Tazobactam/piperacillin for moderate-to-severe pneumonia in patients with risk for aspiration: comparison with imipenem/cilastatin.

BACKGROUND: Treatment of aspiration pneumonia is becoming an important issue due to aging of populations worldwide. Effectiveness of tazobactam/piperacillin (TAZ/PIPC) in aspiration pneumonia is not clear. PURPOSE: To compare clinical efficacy between TAZ/PIPC (1:4 compound) and imipenem/cilastatin (IPM/CS) in patients with moderate-to-severe aspiration pneumonia. PATIENTS AND METHODS: In this open-label, randomized study either TAZ/PIPC 5 g or IPM/CS 1 g was intravenously administered every 12 h to patients with moderate-to-severe community-acquired aspiration pneumonia or nursing home-acquired pneumonia with risk for aspiration pneumonia for average 11 days. The primary outcome was clinical response rate at the end of treatment (EOT) in validated per-protocol (VPP) population. Secondary outcomes were clinical response during treatment (days 4 and 7) and at the end of study (EOS) in VPP population, and survival at day 30 in modified intention-to-treat (MITT) population. RESULTS: There was no difference between the groups in primary or secondary outcome. However, significantly faster improvement as measured by axillary temperature (p < 0.05) and WBC count (p = 0.01) was observed under TAZ/PIPC treatment. In patients with gram-positive bacterial infection, TAZ/PIPC was more effective at EOT in VPP population (p = 0.03). CONCLUSION: TAZ/PIPC is as effective and safe as IPM/CS in the treatment of moderate- to-severe aspiration pneumonia

The prognostic impact of peripheral blood eosinophil counts in metastatic renal cell carcinoma patients treated with nivolumab

The version of record of this article, first published in Clinical and Experimental Medicine, is available online at Publisher’s website: https://doi.org/10.1007/s10238-024-01370-8.Although immune checkpoint inhibitors (ICIs) have gained approval for metastatic renal cell carcinoma (mRCC), the response rate is still limited. Therefore, it is urgent to explore novel markers of responses to ICIs that can help assess clinical benefits. Recently, it has been noted that peripheral blood eosinophil counts are an independent factor correlated with clinical outcome of ICIs in some types of cancer. We investigated peripheral blood absolute eosinophil counts (AECs) at baseline and 4 weeks after the initiation of nivolumab for mRCC patients between February 2016 and May 2022. In addition, we examined clinicopathological features including irAEs and analyzed the correlation between AECs and clinical efficacy of nivolumab. The median progression-free survival (PFS) and overall survival (OS) for all patients were 5.7 and 25.5 months, respectively. The median AECs in patients with irAEs were significantly higher at baseline and 4 weeks after the treatment compared to those without irAEs (p < 0.001 and p = 0.001). With the cutoff value of AECs of 329 cells/µL at 4 weeks after the treatment for prediction of irAEs, high-AECs groups had significantly higher number of responders compared with that in low-AECs group (p < 0.001). Accordingly, the PFS and OS were significantly better in patients with high-AECs group than those in low-AECs group (p = 0.03 and p = 0.009). High-AECs at 4 weeks after the treatment serve as the prominent surrogate marker associated with the incidence of irAEs and better clinical outcome in mRCC patients receiving nivolumab

Androgen-Regulated Transcriptional Control of Sialyltransferases in Prostate Cancer Cells

The expression of gangliosides is often associated with cancer progression. Sialyltransferases have received much attention in terms of their relationship with cancer because they modulate the expression of gangliosides. We previously demonstrated that GD1a production was high in castration-resistant prostate cancer cell lines, PC3 and DU145, mainly due to their high expression of β-galactoside α2,3-sialyltransferase (ST3Gal) II (not ST3Gal I), and the expression of both ST3Gals was regulated by NF-κB, mainly by RelB. We herein demonstrate that GD1a was produced in abundance in cancerous tissue samples from human patients with hormone-sensitive prostate cancers as well as castration-resistant prostate cancers. The expression of ST3Gal II was constitutively activated in castration-resistant prostate cancer cell lines, PC3 and DU145, because of the hypomethylation of CpG island in its promoter. However, in androgen-depleted LNCap cells, a hormone-sensitive prostate cancer cell line, the expression of ST3Gal II was silenced because of the hypermethylation of the promoter region. The expression of ST3Gal II in LNCap cells increased with testosterone treatment because of the demethylation of the CpG sites. This testosterone-dependent ST3Gal II expression was suppressed by RelB siRNA, indicating that RelB activated ST3Gal II transcription in the testosterone-induced demethylated promoter. Therefore, in hormone-sensitive prostate cancers, the production of GD1a may be regulated by androgen. This is the first report indicating that the expression of a sialyltransferase is transcriptionally regulated by androgen-dependent demethylation of the CpG sites in its gene promoter

RelB is required for the androgen-dependent regulation of ST3Gal I and II in LNCap cells.

