ASCL1 regulates super-enhancer-associated miRNAs to define molecular subtypes of small cell lung cancer.

Small cell lung cancer (SCLC) is a highly aggressive neuroendocrine tumor with dismal prognosis. Recently, molecular subtypes of SCLC have been defined by the expression status of ASCL1, NEUROD1, YAP1, and POU2F3 transcription regulators. ASCL1 is essential for neuroendocrine differentiation and is expressed in the majority of SCLC. Although previous studies investigated ASCL1 target genes in SCLC cells, ASCL1-mediated regulation of miRNAs and its relationship to molecular subtypes remain poorly explored. Here, we performed genome-wide profiling of chromatin modifications (H3K27me3, H3K4me3, and H3K27ac) by CUT&Tag assay and ASCL1 knockdown followed by RNA sequencing and miRNA array analyses in SCLC cells. ASCL1 could preferentially regulate genes associated with super-enhancers (SEs) defined by enrichment of H3K27ac marking. Moreover, ASCL1 positively regulated several SE-associated miRNAs, such as miR-7, miR-375, miR-200b-3p, and miR-429, leading to repression of their targets, whereas ASCL1 suppressed miR-455-3p, an abundant miRNA in other molecular subtypes. We further elucidated unique patterns of SE-associated miRNAs in different SCLC molecular subtypes, highlighting subtype-specific miRNA networks with functional relevance. Notably, we found apparent de-repression of common target genes of different miRNAs following ASCL1 knockdown, suggesting combinatorial action of multiple miRNAs underlying molecular heterogeneity of SCLC (e.g., co-targeting of YAP1 by miR-9 and miR-375). Our comprehensive analyses provide novel insights into SCLC pathogenesis and a clue to understanding subtype-dependent phenotypic differences.

T-cell lymphoma with a granulomatous lesion of the lungs after autologous hematopoietic stem cell transplantation for Epstein-Barr virus-positive diffuse large B-cell lymphoma: a unique rare case of metachronous B-cell and T-cell lymphoma.

BACKGROUND: Epstein-Barr virus (EBV) is associated with the pathogenesis of a variety of malignancies, most notably lymphomas. Especially in the background of immunodeficiency, such as primary immunodeficiency disorder (PID) and post-transplant lymphoproliferative disorder (PTLD), the role of EBV might be crucial. PIDs are rare heterogeneous diseases affecting the development and/or the function of the innate and adaptive immune system. Malignancy is the second-highest cause of death after infection, and lymphoma accounts for about half of malignancies. The most frequently reported lymphoma type is diffuse large B-cell lymphoma (DLBCL) and the incidence of T-cell lymphoma is rare. PTLDs are also rare serious lymphoid and/or plasmacytic proliferative disorders that occur after undergoing solid organ or hematopoietic stem cell transplantation (HSCT). In the context of HSCT, most reported PTLDs have occurred in patients who received allogenic HSCT, but only a few cases have been reported in autologous HSCT (AutoHSCT) recipients. CASE PRESENTATION: A 53-year-old female patient initially presented with enlargement of the left cervical lymph nodes and was diagnosed with EBV-positive DLBCL. She was treated with R-CHOP, R-ACES, and AutoHSCT and went into remission. Four years later, computed tomography results revealed multiple lung nodules and abnormal infiltration, and sustained and progressing hypogammaglobulinemia was observed. The pathological specimen of video-assisted thoracoscopic surgical lung biopsy demonstrated extensive invasion of lymphocytes with notable granuloma findings. Flow cytometric immunophenotyping analysis showed that lymphocytes were positive for CD3 and CD5; especially, CD3 was expressed in the cytoplasm. Southern blot analysis revealed rearrangements of the T-cell receptor Cß1 gene. She was diagnosed with peripheral T-cell lymphoma, not otherwise specified, accompanied by notable granulomatous lesions. CONCLUSION: Here, as a unique case of metachronous B-cell and T-cell lymphoma, we report a rare case of T-cell lymphoma that mainly affected the lungs with the presentation of notable granulomatous findings following AutoHSCT for EBV-positive DLBCL at the age of 53 years. These lung lesions of granulomatous T-cell lymphoma could be related to the underlying primary immunodeficiency background associated with sustained hypogammaglobulinemia.

