Cabozantinib plus Nivolumab and Ipilimumab in Renal-Cell Carcinoma.

BACKGROUND: The efficacy and safety of treatment with cabozantinib in combination with nivolumab and ipilimumab in patients with previously untreated advanced renal-cell carcinoma are unknown. METHODS: In this phase 3, double-blind trial, we enrolled patients with advanced clear-cell renal-cell carcinoma who had not previously received treatment and had intermediate or poor prognostic risk according to the International Metastatic Renal-Cell Carcinoma Database Consortium categories. Patients were randomly assigned to receive 40 mg of cabozantinib daily in addition to nivolumab and ipilimumab (experimental group) or matched placebo in addition to nivolumab and ipilimumab (control group). Nivolumab (3 mg per kilogram of body weight) and ipilimumab (1 mg per kilogram) were administered once every 3 weeks for four cycles. Patients then received nivolumab maintenance therapy (480 mg once every 4 weeks) for up to 2 years. The primary end point was progression-free survival, as determined by blinded independent review according to Response Evaluation Criteria in Solid Tumors, version 1.1, and was assessed in the first 550 patients who had undergone randomization. The secondary end point was overall survival, assessed in all patients who had undergone randomization. RESULTS: Overall, 855 patients underwent randomization: 428 were assigned to the experimental group and 427 to the control group. Among the first 550 patients who had undergone randomization (276 in the experimental group and 274 in the control group), the probability of progression-free survival at 12 months was 0.57 in the experimental group and 0.49 in the control group (hazard ratio for disease progression or death, 0.73; 95% confidence interval, 0.57 to 0.94; P = 0.01); 43% of the patients in the experimental group and 36% in the control group had a response. Grade 3 or 4 adverse events occurred in 79% of the patients in the experimental group and in 56% in the control group. Follow-up for overall survival is ongoing. CONCLUSIONS: Among patients with previously untreated, advanced renal-cell carcinoma who had intermediate or poor prognostic risk, treatment with cabozantinib plus nivolumab and ipilimumab resulted in significantly longer progression-free survival than treatment with nivolumab and ipilimumab alone. Grade 3 or 4 adverse events were more common in the experimental group than in the control group. (Funded by Exelixis; COSMIC-313 ClinicalTrials.gov number, NCT03937219.).

Projection of August 2021 pumice dispersion from the Fukutoku-Oka-no-Ba eruption in the western North Pacific.

Marine hazards often occur unexpectedly. Long-term (> few weeks) projections are sometimes needed to predict the potential route of drifting targets (e.g. pumice, oil, shipwreck) in order to prevent further disaster, yet reliable long-term forecast data may be unavailable. The present study examined the long-term projection of pumice dispersion originating from the 2021 submarine eruption of Fukutoku-Oka-no-Ba volcano, Japan, based on hindcast reanalysis of the past 28 years of wind and ocean currents using the particle tracking method. The ensemble distribution showed a wide dispersion, which was dominated by the ocean currents. By contrast, wind provided a relatively uniform transport. Apart from the prevailing wind, typhoons also play a role in affecting pumice dispersion. The multi-year simulation provides a general view of pumice dispersion accounting for different uncertainty, which could be used for deducing the potential dispersion under different wind and ocean conditions.

Treatment of Adenoid Cystic Carcinoma of the Palate and Reconstruction of Defect With Nasoseptal Flap: A Clinical Case and Review of Literature.

Adenoid cystic carcinoma (ACC) is a malignant tumor arising from the salivary glands. While surgery is the mainstay of treatment for ACC of the palate, adjuvant radiotherapy and/or chemotherapy should be considered in high-risk cases. Oronasal fistula, a complication of palatal surgery, may cause speech disturbance and food regurgitation; the nasoseptal flap is a potential option to repair this defect as it is readily available and reliable. Here, we present a case of locally advanced ACC of the palate in a patient who underwent endoscopic-assisted transoral tumor excision with nasoseptal flap reconstruction postoperative chemoradiotherapy.

Development and validation of interactive creativity task platform.

