Efficacy and safety of ibrutinib in Japanese patients with relapsed or refractory mantle cell lymphoma.

In this multicenter, single-arm, phase II study, the efficacy and safety of ibrutinib were examined in Japanese patients with relapsed or refractory mantle cell lymphoma (MCL). Patients (age ≥20 years) with relapsed or refractory MCL who had progressed after receiving at least one prior treatment regimen, were enrolled. Patients were treated with oral ibrutinib (560 mg once daily; 28-day cycle) until disease progression (or relapse), unacceptable toxicity, or study end. The primary end-point was overall response rate. Secondary end-points included duration of response (DOR), time to response, progression-free survival (PFS), overall survival, and safety. Of the 16 patients who received treatment, 5 patients discontinued the study (progressive disease, 4; sepsis, 1). Median duration of ibrutinib exposure was 6.5 months (range, 2.8-8.3 months). The overall response rate was 87.5% (90% confidence interval, 65.6-97.7; complete response = 2 [12.5%]; partial response = 12 [75.0%]). Median time to response for all responders (n = 14) was 1.8 months (range, 0.7-5.3 months). The median DOR and PFS were not estimable due to censoring (range: DOR, 1.1-6.4+ months; PFS, 2.8-8.0+ months). Overall survival data were immature due to the limited observation period. A total of 8/16 patients (50%) had at least one grade 3 adverse event (AE), and 5 (31.3%) patients reported serious AEs. The most commonly reported AEs were diarrhea and stomatitis (37.5% each), platelet count decrease (31.3%), and anemia (25%). Overall, orally administered single agent ibrutinib was efficacious with an acceptable safety profile in Japanese patients with relapsed or refractory MCL. Clinical trial registration NCT02169180 (ClinicalTrials.gov).

Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos.

Nuclear reprogramming of differentiated cells can be induced by oocyte factors. Despite numerous attempts, these factors and mechanisms responsible for successful reprogramming remain elusive. Here, we identify one such factor, necessary for the development of nuclear transfer embryos, using porcine oocyte extracts in which some reprogramming events are recapitulated. After incubating somatic nuclei in oocyte extracts from the metaphase II stage, the oocyte proteins that were specifically and abundantly incorporated into the nuclei were identified by mass spectrometry. Among 25 identified proteins, we especially focused on a multifunctional protein, DJ-1. DJ-1 is present at a high concentration in oocytes from the germinal vesicle stage until embryos at the four-cell stage. Inhibition of DJ-1 function compromises the development of nuclear transfer embryos but not that of fertilized embryos. Microarray analysis of nuclear transfer embryos in which DJ-1 function is inhibited shows perturbed expression of P53 pathway components. In addition, embryonic arrest of nuclear transfer embryos injected with anti-DJ-1 antibody is rescued by P53 inhibition. We conclude that DJ-1 is an oocyte factor that is required for development of nuclear transfer embryos. This study presents a means for identifying natural reprogramming factors in mammalian oocytes and a unique insight into the mechanisms underlying reprogramming by nuclear transfer.

Enhancement of intestinal IgA production by Ajoene in mice.

We investigated the effects of ajoene on intestinal IgA production. Ajoene (1.35, 4.5, and 13.5 µg/kg/d) was administered to mice for 4 weeks. The fecal IgA level in the 13.5 µg/kg/d group increased after 3 weeks. The intestinal IgA level also increased in a dose-dependent manner upon ajoene administration. An oil-macerated garlic extract, with 1500 µg/g of ajoene, enhanced the intestinal IgA production.

High probability of successive occurrence of Nankai megathrust earthquakes.

Great earthquakes along the Nankai megathrust in south-western Japan feature in the top priority list of Japan's disaster management agenda. In May 2019, an alert system was incepted to issue public warnings when the probability of an earthquake occurrence along the Nankai megathrust became higher than usual. One of the cases that trigger the issuance of public warnings is when a great earthquake occurred and another one of the same scale is anticipated within a short period of time. Although such "twin ruptures" have occurred multiple times along the Nankai megathrust, the quantification of the probability of such twin ruptures has never been attempted. Based on global statistics and local earthquake occurrence history, we estimated the probability of a successive occurrence of two M8 or larger earthquakes within 3 years globally and along the Nankai megathrust to be 5.0-18% and 4.3-96%, respectively. The timing of the second earthquake followed the Omori-Utsu law in global statistics, which allowed the estimation of the probability for the successive occurrence of Nankai megathrust earthquakes in arbitrary time frames. The predicted probability for the one-week timeframe was 100-3600-fold higher than that of the norm, endorsing the necessity for the warning scheme.

Successful Resuscitation Following Intraoperative Acute Pulmonary Embolism With a Focus on Control of Bleeding After Thrombolytic Therapy: A Case Report.

Acute pulmonary embolism is a serious perioperative complication. Current guidelines focus on hemodynamic stabilization and rapid restoration of pulmonary artery blood flow. However, various complications, most notably bleeding, are associated with treatment of the embolism. We report a case of acute pulmonary embolism with cardiopulmonary arrest during orthopedic surgery. Prompt thrombolysis and gaining control of both thrombolytic therapy-induced bleeding from the wound and a hepatic cyst enabled the patient to recover without neurological deficits.

