Long non-coding RNAs (lncRNAs) are known to be involved in the processes of tumourigenesis and malignant behaviours in many types of cancer, including acute myeloid leukaemia (AML). Accumulating evidence has revealed that novel lncRNAs exerted critical roles in these processes. In the present study, we investigated the effects of lncRNA linc00239 (NR_026774.1), which is 662 nucleotides (nt) in length and was found to be upregulated in AML patients, on malignant behaviours and chemosensitivity in AML cells, including KG-1 and HL-60. linc00239 expression was detected in KG-1 and HL-60 cells by quantitative PCR and northern blotting, and it was found that linc00239 is detectable by both of these assays. After knockdown or overexpression of linc00239 in AML cells, the results revealed that the presence of linc00239 promoted proliferation, colony formation and migration ability. Furthermore, the presence of linc00239 increased chemoresistance to doxorubicin in AML cells partially by preventing doxorubicin-induced apoptotic cell death. It was also determined that the presence of linc00239 was related to activation of the phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway. Inhibition of PI3K/Akt/mTOR using 1 µM NVP-BEZ235 (BEZ) abolished the inhibitory effect of linc00239 on chemosensitivity and the preventative effect on doxorubicin-induced cell death. Collectively, our data revealed that linc00239 is a novel tumour promoter in AML cells and indicated that it is a potential therapeutic target.
erastin, a classical inducer of non-apoptotic cell death, exerts cytotoxicity in several types of cancer cells, including gastric cancer cells, by depleting glutathione, which is a primary cellular antioxidant, thus causing reactive oxygen species (roS) accumulation. although numerous studies have focused on the non-apoptotic cell death induced by erastin, whether erastin induces apoptosis remains unknown. The present study confirmed the cytotoxicity of erastin in HGC-27 cells and used a 30% inhibitory concentration (ic 30 , approximately 6.23 µM) for further analysis. The cell cycle analysis revealed that 6.23 µM of erastin inhibited proliferation by blocking the cell cycle at the G1/G0 phase. Further analysis also showed that 6.23 µM of erastin clearly inhibited HGC-27 malignant behaviors, including migration, invasion, colony formation and tumor formation in soft agar. The observation of roS accumulation due to erastin treatment led to determination of the effects of erastin on mitochondrial function and, as expected, erastin treatment decreased transcriptional activity and aTP production in mitochondria and disrupted the mitochondrial potential; these effects were reversed by the addition of the roS scavenger nac. To evaluate the effect of erastin in inducing apoptosis, HGC-27 cells were treated with 6.23 µM of erastin for 7 days and then analyzed. Evident apoptotic cell death was induced by erastin and this apoptosis was reversed by the addition of an apoptosis inhibitor (zVAD) or nac but not by the addition of a ferroptosis inhibitor (ferrostatin-1). Furthermore, the detection of caspase-3 and poly (adenosine diphosphate-ribose) polymerase (ParP) also confirmed that treatment with erastin promoted the cleavage of caspase-3 and ParP, which are hallmarks of apoptosis. Taken together, the present study revealed that a low dose of erastin inhibited malignant behavior and induced apoptosis by causing mitochondrial dysfunction.
Pancreatic cancer has the worst prognosis of any gastrointestinal cancer, with the mortality approaching the incidence. Early detection is crucial for improving patients' prognosis. CA242 has been widely reported to play a role in diagnosis of pancreatic cancer. However, published data on this subject are inconclusive. Therefore, we performed a meta-analysis to evaluate the diagnostic value of CA242 in pancreatic cancer. We searched all the eligible studies through PubMed, Embase, and the Cochrane Library databases without language limitation. Studies were assessed for quality using the quality assessment of studies of diagnostic accuracy (QUADAS). Positive likelihood ratio (PLR) and negative likelihood ratio (NLR) were pooled separately and compared with overall accuracy measures diagnostic odds ratio (DOR) and symmetric summary receiver operating characteristic (SROC). The PLR and NLR and their 95 % confidence interval (CI) were calculated using a fixed effects model according to the Mantel-Haensed method and random effects model based on the work of DerSimonian and Laird, respectively. A total of eight studies were included for analysis. The pooled sensitivity was 0.719 (95 % CI 0.690-0.746). The pooled specificity was 0.868 (95 % CI 0.849-0.885). The DOR estimate was performed and the result was (16.261). Our meta-analysis showed that CA242 could play an important role in the diagnosis of pancreatic cancer.