Lung-thorax compliance measured during a spontaneous breathing trial is a good index of extubation failure in the surgical intensive care unit: a retrospective cohort study.

BACKGROUND: Extubation failure is associated with mortality and morbidity in the intensive care unit. Ventilator weaning protocols have been introduced, and extubation is conducted based on the results of a spontaneous breathing trial. Room for improvement still exists in extubation management, and additional objective indices may improve the safety of the weaning and extubation process. Static lung-thorax compliance reflects lung expansion difficulty that is caused by several conditions, such as atelectasis, fibrosis, and pleural effusion. Nevertheless, it is not used commonly in the weaning and extubation process. In this study, we investigated whether lung-thorax compliance is a good index of extubation failure in adults even when patients pass a spontaneous breathing trial. METHODS: In a single-center, retrospective cohort study, patients over 18 years of age were mechanically ventilated, weaned with proportional assist ventilation, and underwent a spontaneous breathing trial process in surgical intensive care units of Kagawa University Hospital from July 2014 to June 2016. Extubation failure was the outcome measure of the study. We defined extubation failures as when patients were reintubated or underwent non-invasive positive-pressure ventilation within 24 h after extubation. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the clinical involvement of several parameters. The area under the curve (AUC) was calculated to assess the discriminative power of the parameters. RESULTS: We analyzed 173 patients and compared the success and failure groups. Most patients (162, 93.6%) were extubated successfully, and extubation failed in 11 patients (6.4%). The averages of lung-thorax compliance values in the success and failure groups were 71.9 ± 23.0 and 43.3 ± 14.6 mL/cmH2O, respectively, and were significantly different (p < 0.0001). In the ROC curve analysis, the AUC was highest for lung-thorax compliance (0.862), followed by the respiratory rate (0.821), rapid shallow breathing index (0.781), Acute Physiology and Chronic Health Evaluation II score (0.72), heart rate (0.715), and tidal volume (0.695). CONCLUSIONS: Lung-thorax compliance measured during a spontaneous breathing trial is a potential indicator of extubation failure in postoperative patients.

Effects of low-intensity bodyweight training with slow movement on motor function in frail elderly patients: a prospective observational study.

BACKGROUND: Slow-motion training, an exercise marked by extremely slow movements, yields a training effect like that of a highly intense training, even when the applied load is small. This study evaluated the effects of low-intensity bodyweight training with slow movement on motor function in frail, elderly patients. METHODS: Ninety-seven elderly men and women aged 65 years or older, whose level of nursing care was classified as either support required (1 and 2) or long-term care required (care level 1 and 2), volunteered to participate. Two facilities were used. Participants in the first facility used low-intensity bodyweight training with slow movement (the LST group, n = 65), and participants in another facility used machine training (the control group, n = 31). Exercises were conducted for 3 months, once or twice a week, depending on the required level of nursing care. Changes in motor function were examined. RESULTS: Post-exercise measurements showed significant improvements from the pre-exercise levels after 3 months, based on the results of the Timed Up and Go test (p = 0.0263) and chair-stand test (p = 0.0016) in the low-intensity exercise with slow movement and tonic force generation (LST) group. Although the ability to stand on one leg with eyes open tended to improve, no significant change was found (p = 0.0964). CONCLUSIONS: We confirmed that carrying out LST bodyweight training for 3 months led to improvements in ambulatory function and lower-limb muscle strength. In this way, it is possible that LST training performed by holding a bar or by staying seated on a chair contributes to improved motor function in elderly patients within a short time. TRIAL REGISTRATION: UMIN000030853 . Registered 17 January 2018. (retrospectively registered).

Pulmonary Apical Opacities on Thin-Section Computed Tomography: Relationship to Primary Spontaneous Pneumothorax in Young Male Patients and Corresponding Histopathologic Findings.

