Advanced age affects the outcome-predictive power of RIFLE classification in geriatric patients with acute kidney injury

The RIFLE (risk, injury, failure, loss, and end-stage) classification is widely used to gauge the severity of acute kidney injury, but its efficacy has not been formally tested in geriatric patients. To correct this we conducted a prospective observational study in a multicenter cohort of 3931 elderly patients (65 years of age or older) who developed acute kidney injury in accordance with the RIFLE creatinine criteria after major surgery. We studied the predictive power of the RIFLE classification for in-hospital mortality and investigated the potential interaction between age and RIFLE classification. In general, the survivors were significantly younger than the nonsurvivors and more likely to have hypertension. In patients 76 years of age and younger, RIFLE-R, -I, or -F classifications were significantly associated with increased hospital mortality in a stepwise manner. There was no significant difference, however, in hospital mortality in those over 76 years of age between patients with RIFLE-R and RIFLE-I, although RIFLE-F patients had significantly higher mortality than both groups. Thus, the less severe categorizations of acute kidney injury per RIFLE classification may not truly reflect the adverse impact on elderly patients

Genomics and proteomics of immune modulatory effects of a butanol fraction of echinacea purpurea in human dendritic cells

<p>Abstract</p> <p>Background</p> <p><it>Echinacea </it>spp. extracts and the derived phytocompounds have been shown to induce specific immune cell activities and are popularly used as food supplements or nutraceuticals for immuno-modulatory functions. Dendritic cells (DCs), the most potent antigen presenting cells, play an important role in both innate and adaptive immunities. In this study, we investigated the specific and differential gene expression in human immature DCs (iDCs) in response to treatment with a butanol fraction containing defined bioactive phytocompounds extracted from stems and leaves of <it>Echinacea purpurea</it>, that we denoted [BF/S+L/Ep].</p> <p>Results</p> <p>Affymetrix DNA microarray results showed significant up regulation of specific genes for cytokines (IL-8, IL-1β, and IL-18) and chemokines (CXCL 2, CCL 5, and CCL 2) within 4 h after [BF/S+L/Ep] treatment of iDCs. Bioinformatics analysis of genes expressed in [BF/S+L/Ep]-treated DCs revealed a key-signaling network involving a number of immune-modulatory molecules leading to the activation of a downstream molecule, adenylate cyclase 8. Proteomic analysis showed increased expression of antioxidant and cytoskeletal proteins after treatment with [BF/S+L/Ep] and cichoric acid.</p> <p>Conclusion</p> <p>This study provides information on candidate target molecules and molecular signaling mechanisms for future systematic research into the immune-modulatory activities of an important traditional medicinal herb and its derived phytocompounds.</p

Jun Dimerization Protein 2 Controls Senescence and Differentiation via Regulating Histone Modification

Transcription factor, Jun dimerization protein 2 (JDP2), binds directly to histones and DNAs and then inhibits the p300-mediated acetylation both of core histones and of reconstituted nucleosomes that contain JDP2 recognition DNA sequences. JDP2 plays a key role as a repressor of adipocyte differentiation by regulation of the expression of the gene C/EBPδ via inhibition of histone acetylation. Moreover, JDP2-deficient mouse embryonic fibroblasts (JDP2−/− MEFs) are resistant to replicative senescence. JDP2 inhibits the recruitment of polycomb repressive complexes (PRC1 and PRC2) to the promoter of the gene encoding p16Ink4a, resulting from the inhibition of methylation of lysine 27 of histone H3 (H3K27). Therefore, it seems that chromatin-remodeling factors, including the PRC complex controlled by JDP2, may be important players in the senescence program. The novel mechanisms that underline the action of JDP2 in inducing cellular senescence and suppressing adipocyte differentiation are reviewed

Tislelizumab in Patients with Previously Treated Advanced Hepatocellular Carcinoma (RATIONALE-208): A Multicenter, Non-Randomized, Open-Label, Phase 2 Trial

Introduction: Tislelizumab (anti-programmed cell death protein 1 antibody) showed preliminary antitumor activity and tolerability in patients with advanced solid tumors, including hepatocellular carcinoma (HCC). This study aimed to assess the efficacy and safety of tislelizumab in patients with previously treated advanced HCC. Methods: The multi-regional phase 2 study, RATIONALE-208, examined single-agent tislelizumab (200 mg intravenously every three weeks) in patients with advanced HCC with Child-Pugh A, Barcelona Clinic Liver Cancer stage B or C, and who had received one or more prior lines of systemic therapy. The primary endpoint was objective response rate (ORR), radiologically confirmed per Response Evaluation Criteria in Solid Tumors version 1.1 by Independent Review Committee. Safety was assessed in patients who received ≥1 dose of tislelizumab. Results: Between April 9, 2018 and February 27, 2019, 249 eligible patients were enrolled and treated. After a median study follow-up of 12.7 months, ORR was 13% (n = 32/249; 95% confidence interval [CI], 9–18), including five complete and 27 partial responses. Number of prior lines of therapy did not impact ORR (one prior line, 13% [95% CI, 8–20]; two or more prior lines, 13% [95% CI, 7–20]). Median duration of response was not reached. Disease control rate was 53% and median overall survival was 13.2 months. Of the 249 total patients, grade ≥3 treatment-related adverse events were reported in 38 (15%) patients; the most common was liver transaminase elevations in 10 (4%) patients. Treatment-related adverse events led to treatment discontinuation in 13 (5%) patients or dose delay in 46 (19%) patients. No deaths were attributed to the treatment per investigator assessment. Conclusion: Tislelizumab demonstrated durable objective responses, regardless of the number of prior lines of therapy, and acceptable tolerability in patients with previously treated advanced HCC