Hyponatremia, defined as a nonartifactual serum sodium level <135 mmol/L, is the most common fluid and electrolyte abnormality in clinical practice. Traditional managements (fluid restriction, hypertonic saline and loop diuretics, etc.) are difficult to maintain or ineffective. Recently, vasopressin receptor antagonists (VRAs) have shown promise for the treatment of hyponatremia.We aimed to conduct a meta-analysis to evaluate the efficacy and safety of VRAs in patients with euvolemic or hypervolemic hyponatremia. We searched Pubmed, Cochrane Library, Web of Science and Springer, etc. (latest search on June 4, 2015) for English publications with randomized controlled trials. Two authors independently screened the citations and extracted data. We calculated pooled relative risk (RR), risk difference (RD), weighted mean difference (WMD) or standard mean difference (SMD), and 95% confidence intervals (CIs) by using random and fixed effect models.We collected data from 18 trials involving 1806 patients. Both random and fixed effect meta-analyses showed that VRAs significantly increased the net change of serum sodium concentration (WMDrandom = 4.89 mEq/L, 95%CIs = 4.35–5.43 and WMDfixed = 4.70 mEq/L, 95%CIs = 4.45–4.95), response rate (RRrandom = 2.77, 95%CIs = 2.29–3.36 and RRfixed = 2.95, 95%CIs = 2.56–3.41), and 24-hour urine output (SMDrandom = 0.82, 95%CIs = 0.65–1.00 and SMDfixed = 0.79, 95%CIs = 0.66–0.93) compared to placebo. Furthermore, VRAs significantly decreased body weight (WMDrandom = −0.87 kg, 95%CIs = −1.24 to −0.49 and WMDfixed = −0.91 kg, 95%CIs = −1.22 to −0.59). In terms of safety, rates of drug-related adverse events (AEs), rapid sodium level correction, constipation, dry mouth, thirst, and phlebitis in the VRA-treated group were greater than those in control group. However, there was no difference in the total number of AEs, discontinuations due to AEs, serious AEs, death, headache, hypotension, nausea, anemia, hypernatremia, urinary tract infection, renal failure, pyrexia, upper gastrointestinal bleeding, diarrhea, vomiting, peripheral edema, and dizziness between the 2 groups. Random effect meta-analyses showed that post treatment urine osmolality, supine systolic blood pressure, and diastolic blood pressure were lowered (WMDrandom = −233.07 mOsmol/kg, 95%CIs = −298.20–147.94; WMDrandom = −6.11 mmHg, 95%CIs = −9.810 to −2.41; WMDrandom = −2.59 mmHg, 95%CIs = −4.06 to −1.11, respectively), but serum osmolality was increased (WMDrandom = 9.29 mOsmol/kg, 95%CIs = 5.56–13.03). There was no significant change from baseline in serum potassium concentration between the 2 groups (WMDfixed = 0.00 mmHg, 95%CIs = −0.07–0.06).VRAs are relatively effective and safe for the treatment of hypervolemic and euvolemic hyponatremia.
Background: Treatment of BC is conventionally based on the presence/absence of ER/PR or HER2 status of the primary tumor. We have enriched this approach by including major genetic and proteomic changes in tumors of individual patients in order to develop a better treatment-rationale based on an alteration driven signaling algorithm. Methods: Genomic and proteomic data from 75 BC patients seen in our center were retrospectively analyzed. Patients were re-biopsied after consultation and samples were characterized (IHC for ER, PR, and HER2; FFPE samples for genomic [Foundation Medicine] and proteomic analyses [Theranostics]). In vivo studies were conducted using xenograft models. Results: Although alterations of PIK3CA, PIK3R1, AKT, PTEN, MDM2, MDM4, TSC1, mTOR and RICTOR are most frequently observed in our patients, there is a distinct pattern of alteration(s) of the PI3K pathway genes in different subtypes of BC. A total of 76 genes were altered in 48 ER+BC patients. In 79% of ER+BC patients the above mentioned PI3K pathway genes were altered. Analyzing the set of alterations of genes in individual patients, we observed that within these 48 patients 25% exhibited alterations in more than one node of the pathway; the most common combination (alterations) being the amplification/mutation of PIK3CA with the amplification of MDM2/4 genes. The percentage of patients belonging to HER2+ & TNBC exhibiting similar alterations in the PI3K pathway genes were significantly lower (∼40%). Our previous in vivo studies demonstrated that GDC-0980 and BEZ235 enhanced the antitumor activity of ABT888 plus carboplatin in TNBC or trastuzumab in HER2+ BC respectively and blocked the growth of established xenograft tumors by 80% to 90% with a concomitant decrease in tumor Ki67, pS6RP and CD31. Mechanistically the action of the PI3K-mTOR pathway targeted drug(s) was tested using cell line based models of BC subtypes pertaining to their respective genomic alterations. A combination of a pan-PI3K pathway inhibitor, GDC-0941 or isoform-specific inhibitors along with AI, trastuzumab, or HRD inhibitors (PARP) blocked proliferative signals and enhanced apoptosis (cleaved caspase3) in ER+/PIK3CA mutated, HER2+/PIK3CA mutated or PTEN-null TNBC cells respectively as demonstrated by WB, flow cytometry, cell proliferation, viability and cytotoxicity assays. A recent study demonstrated that exposure to chemotherapy induced a phenotypic shift or cell state transition towards a transient CD44Hi/CD24Hi chemotherapy-tolerant state, leading to the activation of downstream non-receptor tyrosine kinase signaling towards an emerging adaptive resistance (Goldman et al., Nature Comm. 2015). Hence drug combination(s) are being tested for their effect on CD44/CD24 expression levels, results of which will be presented in the meeting. Conclusion: Plotting the genetic alterations from the patient on the signaling landscape will be useful in cracking the code leading to improved treatment options. Patient specific in-depth plotting of genetic alterations of the PI3K-mTOR pathway and the relevance of these alterations in the context of (1) mechanisms of PI3K-mTOR pathway targeted drugs and (2) cell signaling are critical in determining choice of drugs in BC subtypes. Citation Format: Carlson JH, Krie A, Williams C, Sun Y, Lin X, Williams K, Klein J, Friedman L, De P, Dey N, Leyland-Jones B. Navigating genomic landscape to find a PI3K-signaling algorithm for a rational combinatin in precision medicine. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr P4-08-04.
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