The cytosolic lncRNA dutA affects STATa signaling and developmental commitment in Dictyostelium.

STATa is a pivotal transcription factor for Dictyostelium development. dutA is the most abundant RNA transcribed by RNA polymerase II in Dictyostelium, and its functional interplay with STATa has been suggested. This study demonstrates that dutA RNA molecules are distributed as spot-like structures in the cytoplasm, and that its cell type-specific expression changes dramatically during development. dutA RNA was exclusively detectable in the prespore region of slugs and then predominantly localized in prestalk cells, including the organizer region, at the Mexican hat stage before most dutA transcripts, excluding those in prestalk O cells, disappeared as culmination proceeded. dutA RNA was not translated into small peptides from any potential open reading frame, which confirmed that it is a cytoplasmic lncRNA. Ectopic expression of dutA RNA in the organizer region of slugs caused a prolonged slug migration period. In addition, buffered suspension-cultured cells of the strain displayed reduced STATa nuclear translocation and phosphorylation on Tyr702. Analysis of gene expression in various dutA mutants revealed changes in the levels of several STATa-regulated genes, such as the transcription factors mybC and gtaG, which might affect the phenotype. dutA RNA may regulate several mRNA species, thereby playing an indirect role in STATa activation.

Protocol for the 2ND-STEP study, Japan Clinical Oncology Group study JCOG1802: a randomized phase II trial of second-line treatment for advanced soft tissue sarcoma comparing trabectedin, eribulin and pazopanib.

BACKGROUND: Soft tissue sarcomas (STS) are a rare type of malignancy comprising a variety of histological diagnoses. Chemotherapy constitutes the standard treatment for advanced STS. Doxorubicin-based regimens, which include the administration of doxorubicin alone or in combination with ifosfamide or dacarbazine, are widely accepted as first-line chemotherapy for advanced STS. Trabectedin, eribulin, pazopanib, and gemcitabine plus docetaxel (GD), which is the empirical standard therapy in Japan, are major candidates for second-line chemotherapy for advanced STS, although clear evidence of the superiority of any one regimen is lacking. The Bone and Soft Tissue Tumor Study Group of the Japan Clinical Oncology Group (JCOG) conducts this trial to select the most promising regimen among trabectedin, eribulin, and pazopanib for comparison with GD as the test arm regimen in a future phase III trial of second-line treatment for patients with advanced STS. METHODS: The JCOG1802 study is a multicenter, selection design, randomized phase II trial comparing trabectedin (1.2 mg/m2 intravenously, every 3 weeks), eribulin (1.4 mg/m2 intravenously, days 1 and 8, every 3 weeks), and pazopanib (800 mg orally, every day) in patients with unresectable or metastatic STS refractory to doxorubicin-based first-line chemotherapy. The principal eligibility criteria are patients aged 16 years or above; unresectable and/or metastatic STS; exacerbation within 6 months prior to registration; histopathological diagnosis of STS other than Ewing sarcoma, embryonal/alveolar rhabdomyosarcoma, well-differentiated liposarcoma and myxoid liposarcoma; prior doxorubicin-based chemotherapy for STS, and Eastern Cooperative Oncology Group performance status 0 to 2. The primary endpoint is progression-free survival, and the secondary endpoints include overall survival, disease-control rate, response rate, and adverse events. The total planned sample size to correctly select the most promising regimen with a probability of > 80% is 120. Thirty-seven institutions in Japan will participate at the start of this trial. DISCUSSION: This is the first randomized trial to evaluate trabectedin, eribulin, and pazopanib as second-line therapies for advanced STS. We endeavor to perform a subsequent phase III trial comparing the best regimen selected by this study (JCOG1802) with GD. TRIAL REGISTRATION: This study was registered with the Japan Registry of Clinical Trials ( jRCTs031190152 ) on December 5, 2019.

Cyclic AMP induction of Dictyostelium prespore gene expression requires autophagy.

Dictyostelium discoideum amoebas display colonial multicellularity where starving amoebas aggregate to form migrating slugs and fruiting bodies consisting of spores and three supporting cell types. To resolve the cell signalling mechanism that control sporulation, we use insertional mutagenesis of amoebas transformed with fusion constructs of spore genes and red fluorescent protein. We identified the defective gene in a mutant lacking spore gene expression as the autophagy gene Atg7. Directed knock-out of atg7 and of autophagy genes like atg5 and atg9 yielded a similar phenotype, with lack of viable spores and excessive differentiation of stalk cells. The atg7-, atg5- and atg9- cells were specifically defective in cAMP induction of prespore genes, but showed enhanced cAMP stimulation of prestalk genes at the same developmental stage. The lack of prespore gene induction in the autophagy mutants was not due to deleterious effects of loss of autophagy on known components of the cAMP pathway, such as cAMP receptors and their cAMP-induced phosphorylation and internalization, PKA and the transcription factors SpaA and GbfA, or to lack of NH3 production by proteolysis, which was previously suggested to stimulate the spore pathway. Our continued mutagenesis approach is the most likely to yield the intriguing link between autophagy and prespore gene induction.

