The objectives of this study were to evaluate the safety, tolerability and pharmacokinetics (PK) of BMS‐986001 as a single oral dose in healthy male subjects. Sixty‐four healthy male subjects were ...randomized to receive a single dose of BMS‐986001 or placebo in this single‐blind, placebo‐controlled, sequential ascending‐dose study. There were eight treatment groups (10, 30, 100, 300, 600, and 900 mg fed; and 100 and 300 mg fasted) of eight subjects each (BMS‐986001 n = 6/placebo n = 2). BMS‐986001 was well tolerated, with no serious adverse events (AEs), deaths, or discontinuations due to AEs reported. AEs were experienced by 14.6% of subjects receiving BMS‐986001; however, these did not appear to be dose related and were not considered to be related to study drug. BMS‐986001 was rapidly absorbed and exhibited a linear dose–exposure relationship across the dose range studied. PK appeared similar whether administered with or without food. Administration of BMS‐986001 as a single dose was generally safe and well tolerated. A linear dose–exposure relationship was seen across all doses studied, with no apparent food effect. Further clinical development is warranted.
The operating range of lean-burn spark-ignition (SI) engines is limited by the cycle-to-cycle variability of the fuel concentration at or near the spark plug at ignition timing. An experimental ...investigation was undertaken to measure the temporal and spatial distribution of hydrocarbon (HC) concentration in a spark-ignition engine, using the infrared (IR) laser absorption at 3392 nm. The purposes were to establish whether there is a correlation between time-resolved HC measurements for a range of global air-to-fuel (A/F) ratios (A/F = 15.5-23) with the strength of the firing stroke and to establish how this varies with fuel port-injection strategies against either open (injection timing 30° crank angle (CA) after intake top dead center) or closed-valves (injection timing 180°CA after intake top dead center), respectively resulting in stratified and near-homogeneous charge distributions. The results showed that IR line-of-sight (LOS) averaged A/F ratio measurements yielded a good agreement with the global A/F ratio readings obtained by the linear air-to-fuel (LAF) zirconia-based sensor. Furthermore, the cyclic variability of the measurements of the fuel concentration increased with increasing A/F ratio. At A/F = 23, closed-valve injection strategy resulted in small spatial stratification of the fuel charge with an ensemble-averaged correlation coefficient of fluctuations of the IR LOS A/F ratios with fluctuations of peak in-cylinder pressure of 0.37. For open-valve injection strategy, which resulted in axial fuel mixture charge-stratification but no radial charge-stratification, a maximum correlation coefficient of the IR LOS A/F ratios with fluctuations of peak pressure of 0.34 was measured (at the measurement location closest to the spark). This correlation was reduced to 0.17 at locations furthest from the spark plug. Finally, results showed that at A/F = 23, fuel stratification can be used to control lean-burn SI combustion, while at A/F = 15.5, no significant difference was observed between the two injection timings. The consequences of these findings on the fuel distribution in the pentroof and the control of the lean limits of SI engines are discussed.
We report on follow-up observations of the gamma-ray burst GRB 060927 using the robotic ROTSE-IIIa telescope and a suite of larger aperture ground-based telescopes. An optical afterglow was detected ...20 s after the burst, the earliest rest-frame detection of optical emission from any GRB. Spectroscopy performed with the VLT about 13 hr after the trigger shows a continuum break at lambda approximately 8070 AA, produced by neutral hydrogen absorption at unk approximately 5.6. We also detect an absorption line at 8158 AA, which we interpret as Si II lambda 1260 at unk = 5.467. Hence, GRB 060927 is the second most distant GRB with a spectroscopically measured redshift. The shape of the red wing of the spectral break can be fitted by a damped Lya profile with a column density with log(N sub(H)/cm super(-2)) = 22.50 plus or minus 0.15. We discuss the implications of this work for the use of GRBs as probes of the end of the dark ages and draw three main conclusions: (1) GRB afterglows originating from unk unk unk should be relatively easy to detect from the ground, but rapid near-infrared monitoring is necessary to ensure that they are found; (2) the presence of large H I column densities in some GRB host galaxies at unk > 5 makes the use of GRBs to probe the reionization epoch via spectroscopy of the red damping wing challenging; and (3) GRBs appear crucial to locate typical star-forming galaxies at unk > 5, and therefore the type of galaxies responsible for the reionization of the universe.