Co-creativity focuses on how individuals produce innovative ideas together. As few studies have explored co-creativity using standardized tests, it is difficult to effectively assess the individual's creativity performance within a group. Therefore, this study aims to develop a platform that allows two individuals to answer creativity tests simultaneously. This platform includes two divergent thinking tasks, the Straw Alternative Uses Test and Bottle Alternative Uses Test, and Chinese Radical Remote Associates Test A and B, which were used to evaluate their open-and closed-ended creative problem-solving performance. This platform has two modes: single-player mode and paired-player mode. Responses from 497 adults were collected, based on which the fluency, flexibility, and originality of divergent thinking were measured. This study also developed a computer scoring technique that can automatically calculate the scores on these creativity tests. The results showed that divergent thinking scores from computer-based calculation and manual scoring were highly positively correlated, suggesting that the scores on a divergent thinking task can be calculated through a system that avoids time-consuming, uneconomical manual scoring. Overall, the two types of tests on this platform showed considerable internal consistency reliability and criterion-related validity. This advanced application facilitates the collection of empirical evidence about co-creativity.

The Effectiveness of Mindfulness-Based-Stress-Reduction for Military Cadets on Perceived Stress.

This study aimed to develop a program of mindfulness-based stress reduction for military cadets (MBSR-MC). On the basis of a pretest-posttest design, participants were assigned to either a control or an experimental group to examine the effectiveness of MBSR-MC. First, 60 volunteering cadets of National Defense University were randomly assigned to the MBSR-MC group (n = 30) and the control group (n = 30). In the pretest, all participants were required to complete the Taiwanese version of the Five Facet Mindfulness Questionnaire (T-FFMQ) and a perceived stress scale (PSS). Subsequently, the MBSR-MC group participated in the 8-week MBSR-MC program, whereas the control group did not receive any experimental treatment. One week following the completion of the program, a posttest consisted of the same questions as the pretest was conducted. Statistical analysis showed that (1) Comparing with the control group, the MBSR-MC group showed superior performance in three subscales of T-FFMQ, namely Acting with awareness, Non-judgment, and Non-reactivity. However, no significant difference was found in the remaining two facets: Observing and Describing. (2) The perceived stress score of the MBSR-MC group was significantly lower than that of the control group. Furthermore, an analysis of mediating effect showed that Acting with awareness, Non-judgment, and Non-reactivity were mediating variables of the relationship between MBSR-MC and perceived stress. The aforementioned results indicated that MBSR-MC training significantly increased military cadets' Acting with awareness, Non-judgment, and Non-reactivity, thereby significantly reducing their perceived stress. Therefore, this study supported the effectiveness of the MBSR-MC program on perceived stress.

Characterization of the Survival Influential Genes in Carcinogenesis.

The genes influencing cancer patient mortality have been studied by survival analysis for many years. However, most studies utilized them only to support their findings associated with patient prognosis: their roles in carcinogenesis have not yet been revealed. Herein, we applied an in silico approach, integrating the Cox regression model with effect size estimated by the Monte Carlo algorithm, to screen survival-influential genes in more than 6000 tumor samples across 16 cancer types. We observed that the survival-influential genes had cancer-dependent properties. Moreover, the functional modules formed by the harmful genes were consistently associated with cell cycle in 12 out of the 16 cancer types and pan-cancer, showing that dysregulation of the cell cycle could harm patient prognosis in cancer. The functional modules formed by the protective genes are more diverse in cancers; the most prevalent functions are relevant for immune response, implying that patients with different cancer types might develop different mechanisms against carcinogenesis. We also identified a harmful set of 10 genes, with potential as prognostic biomarkers in pan-cancer. Briefly, our results demonstrated that the survival-influential genes could reveal underlying mechanisms in carcinogenesis and might provide clues for developing therapeutic targets for cancers.

Carbon Monoxide-Releasing Molecule-3 Alleviates Kupffer Cell Pyroptosis Induced by Hemorrhagic Shock and Resuscitation via sGC-cGMP Signal Pathway.