<p>(A) LNCap cells were transfected with either scrambled RNA or RelB siRNA and incubated for 120 h with or without 100 nM testosterone. Protein extracts were prepared using RIPA lysis buffer, and the RelB expression level of each sample was analyzed by a Western blot analysis. The expression relative to β-actin is shown in each lane after normalizing the values to the expression level of the scrambled RNA–transfected and testosterone-untreated cells. (B) LNCap cells were transfected with the either scrambled RNA or RelB siRNA and incubated for 120 h with or without 100 nM testosterone. The quantitative real-time PCR analyses for ST3Gal I and II were performed, and the expression levels are reported as the means ± S.E. (n = 3) of the fold difference in mRNA after normalizing the values to the expression level of the scrambled RNA–transfected and testosterone-untreated cells. *P<0.05, **P<0.001.</p

Epigenetic regulation of ST3Gal II in LNCap cells.

<p>(A) LNCap cells were treated with 5-aza-2′-deoxycytidine (5-azadC) (0–50 µM) for 120 h, by refeeding with fresh medium with or without 5-azadC at 72 h. The quantitative real-time PCR analyses for ST3Gal II were performed, and the expression levels are reported as the means ± S.E. (n = 3) of the fold difference in mRNA after normalizing the values to the expression level of untreated cells. *P<0.05. (B) LNCap cells were treated with 5 µM trichostatin A (TSA) for 48 h. The quantitative real-time PCR analyses for ST3Gal II were performed, and the expression levels are reported as the means ± S.E. (n = 3) of the fold difference in mRNA after normalizing the values to the expression level of untreated cells. *P<0.05.</p

Control of DNA methylation at the CpG island in the ST3Gal II promoter in prostate cancer cells.

<p>(A) The CpG island in the ST3Gal II p1 promoter and the location of the MSP primers. The vertical bars represent CpG sites and TSS represents the transcriptional start site. (B–D) The MSP analyses of the CpG island of ST3Gal II. DNA was isolated from LNCap cells treated with 5-azadC (0–50 µM) for 120 h (B), castration-resistant prostate cancer cell lines (PC3 and DU145) or LNCap cells treated with or without 100 nM testosterone for 120 h (C) or LNCap cells treated with or without 100 nM testosterone simultaneously with or without 10 µM bicalutamide for 120 h (D). Then, the DNA was treated with sodium bisulfite, and finally amplified with primers specific for the unmethylated (USP) or the methylated (MSP) form of the CpG island in the ST3Gal II promoter (M, methylated control; UA, unmethylated control A; UB, unmethylated control B). The MSP analyses were repeated 3 times with the same results, and a representative image is shown in the figures.</p

The results of the analyses of gangliosides in cancerous tissue samples from human prostate cancer patients.

<p>(A) The acidic GSLs from the cancerous tissue samples from eight patients with prostate cancer, including six patients with advanced hormone-sensitive prostate cancer and two patients with castration-resistant prostate cancer were separated by the molecular size of the oligosaccharides using normal-phase HPLC. Samples from one patient (designated Case 1) were taken from both the prostate and bone metastases for evaluation. (B) The acidic GSLs in the primary cancerous tissue samples were separated by the molecular size of the oligosaccharides using HPLC. The quantity of GD1a is presented as a percentage of the total acidic GSLs with GD1a. (C) The acidic GSLs in cultured prostate cancer cells were separated by the molecular size of the oligosaccharides using HPLC. The assay was done in triplicate, and the means ± S.E. GD1a levels are shown as the ratio to the total acidic GSLs in the cell lines. The mean ± S.E. GD1a level was also presented as the ratio to the total acidic GSLs in the patients' samples (HS+CR) indicated in <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0031234#pone-0031234-g001" target="_blank">Figure 1B</a>. (HS, hormone-sensitive; CR, castration-resistant; F, free glycan).</p