had decreased risks of developing breast cancer compared to those with a high FIB-4 index and NFS, respectively. CONCLUSION: Among patients without fatty liver, a higher liver indicator score was associated with an increased risk of cancer in the digestive organs, regardless of the indicator. Notably, those with a medium FIB-4 index or NFS had a lower risk of developing breast cancer, whereas those with a medium FLI had an increased risk.

Theilovirus 3C Protease Cleaves the C-Terminal Domain of the Innate Immune RNA Sensor, Melanoma Differentiation-Associated Gene 5, and Impairs Double-Stranded RNA-Mediated IFN Response.

Melanoma differentiation-associated gene 5 (MDA5), a member of the retinoic acid-inducible gene I (RIG-I)-like receptors (RLRs), has pivotal roles in innate immune responses against many positive-stranded RNA viruses, including picornavirus and coronavirus. Upon engagement with dsRNA derived from viral infection, MDA5 initiates coordinated signal transduction leading to type I IFN induction to restrict viral replication. In this study, we describe a targeted cleavage events of MDA5 by the 3C protease from Theilovirus. Upon ectopic expression of theilovirus 3C protease from Saffold virus or Theiler's murine encephalomyelitis virus but not encephalomyocarditis virus, fragments of cleaved MDA5 were observed in a dose-dependent manner. When enzymatically inactive Theilovirus 3C protease was expressed, MDA5 cleavage was completely abrogated. Mass spectrometric analysis identified two cleavage sites at the C terminus of MDA5, cleaving off one of the RNA-binding domains. The same cleavage pattern was observed during Theilovirus infection. The cleavage of MDA5 by Theilovirus protease impaired ATP hydrolysis, RNA binding, and filament assembly on RNA, resulting in dysfunction of MDA5 as an innate immune RNA sensor for IFN induction. Furthermore, the cleavage-resistant MDA5 mutant against the 3C protease showed an enhanced IFN response during Saffold virus infection, indicating that Theilovirus has a strategy to circumvent the antiviral immune response by cleaving MDA5 using 3C protease. In summary, these data suggest MDA5 cleavage by 3C protease as a novel immune evasive strategy of Theilovirus.

Impact of a continuous quality improvement program on contrast-induced nephropathy in outpatients with chronic kidney disease: an interrupted time-series study.

BACKGROUND: Contrast-induced nephropathy (CIN) caused by exposure to radioactive contrast media can cause acute kidney injury in patients with chronic kidney disease (CKD). We developed a multifaceted approach in a CIN-quality improvement (QI) program based on a shorter saline hydration protocol for the prevention of CIN in outpatients and assessed the effect of our CIN-QI program on decreasing both the incidence rate of CIN and overall use of contrast agents in patients undergoing contrast-enhanced computed tomography (CT). METHODS: We conducted a multi-center prospective interrupted time-series study from 2006 to 2018 investigating the efficacy of a CIN-QI program in preventing CIN among outpatients with CKD. An automatic medical record system alert was implemented to instruct physicians to consult a nephrologist and administer prophylactic hydration and follow-up when ordering contrast-enhanced imaging in patients with an estimated glomerular filtration rate (eGFR) <45 mL/min/1.73 m2. The primary outcomes were the rates of prophylactic hydration and follow-up kidney function assessment, and the incidence of CIN for eligible patients. The usage rate of contrast-enhanced CT was also examined. RESULTS: A total of 95 594 patients who underwent contrast-enhanced CT were included in the study. The annual prophylactic hydration rate before the CIN-QI program ranged from 2.0% to 23.2% but increased to 59.2%-75.2% during the CIN-QI program (P < .001). The annual rate of follow-up kidney function testing also improved from 18.6%-25.8% to 34.1%-42.5% after implementation of the CIN-QI program (P < .001). The rate of CIN significantly declined in level by 10.0% at the start of the CIN-QI program (P = .002) and in trend by 2.9%/year (P < .001). The number of contrast-enhanced CT orders showed a positive level change in patients with advanced CKD, who were the CIN-QI program target group of patients with eGFR <45 mL/min/1.73 m2, at the start of the implementation of the CIN-QI program. After implementing the CIN-QI program, the number of contrast-enhanced CT orders showed a negative trend change across all patients, which decreased from -1.4%/year to -10.0%/year for patients with advanced CKD. CONCLUSION: The multifaceted approach in the CIN-QI program may be associated with the decreased incidence of CIN and increased rates of prophylactic hydration and follow-up kidney function testing.