Following hepatic ischemia-reperfusion injury, Kupffer cells could be activated by inflammatory factors released from damaged hepatocytes. Carbon monoxide (CO)-releasing molecule (CORM)-3, a water-soluble transition metal carbonyl, exhibits excellent anti-inflammatory and anti-pyroptosis properties. We investigated whether CORM-3 attenuated hemorrhagic shock and resuscitation (HSR)-induced pyroptosis of Kupffer cells through the soluble guanylate-cyclase (sGC)-cyclic guanosine monophosphate (cGMP) signal pathway. NS2028 (10 mg/kg), a blocker of sGC, was administrated at the onset of hemorrhage, but CORM-3 (4 mg/kg) was infused after resuscitation via femoral vein. Serum alanine aminotransferase (ALT), aspartate aminotransferase (AST) levels, tumor necrosis Factor-α (TNF-α), and interleukin-1ß (IL-1ß) were measured at 3, 6, 12, and 24 h after HSR, respectively. Six hours post-HSR, liver injury, pyroptosis of Kupffer cells, and expressions in total caspase-1, cleaved caspase-1, gasdermin D (GSDMD) N-terminal fragment, IL-1ß, and IL-18 were measured by hematoxylin-eosin (H&E), immunofluorescence and western blot assays, respectively (Fig. 1). The rats exposed to HSR exhibited significant upregulated levels of serum ALT, AST, TNF-α, and IL-1ß, elevated liver injury score, increased pyroptosis of Kupffer cells, and accumulated expressions of pyroptosis-associated protein including cleaved caspase-1, GSDMD N-terminal fragment, IL-1ß, and IL-18 than sham-treated rats. However, CORM-3 administration markedly reduced liver injury and pyroptosis of Kupffer cells, whereas these protective effects could be partially blocked by NS2028. CORM-3 can mitigate pyroptosis of Kupffer cells in a blood loss and re-infusion model of rats via sGC-cGMP signal pathway.

Tracking the marine migration routes of South Pacific silver eels.

Three catadromous Pacific eels (2 Anguilla marmorata, 1 A. megastoma) from the Archipelago of Vanuatu were tagged with pop-up satellite archival transmitters and their migration tracks towards their presumed spawning area approximately 870 km northeast of the point of release were reconstructed in order to evaluate their movements in relation to oceanographic conditions. We used the timing of diel vertical migrations to derive the eels' positions. Two A. marmorata exhibited steep-angled turns resulting in a zig-zag migration path along the east-west axis, while one A. megastoma took a relatively straight course towards the presumed spawning area. They migrated with a speed over ground of 21-23 km day-1. In this region, the eastward flow of the South Equatorial Counter Current (SECC, ∼ 5-10°S) separates the westward flowing South Equatorial Current (SEC; ∼0-5°S and 10-18°S) into two branches. During shallower nighttime migration depths around 150 m eels crossed a variable flow field through the southern branch of the westward SEC with westward propagating mesoscale eddies and the eastward SECC, but stayed south of the stronger northern branch of SEC possibly increasing retention time of larvae within this area. The eels headed towards a tongue of high-salinity Subtropical Underwater (STUW) that may have provided cues for orientation. The eels did not move beyond a salinity front of 35.9-36.0 at a depth of 100-200 m, which may have provided cues for orientation towards the spawning area. These 3 tracks may represent the movements of mature silver eels all the way to where they spawn.

New clues on the Atlantic eels spawning behavior and area: the Mid-Atlantic Ridge hypothesis.

The Sargasso Sea has long been considered as the only spawning area for Atlantic eels, despite the absence of direct observations. The present study raises a novel scenario, deviating from Schmidt's dogma, begins with a review of historical and recent observations that were combined to build up a global theory on spawning ecology and migration behavior of Atlantic eels. From this, it is argued that a favorable spawning area could be located eastward of Sargasso Sea at the intersection between the Mid-Atlantic Ridge and the oceanic fronts. Ocean circulation models combined with 3D particle-tracking method confirmed that spawning at this specific area would result in larval distribution fitting the field observation. This study explores the hypothesis that leptocephali are able to swim and orientate to reach their specific growth areas. It proposes a novel framework about spawning ecology, based on orientation, navigation and meeting cues of silver eels to the spawning area. Together this framework may serve as a stepping-stone for solving the long-lasting mystery of eel reproduction which first came out 2,400 years ago and promotes the understanding of oceanic migration and reproduction of marine organisms.

Role of climate variability in the potential predictability of tropical cyclone formation in tropical and subtropical western North Pacific Ocean.