Phylogeny-wide conservation and change in developmental expression, cell-type specificity and functional domains of the transcriptional regulators of social amoebas.

BACKGROUND: Dictyostelid social amoebas self-organize into fruiting bodies, consisting of spores and up to four supporting cell types in the phenotypically most complex taxon group 4. High quality genomes and stage- and cell-type specific transcriptomes are available for representative species of each of the four taxon groups. To understand how evolution of gene regulation in Dictyostelia contributed to evolution of phenotypic complexity, we analysed conservation and change in abundance, functional domain architecture and developmental regulation of their transcription factors (TFs). RESULTS: We detected 440 sequence-specific TFs across 33 families, of which 68% were upregulated in multicellular development and about half conserved throughout Dictyostelia. Prespore cells expressed two times more TFs than prestalk cells, but stalk cells expressed more TFs than spores, suggesting that gene expression events that define spores occur earlier than those that define stalk cells. Changes in TF developmental expression, but not in TF abundance or functional domains occurred more frequently between group 4 and groups 1-3, than between the more distant branches formed by groups 1 + 2 and 3 + 4. CONCLUSIONS: Phenotypic innovation is correlated with changes in TF regulation, rather than functional domain- or TF acquisition. The function of only 34 TFs is known. Of 12 TFs essential for cell differentiation, 9 are expressed in the cell type for which they are required. The information acquired here on conserved cell type specifity of 120 additional TFs can effectively guide further functional analysis, while observed evolutionary change in TF developmental expression may highlight how genotypic change caused phenotypic innovation.

Late presentation of arrhythmogenic right ventricular cardiomyopathy in an octogenarian associated with a pathogenic variant in the plakophilin 2 gene: a case report.

BACKGROUND: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited myocardial disease characterized by fibrofatty replacement and ventricular arrhythmias. ARVC is believed to be a disease of the young, with most cases being diagnosed before the age of 40 years. We report here a case of newly diagnosed ARVC in an octogenarian associated with a pathogenic variant in the plakophilin 2 gene (PKP2). CASE PRESENTATION: An 80-year-old Japanese man was referred for sustained ventricular tachycardia. His baseline electrocardiogram showed negative T waves in V1-V4. Right ventriculography showed right ventricular aneurysm. Because this case met three major criteria, ARVC was diagnosed. He was successfully treated with radiofrequency ablation and oral amiodarone. Genetic analysis identified an insertion mutation in exon 8 of PKP2 (1725_1728dupGATG), which caused a frameshift and premature termination of translation (R577DfsX5). CONCLUSIONS: To the best of our knowledge, this is the first report of newly diagnosed ARVC in an octogenarian associated with a loss-of-function PKP2 pathogenic variant. Although the late clinical presentation of ARVC is rare, it should be included in the differential diagnosis when treating older patients with ventricular tachyarrhythmias.

Improved overall survival over recent decades in patients with hormone-receptor-positive, HER2-negative breast cancer: a single-center retrospective analysis of prognostic factors.

BACKGROUND: Hormone receptor (HR)-positive HER2-negative breast cancer (BC) rates and associated mortality have been increasing among Japanese women. It is unclear whether the prognosis of these patients has improved. METHODS: We retrospectively analyzed 1806 Japanese women with operable invasive HR-positive HER2-negative BC, who underwent complete resection at the National Cancer Center Hospital East between July 1992 and December 2010. We investigated whether overall survival (OS) and recurrence-free survival (RFS) had improved by comparing the 4-year periods 1992-96, 1997-2001, 2002-06, and 2007-10. The prognostic factors were evaluated using uni- and multivariate analyses. RESULTS: The number of ER- and PgR-positive cancers had increased over the years (P < 0.001). Tumor sizes and numbers of involved lymph nodes both gradually decreased (P < 0.001 for both). OS and RFS of all patients significantly improved in each of the periods analyzed: 5-year OS was 92.6%, 94.8%, 95.4% and 97.6% (P < 0.001, Log-rank), and 5-year RFS was 82.1%, 82.8%, 88.6% and 94.5% (P < 0.001) in 1992-96, 1997-2001, 2002-06 and 2007-10, respectively. In multivariate analysis, the history of adjuvant AI and that of TAM had positive-correlation with RFS. CONCLUSIONS: The prognosis for HR-positive HER2-negative BC patients after surgical therapy has improved, resulting in longer OS and RFS across the study periods. These changes could be associated with early detection of tumor and history of hormone therapy.