Visfatin mediates malignant behaviors through adipose-derived stem cells intermediary in breast cancer

Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression

Immune Responses in Pigs Induced by Recombinant DNA Vaccine Co-Expressing Swine IL-18 and Membrane Protein of Porcine Reproductive and Respiratory Syndrome Virus

In this study, two DNA vaccines, which express the membrane (M) protein of porcine respiratory and reproductive syndrome virus (PRRSV) (pEGFP-M) and co-express both M and swine IL-18 (pEGFP-IL18-M), were constructed and their abilities to induce humoral and cellular responses in piglets were comparatively evaluated. Experimental results showed that both recombinant DNA vaccines could not elicit neutralizing antibodies in the immunized piglets. However, both DNA vaccines elicited Th1-biased cellular immune responses. Notably, pigs immunized with the plasmid pEGFP-IL18-M developed significantly higher levels of IFN-γ and IL-2 production response and stronger specific T-lymphocyte proliferation response than the pigs inoculated with the plasmids pEGFP-M and pEGFP-IL18 (P < 0.05). These results illustrated that co-expression of M and IL-18 proteins could significantly improve the potency of DNA vaccination on the activation of vaccine-induced virus-specific cell-mediated immune responses in pigs, which may be used as a strategy to develop a new generation of vaccines against highly pathogenic PRRSV

Comparison of single-incision mini-slings (Ajust) and standard transobturator midurethral slings (Align) in the management of female stress urinary incontinence: A 1-year follow-up

AbstractObjectiveTo investigate the effectiveness and safety of a new single-incision mini-sling (SIMS)—Ajust—compared with the standard transobturator midurethral sling (SMUS)—Align—for the treatment of female stress urinary incontinence (SUI).Materials and MethodsA retrospective cohort study was conducted between January 1, 2010 and August 31, 2012. Women with SUI who underwent either SMUS-Align or SIMS-Ajust were recruited. The primary outcomes included operation time, estimated operative blood loss, postoperative pain, and complications. The secondary outcomes included subjective and objective success, defined as an International Consultation on Incontinence Questionnaire (ICIQ) score of 0 or improvement as felt by the patient and a long-term complication, such as dyspareunia and mesh erosion after 6 months and 12 months of follow-up.ResultsA total of 136 patients were enrolled, including 76 receiving SMUS-Align and 60 receiving SIMS-Ajust. Baseline characteristics of the patients in both groups were similar, without a statistically significant difference. Primary outcomes between both groups were similar, except that women treated with SIMS-Ajust had statistically significantly shorter operation time (p = 0.003), less intent to treat (p < 0.05), and earlier postoperative discharge (p = 0.001) than women treated with SMUS-Align. Secondary outcomes were similar without a significant difference between the two groups (93% vs. 88% success rate in each group).ConclusionOur results showed that SIMS-Ajust was not inferior to SMUS-Align with respect to success rate, and might have a slight advantage in early discharge. A long-term follow-up or prospective study is needed to confirm the above findings

ADSCs stimulated by resistin promote breast cancer cell malignancy via CXCL5 in a breast cancer coculture model

The tumor microenvironment represents one of the main obstacles in breast cancer treatment owing to the presence of heterogeneous stromal cells, such as adipose-derived stem cells (ADSCs), that may interact with breast cancer cells and promote cancer development. Resistin is an adipocytokine associated with adverse breast cancer progression; however, its underlying mechanisms in the context of the breast tumor microenvironment remain largely unidentified. Here, we utilized a transwell co-culture model containing patient-derived ADSCs and breast cancer cell lines to investigate their potential interaction, and observed that breast cancer cells co-cultured with resistin-treated ADSCs (R-ADSCs) showed enhanced cancer cell growth and metastatic ability. Screening by proteome arrays revealed that C-X-C motif chemokine ligand 5 (CXCL5) was released in the conditioned medium of the co-culture system, and phosphorylated ERK was increased in breast cancer cells after co-culture with R-ADSCs. Breast cancer cells treated with the recombinant proteins of CXCL5 showed similarly enhanced cell migration and invasion ability as occurred in the co-culture model, whereas application of neutralizing antibodies against CXCL5 reversed these phenomena. The orthotopic xenograft in mice by breast cancer cells after co-culture with R-ADSCs had a larger tumor growth and more CXCL5 expression than control. In addition, clinical analysis revealed a positive correlation between the expression of resistin and CXCL5 in both tumor tissues and serum specimens of breast cancer patients. The current study suggests that resistin-stimulated ADSCs may interact with breast cancer cells in the tumor microenvironment via CXCL5 secretion, leading to breast cancer cell malignancy