OBJECTIVE: The purpose of this study was to test the hypothesis that apical opacities on computed tomography (CT) are related to occurrence of primary spontaneous pneumothorax (PSP) in young male patients. METHODS: We compared the frequency of apical opacities on thin-section CT between 70 male patients with PSP (PSP group) and 74 male patients without a history of PSP (non-PSP group). We also evaluated histopathologic findings of 39 specimens from 37 surgical cases in the PSP group. RESULTS: Apical opacities were significantly more frequent in the PSP group than in the non-PSP group (right side, P = 0.01; left side, P = 0.005). Histopathologically, subpleural band-like alveolar collapse was seen in 35 specimens (89.7%), which was always accompanied by fibroelastosis and fibroblastic foci. CONCLUSIONS: Apical opacities on CT were significantly associated with PSP in young male patients. These apical opacities histopathologically correspond to fibrotic pleural thickening with subpleural alveolar collapse.

Sex differences in attachment to spouses among older Japanese couples.

AIM: Attachment among older adults can partially explain sex differences in bereavement outcomes, but there is currently little evidence regarding this. The aim was to quantify sex differences in the proportion of spouses as attachment figures among older couples. METHODS: We carried out a secondary analysis of cross-sectional questionnaire survey data. The dataset included information about 5137 respondents aged 65 years or older in Kanonji and Mitoyo, two rural cities in Kagawa prefecture, Japan; those who were never married or were widowed or divorced were excluded. The questionnaire asked participants whom they most want to be close by when they die (this person was defined as an "attachment figure"), and compared the proportion of older people of each sex who named their spouse. We used multiple logistic regression analyses to examine the independent association of sex with the proportion of spouses as attachment figures. RESULTS: Of the 2513 male respondents, 1494 (59.5%) answered "spouse." Of the 2624 female respondents, 904 (34.5%) answered "spouse." Multiple logistic regression analyses adjusted for age, live-in children, annual income, participation in community activities, presence of a long-term primary care doctor, anxiety about death and preferences for place of death showed that men had a higher probability of attachment to spouses than women (odds ratio 2.83, 95% confidence interval 2.43-3.31). CONCLUSIONS: Spouses are more likely to be attachment figures for men than for women. The present study supports the theory that sex differences in attachment might partially explain the differences in the bereavement effect between sexes among older people. Geriatr Gerontol Int 2017; 17: 834-838.

An explicit signature of balancing selection for color-vision variation in new world monkeys.

Color vision is an important characteristic of primates and, intriguingly, Neotropical monkeys are highly polymorphic for this trait. Recent field studies have challenged the conventional view that trichromatic color vision is more adaptive than dichromatic color vision. No study has investigated the pattern of genetic variation in the long to middle wavelength-sensitive (L-M or red-green) opsin gene as compared with that of other genomic regions (neutral references) in wild populations of New World monkeys to look for the signature of natural selection. Here, we report such a study conducted on spider monkeys and capuchin monkeys inhabiting Santa Rosa National Park, Costa Rica. The nucleotide sequence of the L-M opsin gene was more polymorphic than the sequences of the neutral references, although the opsin-gene sequences were not more divergent between the two species than were the sequences of the neutral references. In a coalescence simulation that took into account the observed nucleotide diversity of the neutral references, the Tajima's D value of the L-M opsin gene deviated significantly in a positive direction from the expected range. These results are the first to statistically demonstrate balancing selection acting on the polymorphic L-M opsin gene of New World monkeys. Taking the results of behavioral and genetic studies together, the balancing selection we detected may indicate that coexistence of different color-vision types in the same population, also characteristic of humans, is adaptive.

[Reappraisal of perioperative fluid therapy in children].

Two recently recognized issues are reviewed ; one is a hospital acquired hyponatremia in children treated with intravenous hypotonic maintenance fluids and the other is the pros and cons of glucose addition to these fluids. Children in the perioperative period are at risk for nonosmotic secretion of ADH and stress-induced insulin resistance, which necessitate reducing the volume of maintenance fluid to half the previously recommended volume, and the concentration of additive glucose to approximately 2%. While isotonic fluids are recommended intraoperatively, controversies still exist on the constitution of maintenance fluids in the postoperative period, where the choice of an isotonic solution should be more pertinent to that of a hypotonic solution, but evidence is weak ; further investigations are needed to make a decision.