Efficacy and safety of micafungin in empiric and D-index-guided early antifungal therapy for febrile neutropenia ; A subgroup analysis of the CEDMIC trial

Objectives: The D-index is defined as the area over the neutrophil curve during neutropenia. The CEDMIC trial confirmed the noninferiority of D-index-guided early antifungal therapy (DET) using micafungin to empirical antifungal therapy (EAT). In this study, we evaluated the efficacy and safety of micafungin in these settings. Methods: From the CEDMIC trial, we extracted 67 and 113 patients who received micafungin in the DET and EAT groups, respectively. Treatment success was defined as the fulfilment of all components of a five-part composite end point. Fever resolution was evaluated at seven days after the completion of therapy. Results: The proportion of high-risk treatments including induction chemotherapy for acute leukemia and allogeneic hematopoietic stem cell transplantation was significantly higher in the DET group than in the EAT group (82.1% vs. 52.2%). The efficacy of micafungin was 68.7% (95%CI: 56.2–79.4) and 79.6% (71.0–86.6) in the DET and EAT groups, respectively. When we focused on high-risk treatments, the efficacy was 69.1% (55.2–80.9%) and 78.0% (65.3–87.7%), respectively (P = 0.30). There was no significant difference in any of the 5 components between the two groups. Conclusions: The efficacy of micafungin in patients undergoing high-risk treatment was not strongly impaired in DET compared to that in EAT

RUNX1 transactivates BCR-ABL1 expression in Philadelphia chromosome positive acute lymphoblastic leukemia

The emergence of tyrosine kinase inhibitors as part of a front-line treatment has greatly improved the clinical outcome of the patients with Ph⁺ acute lymphoblastic leukemia (ALL). However, a portion of them still become refractory to the therapy mainly through acquiring mutations in the BCR-ABL1 gene, necessitating a novel strategy to treat tyrosine kinase inhibitor (TKI)-resistant Ph⁺ ALL cases. In this report, we show evidence that RUNX1 transcription factor stringently controls the expression of BCR-ABL1, which can strategically be targeted by our novel RUNX inhibitor, Chb-M'. Through a series of in vitro experiments, we identified that RUNX1 binds to the promoter of BCR and directly transactivates BCR-ABL1 expression in Ph⁺ ALL cell lines. These cells showed significantly reduced expression of BCR-ABL1 with suppressed proliferation upon RUNX1 knockdown. Moreover, treatment with Chb-M' consistently downregulated the expression of BCR-ABL1 in these cells and this drug was highly effective even in an imatinib-resistant Ph⁺ ALL cell line. In good agreement with these findings, forced expression of BCR-ABL1 in these cells conferred relative resistance to Chb-M'. In addition, in vivo experiments with the Ph⁺ ALL patient-derived xenograft cells showed similar results. In summary, targeting RUNX1 therapeutically in Ph⁺ ALL cells may lead to overcoming TKI resistance through the transcriptional regulation of BCR-ABL1. Chb-M' could be a novel drug for patients with TKI-resistant refractory Ph⁺ ALL

Isolation and characterization of cancer stem-like side population cells in human oral cancer cells.

Recent studies suggest that cancer stem cells may be responsible for tumorigenesis and contribute to some individuals\u27 resistance to cancer therapy. Some studies demonstrate that side population (SP) cells isolated from diverse cancer cell lines harbor stem cell-like properties; however, there are few reports examining the role of SP cells in human oral cancer. To determine whether human oral cancer cell lines contain a SP cell fraction, we first isolated SP cells by fluorescence activated cell sorting, followed by culturing in serum-free medium (SFM) using the SCC25 tongue cancer cell line, so that SP cells were able to be propagated to maintain the CSC property. Differential expression profile of stem cell markers (ABCG2, Oct-4 and EpCAM) was examined by RT-PCR in either SP cells or non-SP cells. Growth inhibition by 5-FU was determined by the MTT assay. Clonogenic ability was evaluated by colony formation assay. SCC25 cells contained 0.23% SP cells. The fraction of SP cells was available to grow in SFM cultures. SP cells showed higher mRNA expression of stem cell markers (ABCG2, Oct-4 and EpCAM) as compared with non-SP cells. Moreover, SP cells demonstrated more drug resistance to 5-FU, as compared with non-SP cells. The clone formation efficiency of SP cells was significantly higher than non-SP cells at an equal cell number (P<0.01). We isolated cancer stem-like SP cells from an oral cancer cell line. SP cells possessed the characteristics of cancer stem cells, chemoresistance, and high proliferation ability. Further characterization of cancer stem-like SP cells may provide new insights for novel therapeutic targets

