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A series of bulky organometallic and organic analogues of the bromodomain (BRD) inhibitor (+)‐JQ1 have been prepared. The most potent, N‐[(adamantan‐1‐yl)methyl]‐2‐[(9S)‐7‐(4‐chlorophenyl)‐4,5,13‐trimethyl‐3‐thia‐1,8,11,12‐tetraazatricyclo[8.3.0.02,6]trideca‐2(6),4,7,10,12‐pentaen‐9‐yl]acetamide, 2e, showed excellent potency with an KD=ca. 130 nmvs. BRD4(1) and a ca. 2‐fold selectivity over BRD4(2) (KD=ca. 260 nm). Its binding to the first bromodomain of BRD4 was determined by a protein cocrystal structure. [ABSTRACT FROM AUTHOR]

In spaceflight experiments, model organisms are used to assess the effects of microgravity on specific biological systems. In many cases, only one biological system is of interest to the Principal Investigator. To maximize the scientific return of experiments, the remaining spaceflight tissue is categorized, documented, and stored in the biobank at NASA Ames Research Center, which is maintained by the Ames Life Science Data Archive (ALSDA). The purpose of this study is to evaluate the state of a sample set of tissues from the ALSDA biobank. Garnering information - such as downstream functional analysis for the generation of omics datasets - from tissues is, in part, dependent on the state of sample preservation. RNA integrity number (RIN) values have been calculated for rodent liver tissues that were part of scientific payloads returned from the International Space Station (ISS). Rat livers from Spacelab Life Sciences 1 (SLS-1) and mouse livers from Commercial Biomedical Test Module 3 (CBTM-3), Rodent Research 1 (RR1), and Rodent Research 3 (RR3) were tested. It was found that mean RIN values from CBTM-3, RR1, and RR3 were suitable for downstream functional analysis (RIN > 5) while the mean RIN value for SLS-1 was not (RIN = 2.5 ± 0.1). Information from this study lays the foundation for future efforts in determining the types of assays that are most appropriate for different tissues in the ALSDA biobank and similar preservation facilities, which would aid in shaping the design of experiments. [ABSTRACT FROM AUTHOR]

DIS3 (defective in sister chromatid joining) is the catalytic subunit of the exosome, a protein complex involved in the 3'-5' degradation of RNAs. DIS3 is a highly conserved exoribonuclease, also known as Rrp44. Global sequencing studies have identified DIS3 as being mutated in a range of cancers, with a considerable incidence in multiple myeloma. In this work, we have identified two protein-coding isoforms of DIS3. Both isoforms are functionally relevant and result from alternative splicing. They differ from each other in the size of their N-terminal PIN (PilT N-terminal) domain, which has been shown to have endoribonuclease activity and tether DIS3 to the exosome. Isoform 1 encodes a full-length PIN domain, whereas the PIN domain of isoform 2 is shorter and is missing a segment with conserved amino acids. We have carried out biochemical activity assays on both isoforms of full-length DIS3 and the isolated PIN domains. We find that isoform 2, despite missing part of the PIN domain, has greater endonuclease activity compared with isoform 1. Examination of the available structural information allows us to provide a hypothesis to explain this altered behaviour. Our results also show that multiple myeloma patient cells and all cancer cell lines tested have higher levels of isoform 1 compared with isoform 2, whereas acute myeloid leukaemia and chronic myelomonocytic leukaemia patient cells and samples from healthy donors have similar levels of isoforms 1 and 2. Taken together, our data indicate that significant changes in the ratios of the two isoforms could be symptomatic of haematological cancers. [ABSTRACT FROM AUTHOR]

S100A8 and S100A9 are both members of the S100 family and have been shown to play roles in myeloid differentiation, autophagy, apoptosis, and chemotherapy resistance. In this study we demonstrate that the BET-bromodomain inhibitor JQ1 causes rapid suppression of S100A8 and S100A9 mRNA and protein in a reversible manner. In addition, we show that JQ1 synergises with daunorubicin in causing AML cell death. Daunorubicin alone causes a dose- and time-dependent increase in S100A8 and S100A9 protein levels in AML cell lines which is overcome by cotreatment with JQ1. This suggests that JQ1 synergises with daunorubicin in causing apoptosis via suppression of S100A8 and S100A9 levels. [ABSTRACT FROM AUTHOR]

The article discusses research on the detection of de novo methyltransferase 3A (DNMT3A) R882 codon mutations that helps identify risks facing patients with acute myeloid leukemia (AML). Topics discussed include DNMT3A detection as a biomarker for treatment and monitoring, pre-treatment identification of a subset of patients, and the detection of a pattern for polymerase chain reaction (PCR)-amplified genomic DNA. Also mentioned are the enzymes used in the study.

The article examines the clinical importance of de novo methyltransferase 3A (DNMT3A) gene mutations as an independent adverse prognostic factor for patients diagnosed with acute myeloid leukemia (AML). It notes that detection of DNMT3A mutations provide a useful biomarker for assessing treatment response and for monitoring minimal residual disease post-treatment. Research reveal that DNMT3A-mutated AML patients show improved outcomes with certain induction chemotherapy regimens.

Background and Methods: The Scottish Adjuvant Tamoxifen Trial (main trial) was initiated in April 1978 to assess the effect of tamoxifen given to patients with breast cancer immediately after mastectomy (or mastectomy plus radiation therapy) (adjuvant arm) or only after the patients had had a relapse (control arm); 1323 patients were randomly assigned (667 to the adjuvant arm and 656 to the control arm). Results have been reported for the follow-up period from 2.5 through 8 years. In this article, we report updated results after a median follow-up of 15 years. If agreeable and eligible, patients who were disease free at 5 years in the adjuvant arm of the main trial were entered into a duration trial and randomly assigned either to stop taking tamoxifen (169 patients) or to continue taking it indefinitely until relapse or death (173 patients). For this update, we analyzed information on death, recurrence, survival, and other malignancies for all but 21 of the 560 living patients from the original and duration trials to determine the probabilities of total survival, systemic relapse of disease, and death from breast cancer. All statistical tests are two-sided.Results: The beneficial effect of adjuvant tamoxifen given for 5 years on the probability of total survival (P =.006), systemic relapse (P =.007), and death from breast cancer (P =.002) has been maintained through 15 years. No additional benefit was observed in those randomly assigned to continue taking tamoxifen beyond 5 years.Conclusion: Information from this study suggests that, if adjuvant tamoxifen is given to women with operable breast cancer, it need not be for more than 5 years. [ABSTRACT FROM AUTHOR]