AT-hook DNA-binding motif-containing protein one knockdown downregulates EWS-FLI1 transcriptional activity in Ewing's sarcoma cells.

Ewing's sarcoma is the second most common bone malignancy in children or young adults and is caused by an oncogenic transcription factor by a chromosomal translocation between the EWSR1 gene and the ETS transcription factor family. However, the transcriptional mechanism of EWS-ETS fusion proteins is still unclear. To identify the transcriptional complexes of EWS-ETS fusion transcription factors, we applied a proximal labeling system called BioID in Ewing's sarcoma cells. We identified AHDC1 as a proximal protein of EWS-ETS fusion proteins. AHDC1 knockdown showed a reduced cell growth and transcriptional activity of EWS-FLI1. AHDC1 knockdown also reduced BRD4 and BRG1 protein levels, both known as interacting proteins of EWS-FLI1. Our results suggest that AHDC1 supports cell growth through EWS-FLI1.

SPP1 Derived from Macrophages Is Associated with a Worse Clinical Course and Chemo-Resistance in Lung Adenocarcinoma.

Osteopontin, also called secreted phosphoprotein 1 (SPP1), is a multifunctional secreted phosphorylated glycoprotein. SPP1 is also expressed in tumor cells, and many studies demonstrated that a high level of circulating SPP1 is correlated with a poor prognosis in various cancers. SPP1 is expressed not only by tumor cells but also by stromal cells, such as macrophages. However, there have been no studies distinguishing the SPP1 expression of cancer cells and tumor-associated macrophages (TAMs). Thus, in this study, we tried to accurately evaluate the SPP1 expression status on cancer cells and TAMs separately in patients with non-small cell lung cancer by using double immunohistochemistry. We demonstrated that high SPP1 expression on TAMs predicted a poor prognosis in lung adenocarcinoma patients. Additionally, we investigated the expression mechanisms related to SPP1 using human-monocyte-derived macrophages and revealed that the SPP1 expression level increased in macrophage differentiation mediated by granulocyte-macrophage colony-stimulating factor. Furthermore, SPP1 contributed to anti-cancer drug resistance in lung cancer cell lines. In conclusion, SPP1 production on TAMs predicted a poor prognosis in lung adenocarcinoma patients, and TAM-derived SPP1's involvement in the chemo-resistance of cancer cells was suggested.

Water Droplet-in-Oil Digestion Method for Single-Cell Proteomics.

Recent advances in single-cell proteomics highlight the promise of sensitive analyses in limited cell populations. However, technical challenges remain for sample recovery, throughput, and versatility. Here, we first report a water droplet-in-oil digestion (WinO) method based on carboxyl-coated beads and phase transfer surfactants for proteomic analysis using limited sample amounts. This method was developed to minimize the contact area between the sample solution and the container to reduce the loss of proteins and peptides by adsorption. This method increased protein and peptide recovery 10-fold. The proteome profiles obtained from 100 cells using the WinO method highly correlated with those from 10,000 cells using the in-solution digestion method. We successfully applied the WinO method to single-cell proteomics and quantified 462 proteins. Using the WinO method, samples can be easily prepared in a multi-well plate, making it a widely applicable and suitable method for single-cell proteomics.

Does breast-conserving surgery with radiotherapy in BRCA-mutation carriers significantly increase ipsilateral breast tumor recurrence? A systematic review and meta-analysis.