The first multicenter, randomized, controlled trial of home telemonitoring for Japanese patients with heart failure: home telemonitoring study for patients with heart failure (HOMES-HF).

Home telemonitoring is becoming more important to home medical care for patients with heart failure. Since there are no data on home telemonitoring for Japanese patients with heart failure, we investigated its effect on cardiovascular outcomes. The HOMES-HF study was the first multicenter, open-label, randomized, controlled trial (RCT) to elucidate the effectiveness of home telemonitoring of physiological data, such as body weight, blood pressure, and pulse rate, for Japanese patients with heart failure (UMIN Clinical Trials Registry 000006839). The primary end-point was a composite of all-cause death or rehospitalization due to worsening heart failure. We analyzed 181 recently hospitalized patients with heart failure who were randomly assigned to a telemonitoring group (n = 90) or a usual care group (n = 91). The mean follow-up period was 15 (range 0-31) months. There was no statistically significant difference in the primary end-point between groups [hazard ratio (HR), 0.95; 95% confidence interval (CI), 0.548-1.648; p = 0.572]. Home telemonitoring for Japanese patients with heart failure was feasible; however, beneficial effects in addition to those of usual care were not demonstrated. Further investigation of more patients with severe heart failure, participation of home medical care providers, and use of a more integrated home telemonitoring system emphasizing communication as well as monitoring of symptoms and physiological data are required.

Multi-scale, tailor-made heart simulation can predict the effect of cardiac resynchronization therapy.

BACKGROUND: The currently proposed criteria for identifying patients who would benefit from cardiac resynchronization therapy (CRT) still need to be optimized. A multi-scale heart simulation capable of reproducing the electrophysiology and mechanics of a beating heart may help resolve this problem. The objective of this retrospective study was to test the capability of patient-specific simulation models to reproduce the response to CRT by applying the latest multi-scale heart simulation technology. METHODS AND RESULTS: We created patient-specific heart models with realistic three-dimensional morphology based on the clinical data recorded before treatment in nine patients with heart failure and conduction block treated by biventricular pacing. Each model was tailored to reproduce the surface electrocardiogram and hemodynamics of each patient in formats similar to those used in clinical practice, including electrocardiography (ECG), echocardiography, and hemodynamic measurements. We then performed CRT simulation on each heart model according to the actual pacing protocol and compared the results with the clinical data. CRT simulation improved the ECG index and diminished wall motion dyssynchrony in each patient. These results, however, did not correlate with the actual response. The best correlation was obtained between the maximum value of the time derivative of ventricular pressure (dP/dtmax) and the clinically observed improvement in the ejection fraction (EF) (r=0.94, p<0.01). CONCLUSIONS: By integrating the complex pathophysiology of the heart, patient-specific, multi-scale heart simulation could successfully reproduce the response to CRT. With further verification, this technique could be a useful tool in clinical decision making.

The effects of collaborative research-based programming on public health nurses and their practice.

The study aim was to evaluate a collaborative research-based program for public health nurses. The program was initiated by a college of nursing to address public health issues. Participants were 33 public health nurses who completed a questionnaire survey; data for 25 respondents were analyzed both quantitatively and qualitatively. To understand the experiences of nurses in depth, three group interviews were conducted with 14 nurses. Qualitative analysis revealed three major themes: (i) opportunities for learning from collaboration; (ii) developing competence of changes in practice; and (iii) openness to continuing practice improvement. Study participants reported practical changes and new openness to continued practice improvement. Thus, schools of nursing and public health nurses should welcome and invite opportunities to collaborate to address practice issues using research-based information. Because changing practice can only occur step by step, nursing educators and practitioners should cultivate an environment that expands professional development and addresses practice improvement.

[Hypertension of old people in frailty].

In older people, the therapeutic importance for hypertension is different from young people because of wide interindividual variability in organ failure or dysfunction. The association with the severity and mortality of hypertension is known to be attenuated by aging Here, we describe the therapeutic strategy for hypertension of old people in frailty.