Development of a Normal Porcine Cell Line Growing in a Heme-Supplemented, Serum-Free Condition for Cultured Meat.

A key element for the cost-effective development of cultured meat is a cell line culturable in serum-free conditions to reduce production costs. Heme supplementation in cultured meat mimics the original meat flavor and color. This study introduced a bacterial extract generated from Corynebacterium that was selected for high-heme expression by directed evolution. A normal porcine cell line, PK15, was used to apply the bacterial heme extract as a supplement. Consistent with prior research, we observed the cytotoxicity of PK15 to the heme extract at 10 mM or higher. However, after long-term exposure, PK15 adapted to tolerate up to 40 mM of heme. An RNA-seq analysis of these heme-adapted PK15 cells (PK15H) revealed a set of altered genes, mainly involved in cell proliferation, metabolism, and inflammation. We found that cytochrome P450, family 1, subfamily A, polypeptide 1 (CYP1A1), lactoperoxidase (LPO), and glutathione peroxidase 5 (GPX5) were upregulated in the PK15H heme dose dependently. When we reduced serum serially from 2% to serum free, we derived the PK15H subpopulation that was transiently maintained with 5-10 mM heme extract. Altogether, our study reports a porcine cell culturable in high-heme media that can be maintained in serum-free conditions and proposes a marker gene that plays a critical role in this adaptation process.

Increase of the indoor concentration of volatile organic compounds after the use of incense and scented candle in studio apartments determined using passive sampling.

Burning incenses and scented candles may provide harmful chemicals. Although many studies have evaluated volatile organic chemicals emitted by their use and related health risks, extension of our understanding for guiding appropriate use under various use conditions is necessary. In this study, emission characteristics of commercial incenses and scented candles were evaluated in a laboratory chamber using real-time measurement and the time-weighted average exposure concentrations of monoaromatic compounds and monoterpenes were assessed using passive samplers while volunteers living in a studio apartment use them. After burning incense, the average levels of benzene increased from 1.4 to 100 µg m-3. The presence of a wood core in commercial incense products was the main cause of high benzene emission by burning them although the increase in benzene was also influenced by factors such as the brand of the products, the number of incense sticks burned, the duration of each burning session, and ventilation period. Electrical warming of scented candles increased the levels of monoterpenes by factors of 16-30 on average. Considering the emission characteristics found in this study, exposure to benzene and monoterpenes could be mitigated by cautious use of those products in residential areas.

Instantaneous Thermal Energy for Swift Synthesis of Single-Atom Catalysts for Unparalleled Performance in Metal-Air Batteries and Fuel Cells.

Based on experimental and computational evidence, phthalocyanine (Pc) compounds in the form of quaternary-bound metal-nitrogen (N) atoms are the most effective catalysts for oxygen reduction reaction (ORR). However, the heat treatment process used in their synthesis may compromise the ideal structure, causing the agglomeration of transition metals. To overcome this issue, a novel method is developed for synthesizing iron (Fe) single-atom catalysts with ideal structures supported by thermally exfoliated graphene oxide (GO). This is achieved through a short heat treatment of only 2.5 min involving FePc and N, N-dimethylformamide in the presence of GO. According to the synthesis mechanism revealed by this study, carbon monoxide acts as a strong linker between the single Fe atoms and graphene. It facilitates the formation of a structure containing oxygen species between FeN4 and graphene, which provides high activity and stability for the ORR. These catalysts possess an enormous number of active sites and exhibit enhanced activity toward the alkaline ORR. They demonstrate excellent performance when applied to real electrochemical devices, such as zinc-air batteries and anion exchange membrane fuel cells. It is expected that the instantaneous heat treatment method developed in this study will aid in the development of high-performing single-atom catalysts.

Linking the humification of organic amendments with size aggregate distribution: Insights into molecular composition using FT-ICR-MS.