The out of phase tropical cyclone (TC) formation in the subtropical and tropical western North Pacific associated with local low-level wind vorticity anomaly, driven by the remote central and eastern equatorial Pacific warming/cooling, is investigated based on the reanalysis and observational data in the period of 1979-2017. TC frequencies in the subtropical and tropical western North Pacific appear to be connected to different remote heating/cooling sources and are linked to eastern and central Pacific warming/cooling, which are in turn related to canonical El Niño/Southern Oscillation (ENSO) and ENSO Modoki, respectively. TCs formed in subtropics (SfTC) are generally found to be associated with a dipole in wind vorticity anomaly, which is driven by the tropical eastern Pacific warming/cooling. Tropically formed TCs (TfTC) are seen to be triggered by the single-core of wind vorticity anomaly locally associated with the warming/cooling of central and eastern Pacific. The predicted ENSOs and ENSO Modokis, therefore, provide a potential source of seasonal predictability for SfTC and TfTC frequencies.

Influence of ocean circulation and the Kuroshio large meander on the 2018 Japanese eel recruitment season.

Japanese eel (Anguilla japonica) recruitment to Japan was very low during the early 2017-2018 recruitment season when most glass eels are usually caught, but catches increased in the late recruitment season when recruitment usually decreases. Concurrently, the Kuroshio meander south of Japan had formed again after the previous event ended in 2005. The role of the large meander and ocean circulation features such as the North Equatorial Current (NEC) in the unusual 2017-2018 Japanese eel recruitment timing-pattern was investigated using a three-dimensional particle tracking model that simulated swimming behaviors of virtual larvae (v-larvae) in addition to their drift in ocean currents. Four recruitment seasons were selected for when the Kuroshio large meander was present (2004-2005, 2017-2018) or absent (2009-2010, 2015-2016), and when NEC was shifted north (2004-2005, 2015-2016) or south (2009-2010, 2017-2018). The simulated recruitment timing-patterns were similar to the actual recent-year recruitment, with no early recruitment period v-larvae arrival to southern Japan and increased late period recruitment occurring. Rather than being related to the presence of the Kuroshio large meander, the late arrival appeared to be caused by a southward shifted, weak North Equatorial Current near the spawning area, a longer Subtropical Countercurrent eddy region retention time, and a weak Kuroshio during the early migration and recruitment period of those years. In the late recruitment period, the Kuroshio was stronger than other selected years near the East China Sea and south of Japan and v-larvae were transported more rapidly. The Kuroshio large meander may influence local eel recruitment in Japan, and the recirculation formed by the large meander could potentially enhance recruitment to the Tokai region. Oriented (northwestward) swimming v-larvae were less affected by the large meander, and showed higher recruitment success than those using along-current swimming. Although the Kuroshio large meander did not seem to be responsible for the unusual recruitment pattern in 2018, how Japanese eel larvae and glass eels actually cross out of the Kuroshio and reach coastal waters in Japan remains to be explored.

Oprozomib, pomalidomide, and Dexamethasone in Patients With Relapsed and/or Refractory Multiple Myeloma.

INTRODUCTION: This phase Ib study evaluated oprozomib, an oral proteasome inhibitor, plus pomalidomide-dexamethasone in relapsed/refractory multiple myeloma (RRMM). PATIENTS AND METHODS: Patients received oprozomib once-daily on days 1 to 5 and 15 to 19 (5/14 schedule; 150 mg/day starting dose) or on 2 consecutive days weekly (2/7 schedule; 210 mg/day starting dose) of 28-day cycles, pomalidomide on days 1 to 21 (4 mg/day starting dose), and dexamethasone 20 mg on 2 consecutive days weekly. A 3 + 3 dose-escalation schema was used to determine the maximum tolerated dose. RESULTS: Thirty-one patients were treated (5/14, n = 4; 2/7, n = 27). Oprozomib maximum tolerated dose was not defined. The 2/7 schedule (oprozomib 210 mg/day, pomalidomide 4 mg/day) was selected for dose expansion based on overall safety (n = 17). In this group, the most common adverse events (AEs) were gastrointestinal (diarrhea [88.2%], nausea [58.8%], and vomiting [58.8%]); grade ≥ 3 gastrointestinal AEs were uncommon. The most common grade ≥ 3 AEs were hematologic (anemia [47.1%], neutropenia [35.3%], and thrombocytopenia [29.4%]). One dose-limiting toxicity (gastric hemorrhage) occurred; 3 patients discontinued owing to AEs. The overall response rate was 70.6%. CONCLUSION: Safety and pharmacokinetic profiles were concerns with the oprozomib formulation used in this study and need to be improved. Oprozomib-pomalidomide-dexamethasone (2/7 schedule) had encouraging efficacy, supporting an ongoing phase Ib study evaluating new oprozomib formulations for this combination in relapsed/refractory multiple myeloma.