Abstract Study question Does assisted hatching (AH) affect pregnancy outcomes especially when it was performed selectively on specified group? Summary answer No clinically significant effect of AH on ...pregnancy outcomes was demonstrated for the entire single embryo transfer (SET) cycle after adjusting for covariates. What is known already AH is a technique used in assisted reproduction by artificially thinning or making a small hole in the zona pellucida in order to facilitate the hatching process. It is suggested that AH may improve the chance of embryo implantation and success of pregnancy. However, there is insufficient evidence to conclude that AH improves pregnancy outcomes, despite its widespread and longtime use. In 2014, the Practice Committee of ASRM recommended that AH should not be conducted routinely for all patients. On the other hands, it has been suggested that AH could be effective for patients with poor prognosis. Study design, size, duration A retrospective observational study based on the national ART registry maintained by the Japan Society of Obstetrics and Gynecology (JSOG) was performed. The study included 1,833,485 single embryo transfer (SET) for in vitro fertilization (IVF) and intracytoplasmic sperm injection (ICSI) from January 2010 to December 2019. This study was approved by the Registration and Research Subcommittee of the JSOG and Tokyo University Ethics Committee. Participants/materials, setting, methods To determine the effect of AH, the rate of clinical pregnancy and live birth were compared in SET with and without AH as primary outcome measures. In addition, the prevalence of miscarriage, multiple pregnancy, ectopic pregnancy, placental malposition, and placenta accreta were analyzed as secondary outcomes. We performed inverse probability of treatment weighting and outcome regression analyses. Main results and the role of chance Out of 1,833,485 SET cycles, AH was conducted in 983,242 cycles (53.6%). In all SET cycles, clinical pregnancy rate (CRP) and live birth rate (LBR) were 31.0% vs. 26.2%, and 21.6% vs. 18.7% in AH vs. without AH group, respectively. AH was more frequently performed in patients with advanced maternal age, frozen-thawed ET cycles (88% vs. 47%, AH vs. without AH), blastocyst transfer cycles (70% vs. 42%), patients with tubal factor (17% vs 14.3%), and hormonal replacement cycles (66% vs. 43%). After adjusting for these covariates, the propensity-weighted CPR (28.4% vs. 29.1%, AH vs. without AH) and LBR (20.1% vs. 20.6%) were slightly yet significantly lower in AH group. As secondary outcomes, AH may lead to increased risk of multiple pregnancy (0.21% increase), ectopic pregnancy (0.02%), and placenta accreta (0.03%), and 0.24% decreased risk of miscarriage. On the other hands, subgroup analysis suggested that AH could be effective in the following cycles: frozen-thawed cycles with either blast or cleavage with maternal age under 35 years, and fresh blastocyst transfer cycles with maternal age over 40 years. Limitations, reasons for caution The limitation of this study is that the information regarding the history of repeated implantation failure and methods of AH were not included in this registry system. Another limitation is that duplicate data from same patients who underwent multiple embryo transfers exists in this retrospective study for 10 years. Wider implications of the findings Despite of frequent use of AH in Japan, AH in SET cycles for all patients is not recommended because of increased risk of adverse events without improvement of pregnancy outcomes. On the other hands, AH may improve pregnancy outcomes for some groups associated with maternal age and duration of culture. Trial registration number not applicable’
ABSTRACT
Glutathione S‐transferase (GST) functions in xenobiotic biotransformation and drug metabolism. Increased expression of GSTπ, an isozyme of GST, has been found in cancer cells resistant to ...doxo‐rubicin hydrochloride (DOX) or cis‐diamminedichloro‐platinum (II) (CDDP), and this increase was believed to be correlated with drug resistance of cancer cells. GST is mainly expressed in the cytoplasm;GSTπ in the nucleus has been reported in cancer cells, but the meaning of this result is not known. Here, we studied changes in the amount of nuclear GSTπ after exposure of cancer cells to anticancer drugs, and role of the nuclear GSTπ in drug resistance. We found nuclear GSTπ in cancer cells resistant to DOX, and the amount of nuclear GSTπ was enhanced by treatment of the cancer cells with DOX or CDDP. We also found that a mushroom lectin, an inhibitor of nuclear transport, inhibited the nuclear transfer of GSTπ, suggesting the existence of a specific transport system for the nuclear transfer of GSTπ. Nuclear GSTπ protected DNA against damage by anticancer drugs. These results suggest a possible role of GSTπ in the acquisition of resistance to anticancer drugs by cancer cells.—Goto, S., Ihara, Y., Urata, Y., Izumi, S., Abe, K., Koji, T., Kondo, T. Doxorubicin‐induced DNA intercalation and scavenging by nuclear glutathione S‐transferase π. FASEB J. 15, 2702–2714 (2001)
We present our optical observations of the GRB 070518 afterglow obtained at the 0.8-m Tsinghua University–National Astronomical Observatory of China Telescope (TNT) at Xinglong Observatory. Our ...follow-up observations were performed from 512 s after the burst trigger. With the upper limit of redshift ∼0.7, GRB 070518 is found to be an optically dim burst. The spectra indices βox of optical to X-ray are slightly larger than 0.5, which implies that the burst might be a dark burst. The extinction AV of the host galaxy is 3.2 mag, inferred from the X-ray hydrogen column density with Galactic extinction law, and 0.3 mag with the Small Magellanic Cloud extinction law. Also, it is similar to three other low-redshift optically dim bursts, which belong to X-ray rich gamma-ray bursts or X-ray flashes and have mid-term duration (T90 < 10, except for GRB 070419A, T90= 116 s). Moreover, its R-band afterglow flux is well fitted by a single power law with an index of 0.87. The optical afterglow and the X-ray afterglow in the normal segment might have the same mechanism, as they are consistent with the prediction of the classical external shock model. Besides, GRB 070518 agrees with the Amati relation under reasonable assumptions. The Ghirlanda relation is also tested with the burst.