Soil organic matter (SOM) plays a pivotal role in enhancing physical and biological characteristics of soil. Humic substances constitute a substantial proportion of SOM and their increase can improve crop yields and promote agricultural sustainability. While previous research has primarily assessed the influence that humic acids (HAs) derived from natural water have on soil structure, our study focuses on the impact of HAs on soil aggregation under different fertilizer regimes. During the summer cropping season, maize was cultivated under organic and synthetic fertilizer treatments. The organic fertilizer treatment utilized barley (Hordeum vulgare L.) and hairy vetch (Vicia villosa R.) as an organic amendment five days prior to maize planting. The synthetic treatment included a synthetic fertilizer (NPK) applied at South Korea's recommended rates. The organic treatment resulted in significant improvements in the soil aggregates and stability (mean weight diameter, MWD; p < 0.05) compared to the synthetic fertilizer application. These improvements could be primarily attributed to the increased quantity and quality of HAs in the soil derived from the organic amendment. The amount of extracted HAs in the organic treatment was nearly twice that of the synthetic treatment. Additionally, the organic treatment had a 140 % larger MWD and a 40 % increase in total phenolic content compared to the synthetic treatment. The organic treatment also had an increased macronutrient uptake (p < 0.001), an 11 % increase in aboveground maize biomass, and a 21 % increase in grain yield relative to the synthetic treatment. Thus, the enhancement of HA properties through the incorporation of fresh organic manure can both directly and indirectly increase crop productivity.

The release, degradation, and distribution of PVC microplastic-originated phthalate and non-phthalate plasticizers in sediments.

This study investigated the leaching of phthalate and non-phthalate plasticizers from polyvinyl chloride microplastics (MPs) into sediment and their degradation over a 30-d period via abiotic and biotic processes. The results showed that 3579% of plasticizers were released into the sediment from the MPs and > 99.9% degradation was achieved. Although a significantly higher degradation was found in plasticizer-added microcosms under biotic processes (overall, 94%), there was a noticeable abiotic loss (72%), suggesting that abiotic processes also play a role in plasticizer degradation. Interestingly, when compared with the initial sediment-water partitioning for plasticizers, the partition constants for low-molecular-weight compounds decreased in both microcosms, whereas those for high-molecular-weight compounds increased after abiotic degradation. Furthermore, changes in the bacterial community, abundance of plasticizer-degrading bacterial populations, and functional gene profiles were assessed. In all the microcosms, a decrease in bacterial community diversity and a notable shift in bacterial composition were observed. The enriched potential plasticizer-degrading bacteria were Arthrobacter, Bacillus, Desulfovibrio, Desulfuromonas, Devosia, Gordonia, Mycobacterium, and Sphingomonas, among which Bacillus was recognized as the key plasticizer degrader. Overall, these findings shed light on the factors affecting plasticizer degradation, the microbial communities potentially involved in biodegradation, and the fate of plasticizers in the environment.

A Gellan Gum, Polyethylene Glycol, Hydroxyapatite Composite Scaffold with the Addition of Ginseng Derived Compound K with Possible Applications in Bone Regeneration.

Engineered bone scaffolds should mimic the natural material to promote cell adhesion and regeneration. For this reason, natural biopolymers are becoming a gold standard in scaffold production. In this study, we proposed a hybrid scaffold produced using gellan gum, hydroxyapatite, and Poly (ethylene glycol) within the addition of the ginseng compound K (CK) as a candidate for bone regeneration. The fabricated scaffold was physiochemically characterized. The morphology studied by scanning electron microscopy (SEM) and image analysis revealed a pore distribution suitable for cells growth. The addition of CK further improved the biological activity of the hybrid scaffold as demonstrated by the MTT assay. The addition of CK influenced the scaffold morphology, decreasing the mean pore diameter. These findings can potentially help the development of a new generation of hybrid scaffolds to best mimic the natural tissue.

A new model using deep learning to predict recurrence after surgical resection of lung adenocarcinoma.

