Human Hematopoietic Stem Cells Can Survive In Vitro for Several Months

We previously reported that long-lasting in vitro hematopoiesis could be achieved using the cells differentiated from primate embryonic stem (ES) cells. Thus, we speculated that hematopoietic stem cells differentiated from ES cells could sustain long-lasting in vitro hematopoiesis. To test this hypothesis, we investigated whether human hematopoietic stem cells could similarly sustain long-lasting in vitro hematopoiesis in the same culture system. Although the results varied between experiments, presumably due to differences in the quality of each hematopoietic stem cell sample, long-lasting in vitro hematopoiesis was observed to last up to nine months. Furthermore, an in vivo analysis in which cultured cells were transplanted into immunodeficient mice indicated that even after several months of culture, hematopoietic stem cells were still present in the cultured cells. To the best of our knowledge, this is the first report to show that human hematopoietic stem cells can survive in vitro for several months

Versican is induced in infiltrating monocytes in myocardial infarction

Versican, a large chondroitin sulfate proteoglycan, plays a role in conditions such as wound healing and tissue remodelling. To test the hypothesis that versican expression is transiently upregulated and plays a role in the infarcted heart, we examined its expression in a rat model of myocardial infarction. Northern blot analysis demonstrated increased expression of versican mRNA. Quantitative real-time RT-PCR analysis revealed that versican mRNA began to increase as early as 6 h and reached its maximal level 2 days after coronary artery ligation. Versican mRNA then gradually decreased, while the mRNA of decorin, another small proteoglycan, increased thereafter. Versican mRNA was localized in monocytes, as indicated by CD68-positive staining, around the infarct tissue. The induction of versican mRNA was accelerated by ischemia/reperfusion (I/R), which was characterized by massive cell infiltration and enhanced inflammatory response. To examine the alteration of versican expression in monocytes/macrophages, we isolated human peripheral blood mononuclear cells and stimulated them with granulocyte/macrophage colony-stimulating factor (GM-CSF). Stimulation of mononuclear cells with GM-CSF increased the expression of versican mRNA as well as cytokine induction. The production of versican by monocytes in the infarct area represents a novel finding of the expression of an extracellular matrix gene by monocytes in the infarcted heart. We suggest that upregulation of versican in the infarcted myocardium may have a role in the inflammatory reaction, which mediates subsequent chemotaxis in the infarcted heart

Randomized trial of an intensified, multifactorial intervention in patients with advanced‐stage diabetic kidney disease: Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan)

Aims/Introduction We evaluated the efficacy of multifactorial intensive treatment (IT) on renal outcomes in patients with type 2 diabetes and advanced‐stage diabetic kidney disease (DKD). Materials and Methods The Diabetic Nephropathy Remission and Regression Team Trial in Japan (DNETT‐Japan) is a multicenter, open‐label, randomized controlled trial with a 5‐year follow‐up period. We randomly assigned 164 patients with advanced‐stage diabetic kidney disease (urinary albumin‐to‐creatinine ratio ≥300 mg/g creatinine, serum creatinine level 1.2–2.5 mg/dL in men and 1.0–2.5 mg/dL in women) to receive either IT or conventional treatment. The primary composite outcome was end‐stage kidney failure, doubling of serum creatinine or death from any cause, which was assessed in the intention‐to‐treat population. Results The IT tended to reduce the risk of primary end‐points as compared with conventional treatment, but the difference between treatment groups did not reach the statistically significant level (hazard ratio 0.69, 95% confidence interval 0.43–1.11; P = 0.13). Meanwhile, the decrease in serum low‐density lipoprotein cholesterol level and the use of statin were significantly associated with the decrease in primary outcome (hazard ratio 1.14; 95% confidence interval 1.05–1.23, P Conclusions The risk of kidney events tended to decrease by IT, although it was not statistically significant. Lipid control using statin was associated with a lower risk of adverse kidney events. Further follow‐up study might show the effect of IT in patients with advanced diabetic kidney disease