BACKGROUND: Breast-conserving surgery (BCS) is often preferred for localized, small breast cancers, but its safety and efficacy in BRCA-mutation carriers is still controversial. This meta-analysis aimed to determine whether there was any significant difference in the incidence of ipsilateral breast tumor recurrence (IBTR) between BRCA-mutation carriers who underwent BCS and controls with sporadic breast cancer. METHODS: A PubMed search was conducted through March 2020 to identify studies examining the risk of IBTR after BCS in BRCA-mutation carriers versus controls. The Cochrane risk-of-bias tool was used to assess the risk of bias. The pooled risk ratio (RR) was calculated using the random-effects model. RESULTS: Thirteen studies involving 701 BRCA-mutation carriers and 4788 controls in total were eventually analyzed. In the meta-analysis, IBTR after BCS was significantly higher in BRCA-mutation carriers (RR: 1.589; 95% confidence interval (CI) 1.247-2.024; P < 0.001). Subgroup analysis of the follow-up time found that the RR for IBTR increased as the observation period lengthened (median follow-up: ≧ 7 years [RR: 1.505; 95% CI 1.184-1.913] and ≧ 10 years [RR: 1.601; 95% CI 1.201-2.132], respectively). However, a qualitative meta-analysis of overall survival in three cohort studies found no evidence to suggest a deterioration in overall survival in patients with BCS. CONCLUSIONS: The present study demonstrated that BRCA-mutation carriers with BCS have a higher risk of IBTR, which tended to persist for a long period and become more apparent with longer observation.

Comparison in the development of colorectal cancer after screening colonoscopy between elderly and younger population.

BACKGROUND AND AIMS: This study aimed to evaluate and compare the incidence of colorectal cancer (CRC) in elderly participants aged ≥75 years and those <75 years who had previously undergone a colonoscopy. METHODS: This retrospective cohort study was conducted at the Center for Preventive Medicine at St. Luke's International Hospital in Japan. All participants who underwent screening colonoscopy between 2005 and 2015 were included and followed up until 2020. Our primary outcome was the identification of CRC as confirmed by pathology after screening colonoscopy. We compared the development of CRC between the two groups using survival analyses. A sub-analysis to evaluate the incidence of CRC among participants with and without neoplastic polyp resection at initial colonoscopy was also performed. RESULTS: A total of 8350 participants were enrolled; the median follow-up period was 2982 days (interquartile range:1932-4141), mean age was 52.5 years (SD: 11.5) and 5274 (61.3%) participants were men. The incidence of CRC during the follow-up period was 82 (0.95%) among all participants and 11 (4.31%) among the elderly participants. Elderly participants showed a significantly higher incidence of CRC than the other group [hazard ratio, 2.56; 95% confidence interval (CI), 1.14-5.75]. The sub-analysis showed that out of 2878 participants with a neoplastic polyp at the initial colonoscopy, 52 (1.81%) developed CRC (hazard ratio, 2.85; 95% CI, 1.16-6.98). CONCLUSIONS: A repeat colonoscopy might be warranted in people with high activities of daily living and few comorbidities, especially if there is a history of neoplastic polypectomy at the first colonoscopy.

Efficacy of awake prone positioning for severe illness coronavirus disease 2019 patients: a propensity score-adjusted cohort study.

AIM: Awake prone positioning (PP) in patients with coronavirus disease 2019 (COVID-19) can improve oxygenation. However, evidence showing that it can prevent intubation is lacking. This study investigated the efficacy of awake PP in patients with COVID-19 who received remdesivir, dexamethasone, and anticoagulant therapy. METHODS: This was a two-center cohort study. Patients admitted to the severe COVID-19 patient unit were included. The primary outcome was the intubation rate and secondary outcome was length of stay in the severe COVID-19 unit. After propensity score adjustment, we undertook multivariable regression to calculate the estimates of outcomes between patients who received awake PP and those who did not. RESULTS: Overall, 108 patients were included (54 [50.0%] patients each who did and did not undergo awake PP), of whom 25 (23.2%) were intubated (with awake PP, 5 [9.3%] vs. without awake PP, 20 [37.0%]; P < 0.01). The median length of stay in the severe COVID-19 unit did not significantly differ (with awake PP, 5 days vs. without awake PP, 5.5 days; P = 0.68). After propensity score adjustment, those who received awake PP had a lower intubation rate than those who did not (odds ratio, 0.22; 95% confidence interval, 0.06-0.85; P = 0.03). Length of stay in the severe COVID-19 patient unit did not differ significantly (adjusted percentage difference, -24.4%; 95% confidence interval, -56.3% to 30.8%; P = 0.32). CONCLUSION: Awake PP could be correlated with intubation rate in patients with COVID-19 who are receiving remdesivir, dexamethasone, and anticoagulant therapy.