OBP-301 (a telomerase-specific, replication-competent adenovirus with hTERT promoter) was constructed in a previous study and it showed a strong anticancer effect by inducing cell lysis in human lung ...and prostate cancer cells. This study investigated the effectiveness of a combination therapy of OBP-301 and interleukin-2 (IL-2) in a mouse model of renal cell carcinoma (RCC). The cell-killing effect of OBP-301 was confirmed in vitro in the RENCA cancer cells. In in vivo experiment, luciferase-expressing RENCA cells were implanted in the left kidney and lung of BALB/c mice to prepare the RCC metastatic model. The animals were randomly divided into four treatment groups: PBS, IL-2 alone, OBP-301 alone and the combination. The analyses of orthotopic tumor weight, lung metastasis and luciferin-stained tumor images 14 days after each treatment showed significant tumor growth inhibition in the combination group in comparison with that in the OBP-301- or IL-2-treated groups. In addition, the percentage of regulatory T-cells (Tregs) in the combination group was significantly suppressed in comparison with that in the PBS and single-agent treatment groups. The outcomes of this study suggest that tumor-specific oncolytic immunovirotherapy may become an attractive strategy for the treatment of human RCC.
Abstract
Study question
Does endoplasmic reticulum (ER) stress and Notch signaling affect cumulus-oocyte complex (COC) expansion in pathophysiology of polycystic ovary syndrome (PCOS)?
Summary answer
...Notch signaling is induced via activation of ER stress in granulosa cells (GCs) of PCOS and stimulates COC expansion that is abrogated by Notch inhibition.
What is known already
PCOS presents a variety of symptoms including ovarian dysfunction which is caused by various local factors in follicular microenvironment; among them, ER stress and following activation of unfolded protein response are critical, causing ovarian fibrosis, growth arrest of antral follicles and other ovarian dysfunctions. While Notch signaling pathway plays an important role of various ovarian functions such as ovarian development, follicle growth, luteinization and steroid hormone synthesis, the potential interaction between Notch signaling and ER stress in ovarian function is not determined.
Study design, size, duration
To examine expression levels of Notch signaling, ovaries and granulosa-lutein cells (GLCs) were collected from PCOS patients undergoing surgery or IVF. Human GLCs were collected from follicular fluid of IVF patients and cultured under ER-stressed condition. COCs obtained from PMSG-primed mice were subjected to examine the in vitro effects of ER stress activation and Notch inhibition on COC expansion. To examine the in vivo effects of Notch inhibition, dehydroepiandrosterone-induced PCOS mouse model was used.
Participants/materials, setting, methods
The expression levels of Notch signaling in ovaries and GLCs were investigated by immunohistochemistry and real time qPCR. To examine whether Notch signaling is activated by ER stress, human GLCs were incubated with ER stress inducer or inhibitor and ATF4 was knocked down by RNA interference. To investigate COC expansion level, murine COCs were cultured under ER stress condition with/without Notch signaling inhibitor. The COCs were collected from PCOS mice treated with/without Notch inhibitor.
Main results and the role of chance
We found that the expression levels of Notch2 and Hey2, a transcription factor activated by Notch signaling, were upregulated in GCs of antral follicles from PCOS patients and PCOS mice by using immunohistochemical analysis. Similarly, mRNA levels of these genes were higher in GLCs from PCOS patients than those from control patients. Notch signaling was induced in cultured human GLCs incubated with an ER stress inducer, tunicamycin; the effect was abrogated by incubation with an ER stress inhibitor, tauroursodeoxycholic acid (TUDCA), or knockdown of activating transcription factor 4 (ATF4, a transcription factor induced by ER stress). These findings suggest that Notch signaling is induced by ER stress via ATF4 pathway in human GCs. Measuring under a microscope, the area of expanded COCs was increased in cultured murine COCs incubated with tunicamycin, while this stimulatory effect of tunicamycin was abrogated by adding a Notch signaling inhibitor, DAPT. The area of expanded COCs obtained from PCOS model mice was increased compared to control mice, while administration of DAPT to these mice reduced the area. These results suggest that ER stress-induced Notch signaling stimulate COC expansion contributing PCOS pathophysiology.
Limitations, reasons for caution
COC expansion area was measured only in PCOS model mouse; it is unknown whether COC expansion is induced in PCOS patients. This point requires further investigation in PCOS patients.
Wider implications of the findings
Our findings suggest that ER stress-induced Notch signaling affects COC expansion, associated with ovulatory dysfunction in PCOS. The detailed understandings of PCOS pathophysiology may be beneficial for substantial clinical implications and inhibition of ER stress or Notch signaling may serve as a novel therapeutic approach for PCOS.
Trial registration number
This study was supported by Grants-in-Aid for Scientific Research from the Japan Society for the Promotion of Science (JSPS) (19k09749, 19k24045, 19k24021, 21k16808, 21j12871,), a grant from the Takeda Science Foundation, a grant from The Tokyo Society of Medical Science, a grant from The Japan Society of Fertility Preservation, and a grant from The Japan Society for Menopause and Women’s Health (JMWH) (a JMWH Bayer Grant).
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