Favorable response to doxorubicin combination chemotherapy does not yield good clinical outcome in patients with metastatic breast cancer with triple-negative phenotype

<p>Abstract</p> <p>Background</p> <p>We analyzed the responses to first line treatment and clinical outcomes of metastatic breast cancer patients treated with palliative doxorubicin/cyclophosphamide (AC) according to molecular cancer subtype.</p> <p>Methods</p> <p>A retrospective analysis was performed for 110 metastatic breast cancer patients selected on the basis of palliative AC treatment and the availability of immunohistochemical data for estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor-2 (HER-2/neu) status.</p> <p>Results</p> <p>Of the 110 patients analyzed, 71 (64.5%) were hormone receptor positive (HR+), 14 (12.7%) were HER2+, and 25 (22.7%) were triple negative (TN). There were no differences in age, stage at diagnosis, total number of cycles of palliative chemotherapy, incidence of visceral metastasis, and metastatic sites with the exception of liver among breast cancer subtypes. The overall response rates to AC were 55.9% for the HR+ subgroup, 42.9% for the HER2+ subgroup, and 56.5% for the TN subgroup. The progression-free survival (PFS) in patients with HER2+ and TN were significantly shorter than in the HR+ (median PFS, 9.1 <it>vs </it>8.1 <it>vs </it>11.5 months, respectively; p = 0.0002). The overall survival (OS) was 25.4 months in the TN subgroup and 27.3 months in HER2+ subgroup. The median OS for these two groups was significantly shorter than for patients in the HR+ subgroup (median, 38.5 months; 95% CI, 30.1-46.9 months; p < 0.0001).</p> <p>Conclusions</p> <p>The response to palliative AC chemotherapy did not differ among breast cancer subtypes. Despite chemosensitivity for palliative AC, the TN subtype has a shorter overall survival than non-TN subtypes. Innovative treatment strategies should be developed to slow the course of disease.</p

A retrospective analysis of second-line chemotherapy in patients with advanced gastric cancer

<p>Abstract</p> <p>Background</p> <p>Because treatment of advanced gastric cancer (AGC) patients after failure with first-line chemotherapy remains controversial, we performed this retrospective analysis based on the data obtained from 1455 patients registered in a first-line treatment cohort with respect to receiving or not receiving subsequent chemotherapy.</p> <p>Methods</p> <p>The decision for administering second-line chemotherapy was, in most cases, at the discretion of the physician. Seven-hundred twenty-five (50%) received second-line chemotherapy after first-line failure. Univariate and multivariate analyses were performed on the recognized baseline parameters for survival.</p> <p>Results</p> <p>At the time of initiating second-line chemotherapy, the patients' median age was 56 years (range, 22 to 86) and 139 (19%) had an Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. Seven (1%) complete and 108 (15%) partial responses to second-line chemotherapy were observed for an overall response rate of 16% (95% confidence interval [CI], 13 to 19%). The median progression-free and overall survivals, calculated from the start of second-line chemotherapy, were 2.9 months (95% CI, 2.6 to 3.3) and 6.7 months (95% CI, 5.8 to 7.5), respectively. Multivariate analysis revealed that low baseline hemoglobin level (hazard ratio [HR], 0.74; 95% CI 0.61–0.90) and a poor performance status (HR, 0.66; 95% CI, 0.52–0.83) were independent negative prognostic factors for overall survival.</p> <p>Conclusion</p> <p>Performance status, along with baseline hemoglobin level, could be used to identify the subgroup of patients most likely to benefit from second-line chemotherapy for AGC.</p

CpG methylation at GATA elements in the regulatory region of CCR3 positively correlates with CCR3 transcription

DNA methylation may regulate gene expression by restricting the access of transcription factors. We have previously demonstrated that GATA-1 regulates the transcription of the CCR3 gene by dynamically interacting with both positively and negatively acting GATA elements of high affinity binding in the proximal promoter region including exon 1. Exon 1 has three CpG sites, two of which are positioned at the negatively acting GATA elements. We hypothesized that the methylation of these two CpGs sites might preclude GATA-1 binding to the negatively acting GATA elements and, as a result, increase the availability of GATA-1 to the positively acting GATA element, thereby contributing to an increase in GATA-1-mediated transcription of the gene. To this end, we determined the methylation of the three CpG sites by bisulfate pyrosequencing in peripheral blood eosinophils, cord blood (CB)-derived eosinophils, PBMCs, and cell lines that vary in CCR3 mRNA expression. Our results demonstrated that methylation of CpG sites at the negatively acting GATA elements severely reduced GATA-1 binding and augmented transcription activity in vitro. In agreement, methylation of these CpG sites positively correlated with CCR3 mRNA expression in the primary cells and cell lines examined. Interestingly, methylation patterns of these three CpG sites in CB-derived eosinophils mostly resembled those in peripheral blood eosinophils. These results suggest that methylation of CpG sites at the GATA elements in the regulatory regions fine-tunes CCR3 transcription