This study aimed to develop a deep learning (DL) model for predicting the recurrence risk of lung adenocarcinoma (LUAD) based on its histopathological features. Clinicopathological data and whole slide images from 164 LUAD cases were collected and used to train DL models with an ImageNet pre-trained efficientnet-b2 architecture, densenet201, and resnet152. The models were trained to classify each image patch into high-risk or low-risk groups, and the case-level result was determined by multiple instance learning with final FC layer's features from a model from all patches. Analysis of the clinicopathological and genetic characteristics of the model-based risk group was performed. For predicting recurrence, the model had an area under the curve score of 0.763 with 0.750, 0.633 and 0.680 of sensitivity, specificity, and accuracy in the test set, respectively. High-risk cases for recurrence predicted by the model (HR group) were significantly associated with shorter recurrence-free survival and a higher stage (both, p < 0.001). The HR group was associated with specific histopathological features such as poorly differentiated components, complex glandular pattern components, tumor spread through air spaces, and a higher grade. In the HR group, pleural invasion, necrosis, and lymphatic invasion were more frequent, and the size of the invasion was larger (all, p < 0.001). Several genetic mutations, including TP53 (p = 0.007) mutations, were more frequently found in the HR group. The results of stages I-II were similar to those of the general cohort. DL-based model can predict the recurrence risk of LUAD and identify the presence of the TP53 gene mutation by analyzing histopathologic features.

Development strategy of non-GMO organism for increased hemoproteins in Corynebacterium glutamicum: a growth-acceleration-targeted evolution.

Heme, found in hemoproteins, is a valuable source of iron, an essential mineral. The need for an alternative hemoprotein source has emerged due to the inherent risks of large-scale livestock farming and animal proteins. Corynebacterium glutamicum, regarded for Qualified Presumption of Safety or Generally Recognized as Safe, can biosynthesize hemoproteins. C. glutamicum single-cell protein (SCP) can be a valuable alternative hemoprotein for supplying heme iron without adversely affecting blood fat levels. We constructed the chemostat culture system to increase hemoprotein content in C. glutamicum SCP. Through adaptive evolution, hemoprotein levels could be naturally increased to address oxidative stress resulting from enhanced growth rate. In addition, we used several specific plasmids containing growth-accelerating genes and the hemA promoter to expedite the evolutionary process. Following chemostat culture for 15 days, the plasmid in selected descendants was cured. The evolved strains showed improved specific growth rates from 0.59 h-1 to 0.62 h-1, 20% enhanced resistance to oxidative stress, and increased heme concentration from 12.95 µg/g-DCW to 14.22-15.24 µg/g-DCW. Notably, the putative peptidyl-tRNA hydrolase-based evolved strain manifested the most significant increase (30%) of hemoproteins. This is the first report presenting the potential of a growth-acceleration-targeted evolution (GATE) strategy for developing non-GMO industrial strains with increased bio-product productivity.

Resilience of aerobic methanotrophs in soils; spotlight on the methane sink under agriculture.

Aerobic methanotrophs are a specialized microbial group, catalyzing the oxidation of methane. Disturbance-induced loss of methanotroph diversity/abundance, thus results in the loss of this biological methane sink. Here, we synthesized and conceptualized the resilience of the methanotrophs to sporadic, recurring, and compounded disturbances in soils. The methanotrophs showed remarkable resilience to sporadic disturbances, recovering in activity and population size. However, activity was severely compromised when disturbance persisted or reoccurred at increasing frequency, and was significantly impaired following change in land use. Next, we consolidated the impact of agricultural practices after land conversion on the soil methane sink. The effects of key interventions (tillage, organic matter input, and cover cropping) where much knowledge has been gathered were considered. Pairwise comparisons of these interventions to nontreated agricultural soils indicate that the agriculture-induced impact on the methane sink depends on the cropping system, which can be associated to the physiology of the methanotrophs. The impact of agriculture is more evident in upland soils, where the methanotrophs play a more prominent role than the methanogens in modulating overall methane flux. Although resilient to sporadic disturbances, the methanotrophs are vulnerable to compounded disturbances induced by anthropogenic activities, significantly affecting the methane sink function.