Evaluation of Oral Mucosal Lesions Using the IllumiScan&reg; Fluorescence Visualisation Device: Distinguishing Squamous Cell Carcinoma

We evaluated whether fluorescence intensity (FI) and its coefficient of variation (CV) can be used to diagnose squamous cell carcinoma (SCC) through IllumiScan&reg;, an oral mucosa fluorescence visualisation (FV) device. Overall, 190 patients with oral mucosal lesions (OMLs; SCC, 59; non-SCC OMLs, 131) and 49 patients with normal oral mucosa (NOM) were enrolled between January 2019 and March 2021. The FI of the images was analysed using image analysis software. After establishing regions of interest for SCC, non-SCC, and NOM, the average FI, standard deviation (SD), and CV were compared. There was a significant difference in the average FI for all pairs of comparisons. The SD was not significantly different between the SCC and NOM groups (p = 0.07). The CV differed significantly for NOM (p &lt; 0.001) and non-SCC groups (p &lt; 0.001) relative to the SCC group but was not different between NOM and non-SCC groups (p = 0.15). Univariate analysis of SCC and non-SCC groups showed significant differences for all factors, except age. However, multivariate analysis showed a significant intergroup difference only in the CV (p = 0.038). Therefore, analysing the CV in FV images of OML may be useful for the diagnosis of oral cancer

Persistent Overexpression of Phosphoglycerate Mutase, a Glycolytic Enzyme, Modifies Energy Metabolism and Reduces Stress Resistance of Heart in Mice

<div><p>Background</p><p>Heart failure is associated with changes in cardiac energy metabolism. Glucose metabolism in particular is thought to be important in the pathogenesis of heart failure. We examined the effects of persistent overexpression of phosphoglycerate mutase 2 (Pgam2), a glycolytic enzyme, on cardiac energy metabolism and function.</p><p>Methods and Results</p><p>Transgenic mice constitutively overexpressing Pgam2 in a heart-specific manner were generated, and cardiac energy metabolism and function were analyzed. Cardiac function at rest was normal. The uptake of analogs of glucose or fatty acids and the phosphocreatine/βATP ratio at rest were normal. A comprehensive metabolomic analysis revealed an increase in the levels of a few metabolites immediately upstream and downstream of Pgam2 in the glycolytic pathway, whereas the levels of metabolites in the initial few steps of glycolysis and lactate remained unchanged. The levels of metabolites in the tricarboxylic acid (TCA) cycle were altered. The capacity for respiration by isolated mitochondria <i>in vitro</i> was decreased, and that for the generation of reactive oxygen species (ROS) <i>in vitro</i> was increased. Impaired cardiac function was observed in response to dobutamine. Mice developed systolic dysfunction upon pressure overload.</p><p>Conclusions</p><p>Constitutive overexpression of Pgam2 modified energy metabolism and reduced stress resistance of heart in mice.</p></div

Respiration was decreased and ROS production was increased in the isolated mitochondria of Pgam2 mice.

<p>(<b>A</b>) Oxygen consumption in isolated mitochondria was measured using an oxygen electrode cuvette. Total oxygen consumption was lower in Pgam2 mice. Values are the mean ± SEM. *p<0.05 versus NTg mice (NTg: n = 3; Pgam2 mice: n = 5). (<b>B</b>) Generation of H₂O₂ by isolated mitochondria. Malate and pyruvate, or succinate, were used as substrates. The generation of H₂O₂ increased in Pgam2 mice both with malate + pyruvate and with succinate. Values are the mean ± SEM. *p<0.05 versus NTg mice (n = 6 for each group). A.U.: arbitrary unit.</p

Echocardiographic analysis of Pgam2 mice.

<p>Values are expressed as the mean ± SEM. NTg: non-transgenic mice; Pgam2: phosphoglycerate mutase 2 transgenic mice; bpm: beats per minute; LV: left ventricular.</p

Expression of the Pgam protein in NTg or Pgam2 mice with the sham operation or transverse aortic constriction.

<p>Values are expressed as the mean ± SEM. NTg: non-transgenic mice; Pgam2: phosphoglycerate mutase 2 transgenic mice; TAC: transverse aortic constriction. The mean value of NTg mice with the sham operation was used as a standard. *p<0.05 versus the same genotype with the sham operation. †p<0.05 versus NTg mice with the same operation.</p