Germline transmission of MSTN knockout cattle via CRISPR-Cas9

Although the production of several founder animals (F0) for gene editing in livestock has been reported in cattle, very few studies have assessed germline transmission to the next generation due to the long sexual maturation and gestation periods. The present study aimed to assess the germline transmission of MSTN mutations (-12bps deletion) in MSTN mutant F0 male and female cattle. For this purpose, oocytes and semen were collected after the sexual maturation of MSTN cattle, and embryos produced by in vitro fertilization were analyzed. In addition, the embryos were subjected to additional gene (PRNP) editing using electroporation. Embryos produced by in vitro fertilization with MSTN male and female cattle were transferred to a surrogate, and one calf was successfully born. MSTN heterozygous mutation was shown by sequencing of the F1 calf, which had no health issues. As a further experiment, using electroporation, additional gene-edited embryos fertilized with the MSTN male sperm showed a high mutation rate of PRNP (86.2 ± 3.4%). These data demonstrate that the cattle produced through gene editing matured without health issues and had transmitted MSTN mutation from the germ cells. Also, additional mutation of embryos fertilized with the MSTN male sperm could enable further mutagenesis using electroporation. © 2022 Elsevier Inc.N

Optimization of Solid-Phase Lactobacillus Fermentation Conditions to Increase γ-Aminobutyric Acid (GABA) Content in Selected Substrates

The purpose of this study was to optimize conditions of solid-phase fermentation of lactic acid bacteria to enhance GABA contents in grains. Optimal solid-phase fermentation conditions that could enhance the GABA content after fermenting Oryza sativa (brown rice) were investigated by changing the Lactobacillus strain, fermentation temperature, fermentation time, and inoculated bacteria number. Avena sativa, Cicer arietinum, and red and brown Lens culinaris were then fermented using the optimal solid-phase fermentation conditions to measure changes in GABA content and antioxidant activity. As a result of the experiment, the optimal solid-phase fermentation conditions to enhance the GABA contents in grains were: fermentation time, 48 h; amounts of bacteria, inoculating 5% of 1 × 107 CFU/mL of lactic acid bacteria; and fermentation temperature, 36 °C. When fermented under this condition, the GABA content increased from 4.64 mg/g to 6.93 mg/g (49.0%) compared to unfermented raw material. The results of the DPPH and ABTS radical scavenging activity assays confirmed that both the GABA content and radical scavenging activity were increased after fermentation. Such solid fermentation conditions developed in this study can be used to support the development of health functional food materials with enhanced GABA content and antioxidant activity

Paclitaxel with Cisplatin as Salvage Treatment for Patients with Previously Treated Advanced Transitional Cell Carcinoma of the Urothelial Tract

BACKGROUND: This study was performed to evaluate the safety and efficacy of paclitaxel with cisplatin as salvage therapy in patients previously treated with gemcitabine and cisplatin (G/C) for advanced transitional cell carcinoma (TCC) of the urothelial tract. METHODS: Twenty-eight patients with metastatic or locally advanced TCC who had received prior G/C chemotherapy were enrolled. All patients received paclitaxel (175 mg/m2) and cisplatin (60 mg/m2) every 3 weeks for eight cycles or until disease progression. RESULTS: The median age was 61 years (range, 43–83 years), and the median Eastern Cooperative Oncology Group performance status was 1 (range, 0–2). The overall response rate was 36% [95% confidence interval (95% CI) = 18–54], with three complete responses and seven partial responses. The median time to progression was 6.2 months (95% CI = 3.9–8.5), and the median overall survival was 10.3 months (95% CI = 6.1–14.1). The most common Grade 3/4 nonhematologic and hematologic toxicities were emesis (10 of 28 patients; 36%) and neutropenia (5 of 110 cycles; 5%). CONCLUSIONS: Salvage chemotherapy with paclitaxel and cisplatin displayed promising results with tolerable toxicity profiles in patients with metastatic or locally advanced TCC who had been pretreated with G/C