Methane emissions and the microbial community in flooded paddies affected by the application of Fe-stabilized natural organic matter.

Redox chemistry involving the quinone/phenol cycling of natural organic matter (NOM) is known to modulate microbial respiration. Complexation with metals or minerals can also affect NOM solubilization and stability. Inspired by these natural phenomena, a new soil amendment approach was suggested to effectively decrease methane emissions in flooded rice paddies. Structurally stable forms of NOM such as lignin and humic acids (HAs) were shown to decrease methane gas emissions in a vial experiment using different soil types and rice straw as a methanogenic substrate, and this inhibitory behavior was likely enhanced by ferric ion-NOM complexation. A mechanistic study using HAs revealed that complexation facilitated the slow release of the humic components. Interestingly, borohydride-based reduction, which transformed quinone moieties into phenols, caused the HAs to lose their inhibitory capacity, suggesting that the electron-accepting ability of HAs is vital for their inhibitory effect. In rice field tests, the humic-metal complexes were shown to successfully mitigate methane generation, while carbon dioxide emissions were relatively unchanged. Microbial community analysis of the rice fields by season revealed a decrease in specific cellulose-metabolizing and methanogenic genera associated with methane emissions. In contrast, the relative abundance of Thaumarchaeota and Actinomycetota, which are associated with NOM and recalcitrant organics, was higher in the presence of Fe-stabilized HAs. These microbial dynamics suggest that the slow release of humic components is effective in modulating the anoxic soil microbiome, possibly due to their electron-accepting ability. Given the simplicity, cost-effectiveness, and soil-friendly nature of complexation processes, Fe-stabilized NOM represents a promising approach for the mitigation of methane emissions from flooded rice paddies.

The cumulative survival rate of dental implants with micro-threads: a long-term retrospective study.

PURPOSE: This study aimed to evaluate the long-term cumulative survival rate (CSR) of dental implants with micro-threads in the neck over a 10-year follow-up period and to examine the factors influencing the survival rate of dental implants. METHODS: This retrospective study was based on radiographic and dental records. In total, 151 patients received 490 Oneplant® dental implants with an implant neck micro-thread design during 2006-2010 in the Department of Periodontology of Seoul National University Dental Hospital. Implant survival was evaluated using Kaplan-Meier analysis. Cox proportional hazard regression analysis was used to identify the factors influencing implant failure. RESULTS: Ten out of 490 implants (2.04%) failed due to fixture fracture. The CSR of the implants was 97.9%, and no significant difference was observed in the CSR between external- and internal-implant types (98.2% and 97.6%, respectively, P=0.670). In Cox regression analysis, 2-stage surgery significantly increased the risk of implant failure (hazard ratio: 4.769, P=0.039). There were no significant differences in influencing factors, including sex, age, implant diameter, length, fixture type, location, surgical procedure, bone grafting, and restoration type. CONCLUSIONS: Within the limitations of this retrospective study, the micro-thread design of the implant neck was found to be favorable for implant survival, with stable clinical outcomes.

Cartilage regeneration using transforming growth factor-beta 3-loaded injectable crosslinked hyaluronic acid hydrogel.

Cartilage defects can be difficult to heal, potentially leading to complications such as osteoarthritis. Recently, a tissue engineering approach that uses scaffolds and growth factors has been proposed to regenerate new cartilage tissues. Herein, we investigated the application of hyaluronic acid (HA) gel loaded with transforming growth factor-beta 3 (TGF-ß3) for enhanced cartilage regeneration. We assessed the clinical conditions required to efficiently enhance the ability of the modified HA gel to repair defective cartilage. Based on our findings, the prepared HA gel exhibited good physicochemical and mechanical properties and was non-toxic and non-inflammatory. Moreover, HA gel-loaded TGF-ß3 (HAT) had improved biocompatibility and promoted the synthesis of cartilage-specific matrix and collagen, further improving its ability to repair defects. The application of HAT resulted in an initial burst release of HA, which degraded slowly in vivo. Finally, HAT combined with microfracture-inducing bone marrow stem cells could significantly improve the cartilage microenvironment and regeneration of cartilage defects. Our results indicate that HA is a suitable material for developing growth factor carriers, whereas HAT is a promising candidate for cartilage regeneration. Furthermore, this differentiated strategy provides a rapid and effective clinical approach for next-generation cartilage regeneration.