A cold seep triggered by a hot ridge subduction.

The Chile Triple Junction, where the hot active spreading centre of the Chile Rise system subducts beneath the South American plate, offers a unique opportunity to understand the influence of the anomalous thermal regime on an otherwise cold continental margin. Integrated analysis of various geophysical and geological datasets, such as bathymetry, heat flow measured directly by thermal probes and calculated from gas hydrate distribution limits, thermal conductivities, and piston cores, have improved the knowledge about the hydrogeological system. In addition, rock dredging has evidenced the volcanism associated with ridge subduction. Here, we argue that the localized high heat flow over the toe of the accretionary prism results from fluid advection promoted by pressure-driven discharge (i.e., dewatering/discharge caused by horizontal compression of accreted sediments) as reported previously. However, by computing the new heat flow values with legacy data in the study area, we raise the assumption that these anomalous heat flow values are also promoted by the eastern flank of the currently subducting Chile Rise. Part of the rift axis is located just below the toe of the wedge, where active deformation and vigorous fluid advection are most intense, enhanced by the proximity of the young volcanic chain. Our results provide valuable information to current and future studies related to hydrothermal circulation, seismicity, volcanism, gas hydrate stability, and fluid venting in this natural laboratory.

Relationship of preseismic, coseismic, and postseismic fault ruptures of two large interplate aftershocks of the 2011 Tohoku earthquake with slow-earthquake activity.

To improve our understanding of the interactions between regular and slow earthquakes along the Japan Trench, we investigated the spatial relationship of slow-earthquake activity with the preseismic, coseismic, and postseismic fault ruptures of interplate earthquakes off the Iwate and Ibaraki coasts, Japan, including two large interplate aftershocks of the 2011 Tohoku earthquake: the 2011 off Iwate earthquake (MJMA 7.4) and the 2011 off Ibaraki earthquake (MJMA 7.6). We found that the coseismic ruptures of these earthquakes did not overlap with the active areas of slow earthquakes, while their foreshocks and aftershocks occurred in slow-earthquake-prone areas. Moreover, the 2011 off Iwate earthquake and the previous M7-class events shared common fault rupture characteristics: coseismic rupture occurred in a common asperity area, and afterslip with many aftershocks was triggered in the active area of slow earthquakes. Off the Ibaraki coast, tremor activity on a subducting seamount located updip of the coseismic rupture of the 2011 off Ibaraki earthquake implies that the seamount acted as a soft barrier to the coseismic rupture of the 2011 off Ibaraki earthquake. This study demonstrates that large earthquakes off the Iwate and Ibaraki coasts feature similar rupture behaviors, spatially complementary distributions of coseismic ruptures with slow-earthquake activity and foreshock and aftershock activities within and around slow-earthquake-prone areas. This information is useful in considering future large earthquakes along the Japan Trench.

Antidiabetic effects of ajoene in genetically diabetic KK-A(y) mice.

Antidiabetic effects of ajoene, derived from garlic, were investigated in genetically diabetic KK-A(y) mice. Four-week-old male KK-A(y) mice were kept on a laboratory diet containing 0.02 or 0.05% of ajoene for 8 wk. The elevation of water intake was suppressed depending on ajoene intake. The levels of plasma glucose in the 0.05% ajoene-containing diet group was significantly suppressed to 73.8% compared with the control group at the 8th wk. Similarly, the plasma triglyceride level was significantly suppressed. It is suggested that hyperglycemia and hypertriglyceridemia are suppressed by ajoene treatment.

Prophylactic effects of ajoene on cerebral injury in stroke-prone spontaneously hypertensive rats (SHRSP).

As part of a basic study on the prevention of cerebral injury, ajoene (0.5 mg/d) and oil-macerated garlic extract (OMGE, containing 0.5 mg ajoene/d) were administrated to stroke-prone spontaneously hypertensive rats (SHRSP) among 8 weeks from 9 weeks of age. In the control group, 3 of 10 rats died (30%), whereas all SHRSP treated by ajoene or OMGE survived. Our results suggested that ajoene and OMGE-treatment reduced the mortality and cerebral injury in SHRSP. The levels of thiobarbituric acid reactive substance (TBARS) and the enzymatic activities of glutathione peroxidase (GSH-Px), superoxide dismutase (SOD) and catalase (CAT) in the serum of stroke stage of SHRSP were measured. The results obtained were as follows; the TBARS level of the ajoene and OMGE-treated groups were lower than those of control groups. On the other hand, the GSH-Px and SOD activities of the ajoene and OMGE-treated groups were higher. Our results suggested that ajoene and OMGE were capable of having prophylactic effects on cerebral injury in SHRSP.

Inhibition by ajoene of skin-tumor promotion in mice.

Ajoene, a major compound containing sulfur in oil-macerated garlic products, inhibited in a two-stage carcinogenesis test on mouse skin. Treatment with ajoene suppressed skin tumor formation, depending on the amount. In particular, the group treated with 250 microg of ajoene had only 4.9% the number of tumors per mouse compared with the control group at 18 weeks.