Predictive factors of mortality of patients with fragility hip fractures at 1 year after discharge : A multicenter, retrospective study in the northern Kyushu district of Japan

Purpose: Fragility hip fractures (FHFs) are associated with a high risk of mortality, but the relative contribution of various factors remains controversial. This study aimed to evaluate predictive factors of mortality at 1 year after discharge in Japan. Methods: A total of 497 patients aged 60 years or older who sustained FHFs during follow-up were included in this study. Expected variables were finally assessed using multivariable Cox proportional hazards models. Results: The 1-year mortality rate was 9.1% (95% confidence interval: 6.8–12.0%, n = 45). Log-rank test revealed that previous fractures (p = 0.003), Barthel index (BI) at discharge (p = 0.011), and place-to-discharge (p = 0.004) were significantly associated with mortality for male patients. Meanwhile, body mass index (BMI; p = 0.023), total Charlson comorbidity index (TCCI; p = 0.005), smoking (p = 0.007), length of hospital stay (LOS; p = 0.009), and BI (p = 0.004) were the counterparts for females. By multivariate analyses, previous vertebral fractures (hazard ratio (HR) 3.33; p = 0.044), and BI <30 (HR 5.42, p = 0.013) were the predictive variables of mortality for male patients. BMI <18.5 kg/m2 (HR 2.70, p = 0.023), TCCI ≥5 (HR 2.61, p = 0.032), smoking history (HR 3.59, p = 0.018), LOS <14 days (HR 13.9; p = 0.007), and BI <30 (HR 2.76; p = 0.049) were the counterparts for females. Conclusions: Previous vertebral fractures and BI <30 were the predictive variables of mortality for male patients, and BMI <18.5 kg/m2, TCCI ≥5, smoking history, LOS <14 days, and BI <30 were those for females. Decreased BI is one of the independent and preventable risk factors. A comprehensive therapeutic approach should be considered to prevent deterioration of activities of daily living and a higher risk of mortality

Japanese Lung Cancer Society Guidelines for Stage IV NSCLC With EGFR Mutations

Patients with NSCLC in East Asia, including Japan, frequently contain EGFR mutations. In 2018, we published the latest full clinical practice guidelines on the basis of those provided by the Japanese Lung Cancer Society Guidelines Committee. The purpose of this study was to update those recommendations, especially for the treatment of metastatic or recurrent EGFR-mutated NSCLC. We conducted a literature search of systematic reviews of randomized controlled and nonrandomized trials published between 2018 and 2019 that multiple physicians had reviewed independently. On the basis of those studies and the advice from the Japanese Society of Lung Cancer Expert Panel, we developed updated guidelines according to the Grading of Recommendations, Assessment, Development, and Evaluation system. We also evaluated the benefits of overall and progression-free survival, end points, toxicities, and patients’ reported outcomes. For patients with NSCLC harboring EGFR-activating mutations, the use of EGFR tyrosine kinase inhibitors (EGFR TKIs), especially osimertinib, had the best recommendation as to first-line treatment. We also recommended the combination of EGFR TKI with other agents (platinum-based chemotherapy or antiangiogenic agents); however, it can lead to toxicity. In the presence of EGFR uncommon mutations, except for an exon 20 insertion, we also recommended the EGFR TKI treatment. However, we could not provide recommendations for the treatment of EGFR mutations with immune checkpoint inhibitors, including monotherapy, and its combination with cytotoxic chemotherapy, because of the limited evidence present in the literature. The 2020 Japanese Lung Cancer Society Guidelines can help community-based physicians to determine the most appropriate treatments and adequately provide medical care to their patients

The Constrained Maximal Expression Level Owing to Haploidy Shapes Gene Content on the Mammalian X Chromosome.