Efficacy and safety results from a phase 1b/2, multicenter, open-label study of oprozomib and dexamethasone in patients with relapsed and/or refractory multiple myeloma.

Oprozomib is an oral proteasome inhibitor with activity in multiple myeloma (MM). Our phase 1b/2 study examined the safety and efficacy of oprozomib with dexamethasone in patients with relapsed and refractory MM. Oprozomib was administered with a 5/14 or 2/7 schedule with dexamethasone. Phase 1b primary objectives were to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of oprozomib; phase 2 primary objectives were to determine overall response rate (ORR) and safety/tolerability of the RP2D. Between July 2, 2013, and August 29, 2016, data were available on 65 enrolled patients (5/14 schedule, n = 19; 2/7 schedule, n = 46). In phase 1b, MTD was 180 mg (5/14 schedule) and not reached (2/7 schedule); RP2D was 300 mg (2/7 schedule). In phases 1b and 2, ORR across dosing cohorts (210-330 mg) for the 2/7 schedule was 58.7% overall and 46.4% for bortezomib-refractory patients (n = 28). All patients reported ≥1 treatment-emergent adverse event (AE); the most common AEs were gastrointestinal. Grade ≥3 AEs occurred in 78.9% and 82.6% of patients on the 5/14 and 2/7 schedules, respectively. The oprozomib and dexamethasone combination has encouraging activity and could be an important MM therapy if gastrointestinal tolerability is improved.

Philippines-Taiwan Oscillations and its connection to tropical cyclone frequency in the western North Pacific Ocean.

An atmospheric component of the Philippine-Taiwan Oscillations (PTOa) is used to examine its potential connection with tropical cyclone (TC) frequency in the western North Pacific in the period of 1979-2014. During positive PTOa years, more TCs are observed in the tropical western Pacific south of 18 °N where cyclonic wind anomaly appears. On the other hand, anti-cyclonic wind anomaly appears in the subtropics north of 18 °N and is associated with less TC formation there. The opposite wind vorticities in tropics/subtropics and associated variability in TC frequency reverse in negative PTOa phase. Besides, the negative contribution of ocean heat content suggests the relative importance of wind vorticity according to the oceanic cyclone genesis potential index. The PTOa provides a more direct explanation of the TC activity compared to other remotely linked phenomena at least for the past 36 years (1979-2014). Therefore, PTOa can potentially serve as a promising index for diagnosing or forecasting TC activity in the western North Pacific Ocean.

Effect of larval swimming in the western North Pacific subtropical gyre on the recruitment success of the Japanese eel.

The possible effect of directional larval swimming on the recruitment success of the Japanese eel, Anguilla japonica, was examined with a three-dimensional particle-tracking ocean circulation model using horizontal northwestward swimming and diel vertical migration (DVM). Four separate experiments included virtual larvae (v-larvae) movement from the spawning area over 290 days (total migration) and 160 days (stage A), from the STCC eddy region in 70 days (stage B), and from the origin of the Kuroshio in 60 days (stage C) to evaluate the effect of directional swimming and DVM compared to simple drifting. Passive or random swimming were not the most effective strategies for larvae dispersing from the spawning area because most v-larvae remained south of 20°N without entering the Kuroshio. Northwestward swimming resulted in wider dispersion and a better chance of successful recruitment, with v-larvae becoming widely distributed in the STCC eddy zone, arriving at the east coast of the Philippines (stage A), escaping the STCC eddy area and reaching the Kuroshio (stage B), and crossing the Kuroshio into the East China Sea shelf (stage C). DVM slightly shortened the migration period due to faster shallow layer ocean currents during nighttime. The NEC transported non-swimming v-larvae westward to the Kuroshio and occasionally northward into the Subtropical Countercurrent (STCC) area where eddies transported v-larvae westward into the Kuroshio, but less than with swimming. Directional swimming increased recruitment success, northwestward swimming was more effective than other directions, and a slower swimming speed was still better than no/random swimming in sensitivity tests. The present study demonstrated a first view of the possibility that Japanese eel larvae might be able to use a strategy of single-direction swimming to increase arrival at their recruitment areas.