Changes in agricultural nitrogen (N) balance of OECD countries and its causes and impacts.

The Organization for Economic Co-operation and Development (OECD) developed soil surface nutrient balance and made it mandatory for member countries to report annual nutrient budgets since 1990. This study aimed to evaluate the status of nitrogen (N) management in member countries and to figure out why N surplus levels differ across countries and how they relate to other agri-environmental indicators, by analyzing the N budgets from 35 OECD countries over the last 30 years. Of the three factors determining N balance (agricultural land area, N input, and N output), agricultural land area decreased in most OECD countries, negatively affecting N balance reduction. However, OECD's average N balance highly decreased from 91 to 46 kg ha-1 over the last 30 years due to the decrease in N input through inorganic fertilizers and manure, especially in EU countries with high N input levels, while N output did not meaningfully change. In comparison, in Japan and Korea, the N balance slightly increased and they became the highest N balance country recently. A higher N balance led to lower N use efficiency and higher ammonia (NH3) and nitrous oxide (N2O) emission intensities. More densely populated countries with smaller agricultural land per capita (ranging from 0.03 to 0.47 ha capita-1) showed a higher N balance (228-80 kg ha-1), presumably due to higher N input for more agricultural production on limited land. The most densely populated countries among OECD members (Belgium, the Netherlands, Korea, and Japan) had similar N input levels. However, two EU countries had much higher N output than two Asian countries due to higher pasture production, which led to a lower N balance and higher N use efficiency. Therefore, highly populated countries with small arable land areas per capita might need multilateral efforts to alleviate agricultural N balance.

The passive sampler assisted human exposure risk characterization for tetrachloroethene soil vapor intrusion scenario.

The potential human health risks associated with soil vapor intrusion and volatile organic compounds (VOCs) exposure were characterized at an industrialized site by the quantification of gaseous VOCs in soil pores using a passive sampling technique. The gaseous tetrachloroethene (PCE) in soil pores varied between 12 and 5,400 µg m-3 showing 3 orders of magnitude variation with dependence on groundwater PCE concentrations. Though the PCE concentration in the air only varied between 0.45 and 1.5 µg m-3 showing negligible variations compared to the variation observed in soil pores. The PCE concentration in the air varied between 0.45 and 1.5 µg m-3. The calculation of fugacity suggested that the PCE in the test site originated from groundwater. Measured PCE in groundwater ranged from 14 to 2,400 times higher than PCE in soil gas. This indicates that conducting a vapor intrusion risk assessment using passive soil gas sampling is critical for accurate risk characterization and assessment. Estimated PCE inhalation cancer risks for street cleaners and indoor residents varied between 10-6 and 10-4 with a low plausible hazard, and between 10-3 and 10-2 with a high risk, respectively. The results of this study demonstrate that passive sampling offers a significantly lower cost and labor-intensive approach compared to traditional methods for assessing pollution distribution in contaminated sites and characterizing risks. This highlights the potential for wider application of passive sampling techniques in environmental studies.

Elucidating growth and biochemical characteristics of rice seedlings under stress from chromium VI salt and nanoparticles.