X chromosomes are unusual in many regards, not least of which is their nonrandom gene content. The causes of this bias are commonly discussed in the context of sexual antagonism and the avoidance of activity in the male germline. Here, we examine the notion that, at least in some taxa, functionally biased gene content may more profoundly be shaped by limits imposed on gene expression owing to haploid expression of the X chromosome. Notably, if the X, as in primates, is transcribed at rates comparable to the ancestral rate (per promoter) prior to the X chromosome formation, then the X is not a tolerable environment for genes with very high maximal net levels of expression, owing to transcriptional traffic jams. We test this hypothesis using The Encyclopedia of DNA Elements (ENCODE) and data from the Functional Annotation of the Mammalian Genome (FANTOM5) project. As predicted, the maximal expression of human X-linked genes is much lower than that of genes on autosomes: on average, maximal expression is three times lower on the X chromosome than on autosomes. Similarly, autosome-to-X retroposition events are associated with lower maximal expression of retrogenes on the X than seen for X-to-autosome retrogenes on autosomes. Also as expected, X-linked genes have a lesser degree of increase in gene expression than autosomal ones (compared to the human/Chimpanzee common ancestor) if highly expressed, but not if lowly expressed. The traffic jam model also explains the known lower breadth of expression for genes on the X (and the Z of birds), as genes with broad expression are, on average, those with high maximal expression. As then further predicted, highly expressed tissue-specific genes are also rare on the X and broadly expressed genes on the X tend to be lowly expressed, both indicating that the trend is shaped by the maximal expression level not the breadth of expression per se. Importantly, a limit to the maximal expression level explains biased tissue of expression profiles of X-linked genes. Tissues whose tissue-specific genes are very highly expressed (e.g., secretory tissues, tissues abundant in structural proteins) are also tissues in which gene expression is relatively rare on the X chromosome. These trends cannot be fully accounted for in terms of alternative models of biased expression. In conclusion, the notion that it is hard for genes on the Therian X to be highly expressed, owing to transcriptional traffic jams, provides a simple yet robustly supported rationale of many peculiar features of X's gene content, gene expression, and evolution

Induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin in Japanese patients with HER2-negative metastatic breast cancer: a multicenter, collaborative, open-label, phase II clinical study for the SBCCSG 35 investigators

Abstract Background To examine the efficacy and safety of induction therapy with paclitaxel and bevacizumab followed by switch maintenance therapy with eribulin (ISMT) in Japanese patients with HER2-negative metastatic breast cancer (MBC). Methods Patients, who had previously undergone a maximum of 2 regimens of chemotherapy, received 3 cycles of induction therapy with paclitaxel (90 mg/m2 intravenously on days 1, 8, and 15 followed by 1-week drug holiday) and bevacizumab (10 mg/kg intravenously after the completion of paclitaxel administration on days 1 and 15). Patients who had complete response, partial response, or stable disease underwent switch maintenance therapy with eribulin (1.4 mg/m2 intravenously on days 1 and 8 followed by 1-week drug holiday). The primary endpoint was time to treatment failure (TTF) for ISMT. Results Fifty-one eligible patients (median age: 66 years; range: 35–74) were enrolled: 19 (37.3%) and 32 (62.7%) had stage IV and recurrence, respectively, 42 (82.4%) had visceral metastases, and 45 (88.2%) received eribulin—38 of whom showed disease progression, and 40 (78.4%) underwent post therapy. Median TTF was 9.2 months (95% confidence interval [CI]: 7.3–11.1), median progression-free survival was 10.7 months (95% CI: 9.6–11.8), and median overall survival was 20.0 months (95% CI: 16.0–24.0). Relative dose intensity was 97.7% (range: 33.3–100.0) for induction therapy and was 83.3% (range: 49.3–100.6%) for eribulin maintenance therapy. The most common adverse event was alopecia (51 [100%]) in induction therapy and was peripheral sensory neuropathy (37 [82.2%]) in eribulin maintenance therapy. Eribulin was effective with manageable tolerability. Conclusions ISMT may be a promising therapeutic option for patients with MBC. Trial registration UMIN000015971. Registration date: January 1, 2015