Frequency of tooth brushing as a predictive factor for future kidney function decline.

BACKGROUND: Tooth brushing is important for maintaining oral health and preventing periodontal diseases (PDs), which commonly arise in patients with chronic kidney disease (CKD). However, the association between tooth brushing frequency and kidney function decline remains unclear. METHODS: We conducted a retrospective longitudinal study at St Luke's International Hospital, Japan, and participants who underwent health examinations at the Centre for Preventive Medicine from 2005 to 2011 were included. Participants' tooth brushing frequencies were assessed; multivariate analyses were conducted using a generalized estimating equation to evaluate the association between tooth brushing frequency and a composite renal outcome-composed of a 25% estimated glomerular filtration rate (eGFR) reduction, an eGFR of < 15 mL/min/1.73 m2, and a requirement for regular dialysis-after adjusting for potential covariates. We also stratified participants by baseline CKD risk category to perform sub-analyses. RESULTS: Overall, 76,472 participants were included (mean age of 45.9 years) and 38,233 (50%) were male. During follow-up, 8219 participants (10.8%) experienced composite renal outcomes. Brushing teeth at least once to twice a day was associated with significantly lower incidences of composite renal outcomes than brushing teeth less frequently (adjusted odds ratio [OR] 0.26; 95% confidence interval [CI] 0.24-0.28 for once to twice a day; adjusted OR 0.65; 95% CI 0.62-0.69 for after every meal). In our sub-analyses, brushing at least once to twice a day related to a decreased likelihood of composite renal outcomes; however, this effect was only observed within the low and moderate baseline risk groups. CONCLUSION: Frequent tooth brushing benefits oral health and may be associated with slower kidney function decline, which could have implications for other systemic diseases. However, a longitudinal cohort study is required to confirm whether tooth brushing and overall oral health can haver a role in improving  renal outcomes.

Both increased and decreased sleep duration over time are associated with subsequent cancer development.

PURPOSE: Changes in sleep duration have been reported to correlate with lifestyle-related diseases in humans. However, equivalent studies regarding the effects of sleep on cancer progression are lacking. This study aimed to determine whether or not increase or decrease in sleep duration over time is associated with subsequent cancer development. METHODS: A large-scale, retrospective cohort study was conducted at a preventive medicine health center at a general community hospital in Tokyo, Japan. All participants who underwent health checkups at the hospital between January 2005 and December 2018 were included. The primary study outcome was development of any type of cancer according to the slope of sleep duration over the study period. The Cox proportional hazard model was used to adjust the outcomes based on potential covariates. RESULTS: Of 15,025 participants, 7,692 (51.2%) were men. The mean age (standard deviation) was 66.0 (7.5) years. During a median follow-up of 2,588 (interquartile range: 1,583-3,695) days, 1,396 (9.3%) participants developed cancer of any type. Compared to hazard ratio in the stable sleep duration group (- 0.1 to + 0.1 h/day in 1 year), both greatly decreased (less than - 0.2 h/day in 1 year; hazard ratio (HR), 2.13; 95% confidence interval (CI), 1.72-2.62) and increased (more than + 0.2 h/day in 1 year; HR, 2.55; 95% CI 2.14-3.04) groups showed significantly higher hazard ratio for the development of any type of cancer. CONCLUSION: Both increased and decreased sleep duration over time are associated with subsequent cancer development.

Aspartate aminotransferase/alanine aminotransferase ratio and subsequent cancer development.