Plants are usually provoked by a variety of heavy metal (HM) stressors that have adverse effects on their growth and other biochemical characterizations. Among the HMs, chromium has been considered the most toxic for both plants and animals. The present study was conducted to compare the phytotoxic effects of increasing chromium (VI) salt and nanoparticles (NPs) concentrations on various growth indexes of rice (Oryza sativa L. var. swat 1) seedlings grown in a hydroponic system. The 7-day rice seedlings were exposed to Cr (VI) salt and NPs hydroponic suspensions which were adjusted to the concentration of 0, 50, 100, 150, 200 and 250 mg/L. Both the Cr (VI) salt and NPs with lower concentrations (up to 100mg/L) exerted minimum inhibitory effects on the growth performance of rice seedlings. However, a significant decrease in shoot and root length and their fresh and dry weight was recorded at higher doses of Cr (VI) salt (200 mg/L) and NPs (250 mg/L). The stress induced by Cr (VI) salt has drastically affected the roots, whereas, Cr (VI) NPs significantly affected the shoot tissues. Photosynthetic pigments decreased significantly in a dose-dependent manner, and the reduction was more pronounced in rice seedlings exposed to Cr (VI) NPs compared to Cr (VI) salt. Cr (VI) NPs enhanced the membrane permeability in shoots and roots as compared to that of Cr (VI) salt, which resulted in higher concentration of reactive oxygen species (ROS) and increased lipid peroxidation. The activities of antioxidant enzymes superoxide dismutase (SOD), peroxidase (POD), catalase (CAT) and ascorbate peroxidase (APX) increased significantly in shoot/root tissue following exposure to higher doses of Cr (VI) salt (200 mg/L) and NPs stress (250 mg/L), while minor changes in CAT and APX activities were observed in root and shoot tissues after exposure to higher concentration of Cr (VI) NP. Furthermore, the increasing concentrations of Cr (VI) NPs increased the length of stomatal guard cells. Conclusively, Cr (VI) salt and NPs in higher concentrations have higher potential to damage the growth and induce oxidative stress in rice plants.

Foci-Xpress: Automated and Fast Nuclear Foci Counting Tool.

In the nucleus, distinct, discrete spots or regions called "foci" have been identified, each harboring a specific molecular function. Accurate and efficient quantification of these foci is essential for understanding cellular dynamics and signaling pathways. In this study, we present an innovative automated image analysis method designed to precisely quantify subcellular foci within the cell nucleus. Manual foci counting methods can be tedious and time-consuming. To address these challenges, we developed an open-source software that automatically counts the number of foci from the indicated image files. We compared the foci counting efficiency, velocity, accuracy, and convenience of Foci-Xpress with those of other conventional methods in foci-induced models. We can adjust the brightness of foci to establish a threshold. The Foci-Xpress method was significantly faster than other conventional methods. Its accuracy was similar to that of conventional methods. The most significant strength of Foci-Xpress is automation, which eliminates the need for analyzing equipment while counting. This enhanced throughput facilitates comprehensive statistical analyses and supports robust conclusions from experiments. Furthermore, automation completely rules out biases caused by researchers, such as manual errors or daily variations. Thus, Foci-Xpress is a convincing, convenient, and easily accessible focus-counting tool for cell biologists.

Arthroscopic Reduction and Internal Fixation in Patients with Acetabular Posterior Wall Fractures.

Background: This study aimed to access the radiologic and clinical outcomes after arthroscopic reduction and internal fixation with screws in patients with posterior wall fractures of the acetabulum. Methods: From May 2013 to December 2019, 13 patients (11 men and 2 women) with posterior wall fractures of the acetabulum were treated with arthroscopic reduction and internal fixation with screws at two medical centers. The mean age at the index operation was 39 years (range, 22-58 years). The mean duration of follow-up was 23 months (range, 12-46 months). Clinical assessment was performed using the modified Merle d'Aubigné and Postel functional scoring system. The maximum displacement of acetabular or femoral head fragments detected on radiographs was used as radiographic results. Secondary osteoarthritis, osteonecrosis, or heterotrophic ossification was assessed at the latest follow-up. Results: Bony union was shown at 12 weeks of follow-up in all patients. The radiologic outcomes showed an anatomical reduction in 11 patients and a satisfactory reduction in 2 patients. The modified Merle d'Aubigné and Postel functional score was excellent in 7 patients, good in 5 patients, and fair in 1 patient. Two patients had transient pudendal nerve palsy after hip arthroscopy. However, no sciatic nerve palsy occurred. At the latest follow-up, there was no heterotopic ossification, osteonecrosis of the femoral head, or posttraumatic osteoarthritis. Conclusions: Arthroscopic reduction and internal fixation with cannulated screws can be good alternative options with good radiographic and clinical outcomes, convenient removal of intra-articular loose body, and low complication rates.

