A Single Preoperative Dose of Tranexamic Acid Reduces Perioperative Blood Loss: A Meta-analysis.

OBJECTIVE: To review the efficacy and safety of a single dose of intravenous tranexamic acid (TXA) given preoperatively. SUMMARY BACKGROUND DATA: TXA is a synthetic antifibrinolytic that has been used in various surgical disciplines to reduce blood loss, blood transfusions, ecchymosis, and hematoma formation. However, there is no universal standard on the most effective dose and route of TXA administration, limiting its routine use in many centers. This study evaluates the current evidence for the efficacy and safety of a single preoperative dose of TXA on surgical blood loss in all surgical disciplines. METHODS: With the guidance of a research librarian, in accordance with the Cochrane Handbook Medline, Cochrane Central and Embase were searched in November 2018. Search terms included "Tranexamic Acid" AND "Intravenous," with studies limited to randomized controlled trails in adult humans. Two independent reviewers and an arbitrator assessed articles for inclusion. Criteria included a single preoperative bolus dose of intravenous TXA, surgical patients, and intraoperative blood loss measurement or perioperative blood loss up to 24 hours postsurgery. Quality assessment was done using the Cochrane Collaboration risk-of-bias tool by 2 reviewers. Statistical analysis was carried out using Cochrane Review Manager 5.3. The primary outcome was surgical blood loss. Secondary outcomes included venous thromboembolic complications, transfusion requirements, and dosing. RESULTS: A total of 1906 articles were screened, 57 met inclusion criteria. The majority of included studies were orthopedic (27), followed by obstetric and gynecological (16), oral maxillofacial and otolaryngology (10), cardiac (3), and 1 plastic surgery study focusing on acute burn reconstruction. Across all surgical specialties (n = 5698), the perioperative estimated blood loss was lower in patients receiving TXA, with a standard mean difference of -153.33 mL (95% CI = -187.79 to -118.87). Overall, surgical patients with TXA had a 72% reduced odds of transfusion (odds ratio = 0.28 [95% CI = 0.22-0.36]). The most frequently used dose of TXA was 15 mg/kg. There was no difference in the incidence of venous thromboembolic events between TXA and control groups. CONCLUSIONS: While there is a growing body of evidence to support benefits of perioperative TXA use, this is the first meta-analysis to identify the efficacy and safety of a single preoperative dose of IV TXA. The potential implications for expanding the use of preoperative TXA for elective day surgery procedures is substantial. Preoperative intravenous TXA reduced perioperative blood loss and transfusion requirements in a variety of surgical disciplines without increasing the risk of thromboembolic events. Therefore, it should be considered for prophylactic use in surgery to reduce operative bleeding.

The crucial role of DNA-dependent protein kinase and myelin transcription factor 1-like protein in the miR-141 tumor suppressor network.

Glioblastoma is the most aggressive brain tumor. Although miR-141 has been demonstrated to primarily function as a tumor suppressor in numerous malignancies, including glioblastoma, the mechanisms involved remain poorly understood. Here, it is shown that miR-141 is downregulated in glioblastoma cell lines and tissues and may exert its biological function via directly targeting myelin transcription factor 1-like (MYT1L). Using two glioblastoma cell lines that differ from each other by the functionality of DNA-dependent protein kinase (DNAPK), a functional involvement of DNAPK in the miR-141 tumor suppression network was observed. In M059K cells with a normal function of DNAPK, the enforced expression of miR-141 attenuated MYT1L expression and suppressed cell proliferation. Conversely, the inhibition of miR-141 expression promoted cell proliferation; however, in M059J cells with a loss-of-function DNAPK, miR-141 constitutively inhibited cell proliferation upon ectopic overexpression or inhibition. An overexpression of miR-141 suppressed M059J cell migration, while it had no effect on M059K. Furthermore, the ectopic expression of miR-141 induced an S-phase arrest in both cell lines, whereas the inhibition of miR-141 caused a G1 arrest in M059J and accelerated the S phase in M059K. An overexpression and suppression of miR-141 resulted in an aberrant expression of cell-cycle proteins, including p21. Moreover, MYT1L may be a transcription factor of p21 in p53-mutant cells, whereas DNAPK may function as a repressor of MYT1L. The findings revealed the crucial role of DNAPK in miR-141-mediated suppression of gliomagenesis and demonstrated that it may be a target molecule in miR-141-associated therapeutic interventions for glioblastoma.

Profiling of Small Nucleolar RNAs by Next Generation Sequencing: Potential New Players for Breast Cancer Prognosis.