BACKGROUND: We aimed to evaluate the association between the aspartate aminotransferase (AST)/alanine aminotransferase (ALT) ratio and subsequent development of any type of cancer in an apparently healthy population. METHODS: We conducted a retrospective cohort study at St. Luke's International Hospital, Tokyo, Japan between 2005 and 2018. All participants who visited for voluntary health checkups were included. We divided the participants into different quintiles based on the baseline AST/ALT ratios and examined the outcomes. RESULTS: A total of 85,658 participants were included. The mean age was 44.7 years (standard deviation 12.0) at baseline, and 42,913 (50.1%) of them were men. During a median follow-up of 61.6 months, 4701 (5.5%) participants developed some type of cancer. Compared with the middle AST/ALT ratio group, no other groups had similar adjusted hazard ratios (HR) for the development of any type of cancer in both men and women. When stratified by alcohol consumption, very high (adjusted HR 1.36; 95% CI 1.13-1.63) and high (adjusted HR 1.26; 95% CI 1.05-1.50) AST/ALT ratio groups among men who were regular drinkers had increased adjusted HRs for any type of cancer development, but the very high AST/ALT ratio group among men who were abstainers (adjusted HR 0.64; 95% CI 0.42-0.97) and very low AST/ALT ratio group among men who were occasional drinkers (adjusted HR 0.69; 95% CI 0.48-0.98) had lower adjusted HRs compared with the middle AST/ALT ratio group. Among women, regardless of alcohol consumption, adjusted HR for any type of cancer development was similar across all AST/ALT ratio groups. CONCLUSION: People with higher AST/ALT ratios tended to have a higher risk of developing any type of cancer among men who were regular drinkers, but this risk was lower among men who were abstainers. Among women, regardless of alcohol consumption, there was no association between the development of any type of cancer and AST/ALT ratio.

Association Between Antidiarrheal Drug Prescription and Return Visits Among Adult Patients With Acute Diarrhea.

Whether antidiarrheal medications have benefits or demerits when administered to adult patients with diarrhea remains controversial. We aimed to evaluate the association between antidiarrheal drug prescription and clinical outcomes in adult patients with acute diarrhea. This retrospective cohort study was conducted by collecting secondary data of patients' health records at St. Luke's International Hospital from April 1, 2004, to March 31, 2016. We included all participants aged 20-59 years who visited the division of general internal medicine or the emergency room in the hospital due to acute diarrheal symptoms. We excluded those who had chronic diarrhea or were immunocompromised (e.g., those with cancer or immunosuppressant usage). Our primary outcome was return visits within two weeks; the secondary outcome was admission to the hospital due to acute diarrhea within two weeks from the first visit. We compared the outcomes between patients with and without antidiarrheal drug prescriptions.  During the study period, a total of 10,246 patients were included, of which 204 (2.0%) were prescribed antidiarrheal drugs. The mean age of the patients was 35.0 (standard deviation: 10.7) years, and 4,130 (40.3%) were men. Patients who were prescribed antidiarrheal drugs were more likely to be prescribed antibiotics (p<0.01). The adjusted odds ratios for return visits among patients with and without antidiarrheal drug prescription were 1.24-1.59, which were not significant. We demonstrated that antidiarrheal drug prescription was not associated with return visits or hospital admission among adult patients with acute diarrhea. This finding suggests that antidiarrheal medications have more benefits than risks in adult patients with acute diarrhea.

HEATR1, a novel interactor of Pontin/Reptin, stabilizes Pontin/Reptin and promotes cell proliferation of oral squamous cell carcinoma.

Pontin and Reptin are closely related proteins belonging to the AAA+ (ATPases Associated with various cellular Activities) family. They form a hetero-oligomeric complex, Pontin/Reptin, which is involved in protein stability and assembly of the protein complexes as a molecular chaperone. Overexpression of Pontin and Reptin in tumor cells has been reported and is implicated in the development of various cancers. However, the molecular mechanism of Pontin/Reptin function in oral squamous cell carcinoma (OSCC) development remains unclear. Here, we identify HEAT repeat-containing protein 1 (HEATR1) as a novel binding factor of Pontin/Reptin. Functionally, HEATR1 stabilizes Pontin/Reptin and positively regulates OSCC cell proliferation by activating mTOR and pre-rRNA synthesis. We also find that HEATR1 expression is markedly upregulated in tumor region of OSCC tissue. Hence, we propose that HEATR1 is involved in the regulation of mTOR and ribosome biogenesis as a potential protein stabilizer of Pontin/Reptin in OSCC.