Potential impact of ocean circulation on the declining Japanese eel catches.

Recruitment of Japanese eels, Anguilla japonica, has declined in recent decades possibly due to both anthropogenic and ocean-atmosphere factors. The potential impact of ocean circulation on the decreasing Japanese eel catches in the western North Pacific was examined based on a three-dimensional particle-tracking method, in which virtual larvae (v-larvae) were programmed to swim horizontally and vertically, in addition to being transported by ocean currents after being released in their North Equatorial Current (NEC) spawning area. Transport patterns varied among years between 1993 and 2013, and dispersion of v-larvae towards East Asia decreased in the last two decades, especially for the western Taiwan and Japan regions. In recent years, instead of entering the Kuroshio and moving towards East Asia as in the 1990s', more v-larvae tended to enter the southern areas due to the weakening of the NEC and strengthening of subsurface southward flow near the spawning area. Changes in ocean circulation in the western Pacific appear to be caused by the weakening of subtropical and tropical wind stress curl in the past two decades. This suggests that decadal changes in ocean circulation have occurred that affect the larval migration success of the Japanese eel to their recruitment areas.

[Plan for Improving the Initial Ambulation of Acute Stroke Patients].

BACKGROUND & PROBLEMS: Acute stroke patients should receive a rehabilitation assessment within 24-48 hours of hospitalization. Initial ambulation is known to reduce the occurrence of complications, improve the ability to perform activities of daily living, and reduce the risk of long-term disability. PURPOSE: To raise the initial ambulation willingness of acute stroke patients and to increase the willingness of these patients to receive rehabilitation treatment as soon as possible in order to reduce the long-term physical damage of the stroke incident. RESOLUTIONS: To develop and implement standard operating procedures for the initiation of ambulation (first time leaving the hospital bed) in acute stroke patients, to use health education brochures with texts and illustrations, and to have nurses physically assist patients to initiate ambulation. RESULTS: The rate of ambulation initiation in acute stroke patients rose from 32.0% pre-intervention to 85.4% post-intervention. CONCLUSIONS: Acute stroke patients who initiate ambulation soon after experiencing a stroke may reduce their risk of acute complications, increase their ability to perform activities of daily living, and reduce the risk of long-term disability. Thus, encouraging early ambulation is extremely important to improving the prognosis of this patient population.

Physical and biological roles of mesoscale eddies in Japanese eel larvae dispersal in the western North Pacific Ocean.

The physical and biological roles of mesoscale eddies in Japanese eel larvae dispersal are investigated using a three-dimensional (3D) particle-tracking method, with a focus on the Subtropical Counter Current eddies of the western North Pacific Ocean. Virtual eel larvae (v-larvae) movements depends on the 3D ocean currents and active swimming behavior, including vertical swimming (diel vertical migration), horizontal directional swimming toward settlement habitat, and horizontal swimming toward available food. V-larvae are able to remain in eddies passively due to mesoscale eddy nonlinearity and/or actively due to attraction to rich food supplies. Thus, both physical trapping and biological attraction to food contribute to the retention of v-larvae in eddies. Physical trapping dominates the retention of v-larvae whose swimming speeds are slower than the eddy propagation speed, whereas biological food attraction prevails in the retention of v-larvae swimming faster than eddy propagation. Food availability differs between warm (anti-cyclonic) and cold (cyclonic) eddies, with the latter providing a richer food supply. Fish larvae that are retained for longer durations in cold eddies (shorter durations in warm eddies) are able to obtain more food and potentially grow faster, which enhances survival rates.