One of the most abundant, yet least explored, classes of RNA is the small nucleolar RNAs (snoRNAs), which are well known for their involvement in post-transcriptional modifications of other RNAs. Although snoRNAs were only considered to perform housekeeping functions for a long time, recent studies have highlighted their importance as regulators of gene expression and as diagnostic/prognostic markers. However, the prognostic potential of these RNAs has not been interrogated for breast cancer (BC). The objective of the current study was to identify snoRNAs as prognostic markers for BC. Small RNA sequencing (Illumina Genome Analyzer IIx) was performed for 104 BC cases and 11 normal breast tissues. Partek Genomics Suite was used for analyzing the sequencing files. Two independent and proven approaches were used to identify prognostic markers: case-control (CC) and case-only (CO). For both approaches, snoRNAs significant in the permutation test, following univariate Cox proportional hazards regression model were used for constructing risk scores. Risk scores were subsequently adjusted for potential confounders in a multivariate Cox model. For both approaches, thirteen snoRNAs were associated with overall survival and/or recurrence free survival. Patients belonging to the high-risk group were associated with poor outcomes, and the risk score was significant after adjusting for confounders. Validation of representative snoRNAs (SNORD46 and SNORD89) using qRT-PCR confirmed the observations from sequencing experiments. We also observed 64 snoRNAs harboring piwi-interacting RNAs and/or microRNAs that were predicted to target genes (mRNAs) involved in tumorigenesis. Our results demonstrate the potential of snoRNAs to serve (i) as novel prognostic markers for BC and (ii) as indirect regulators of gene expression.

Genome-wide profiling of transfer RNAs and their role as novel prognostic markers for breast cancer.

Transfer RNAs (tRNAs, key molecules in protein synthesis) have not been investigated as potential prognostic markers in breast cancer (BC), despite early findings of their dysregulation and diagnostic potential. We aim to comprehensively profile tRNAs from breast tissues and to evaluate their role as prognostic markers (Overall Survival, OS and Recurrence Free Survival, RFS). tRNAs were profiled from 11 normal breast and 104 breast tumor tissues using next generation sequencing. We adopted a Case-control (CC) and Case-Only (CO) association study designs. Risk scores constructed from tRNAs were subjected to univariate and multivariate Cox-proportional hazards regression to investigate their prognostic value. Of the 571 tRNAs profiled, 76 were differentially expressed (DE) and three were significant for OS in the CC approach. We identified an additional 11 tRNAs associated with OS and 14 tRNAs as significant for RFS in the CO approach, indicating that CC alone may not capture all discriminatory tRNAs in prognoses. In both the approaches, the risk scores were significant in the multivariate analysis as independent prognostic factors, and patients belonging to high-risk group were associated with poor prognosis. Our results confirmed global up-regulation of tRNAs in BC and identified tRNAs as potential novel prognostic markers for BC.

Non-coding RNAs including miRNAs, piRNAs, and tRNAs in human cancer.

Over 98% of our genes code for RNA transcripts that will never become translated into protein. Numerous non-coding RNA (ncRNA) transcripts are structurally and functionally diverse. In particular, micro RNAs (miRNAs), piwi-interacting RNAs (piRNAs), and, more recently, transfer RNAs (tRNAs) are implicated as regulators of key genes and processes that are involved in various human diseases, including cancer. Here, we summarize the recent findings and perspectives in the small RNA and cancer research.

A suppressive role of ionizing radiation-responsive miR-29c in the development of liver carcinoma via targeting WIP1.

Hepatocellular carcinoma (HCC) is the third most common cause of cancer-related deaths worldwide, and it has been linked to radiation exposure. As a well-defined oncogene, wild-type p53-induced phosphatase 1 (WIP1) plays an inhibitory role in several tumor suppressor pathways, including p53. WIP1 is amplified and overexpressed in many malignancies, including HCC. However, the underlying mechanisms remain largely unknown. Here, we show that low-dose ionizing radiation (IR) induces miR-29c expression in female mouse liver, while inhibiting its expression in HepG2, a human hepatocellular carcinoma cell line which is used as a model system in this study. miR-29c expression is downregulated in human hepatocellular carcinoma cells, which is inversely correlated with WIP1 expression. miR-29c attenuates luciferase activity of a reporter harboring the 3'UTR binding motif of WIP1 mRNA. Ectopic expression of miR-29c significantly represses cell proliferation and induces apoptosis and G1 arrest in HepG2. In contrast, the knockdown of miR-29c greatly enhances HepG2 cell proliferation and suppresses apoptosis. The biological effects of miR-29c may be mediated by its target WIP1 which regulates p53 activity via dephosphorylation at Ser-15. Finally, fluorescence in situ hybridization (FISH) and immunohistochemical analyses indicate that miR-29c is downregulated in 50.6% of liver carcinoma tissues examined, whereas WIP1 is upregulated in 45.4% of these tissues. The expression of miR-29c inversely correlates with that of WIP1 in HCC. Our results suggest that the IR-responsive miR-29c may function as a tumor suppressor that plays a crucial role in the development of liver carcinoma via targeting WIP1, therefore possibly representing a target molecule for therapeutic intervention for this disease.