Single-Cell Hemoprotein Diet Changes Adipose Tissue Distributions and Re-Shapes Gut Microbiota in High-Fat Diet-Induced Obese Mice.

We have previously observed that feeding with single-cell hemoprotein (heme-SCP) in dogs (1 g/day for 6 days) and broiler chickens (1 ppm for 32 days) increased the proportion of lactic acid bacteria in the gut while reducing their body weights by approximately 1~2%. To define the roles of heme-SCP in modulating body weight and gut microbiota, obese C57BL/6N mice were administered varied heme-SCP concentrations (0, 0.05, and 0.5% heme-SCP in high fat diet) for 28 days. The heme-SCP diet seemed to restrain weight gain till day 14, but the mice gained weight again later, showing no significant differences in weight. However, the heme-SCP-fed mice had stiffer and oilier bodies compared with those of the control mice, which had flabby bodies and dull coats. When mice were dissected at day 10, the obese mice fed with heme-SCP exhibited a reduction in subcutaneous fat with an increase in muscle mass. The effect of heme-SCP on the obesity-associated dyslipidemia tended to be corroborated by the blood parameters (triglyceride, total cholesterol, and C-reactive protein) at day 10, though the correlation was not clear at day 28. Notably, the heme-SCP diet altered gut microbiota, leading to the proliferation of known anti-obesity biomarkers such as Akkermansia, Alistipes, Oscillibacter, Ruminococcus, Roseburia, and Faecalibacterium. This study suggests the potential of heme-SCP as an anti-obesity supplement, which modulates serum biochemistry and gut microbiota in high-fat diet-induced obese mice.

ROSEWOOD: A Phase II Randomized Study of Zanubrutinib Plus Obinutuzumab Versus Obinutuzumab Monotherapy in Patients With Relapsed or Refractory Follicular Lymphoma.

PURPOSE: The combination of zanubrutinib plus obinutuzumab (ZO) was found to be well tolerated with an early signal of efficacy in a phase Ib study. ROSEWOOD is a phase II, randomized study that assessed the efficacy and safety of ZO versus obinutuzumab in patients with relapsed/refractory (R/R) follicular lymphoma (FL). METHODS: Patients with R/R FL who had received ≥2 lines of therapy, including an anti-CD20 antibody and an alkylating agent, were randomly assigned 2:1 to receive ZO or obinutuzumab (O). The primary end point was overall response rate (ORR) by independent central review (ICR). Secondary end points included duration of response (DOR), progression-free survival (PFS), overall survival, and safety. RESULTS: A total of 217 patients were randomized (ZO, 145; O, 72). Median study follow-up was 20.2 months. The study met its primary end point: ORR by ICR was 69% (ZO) versus 46% (O; P = .001). Complete response rate was 39% (ZO) versus 19% (O); 18-month DOR rate was 69% (ZO) versus 42% (O). Median PFS was 28.0 months (ZO) versus 10.4 months (O; hazard ratio, 0.50 [95% CI, 0.33 to 0.75]; P < .001). The most common adverse events with ZO were thrombocytopenia, neutropenia, diarrhea, and fatigue; incidences of atrial fibrillation and major hemorrhage were 3% and 1%, respectively. CONCLUSION: The combination of ZO met its primary end point of a superior ORR versus O, and demonstrated meaningful activity and a manageable safety profile in patients with R/R FL. ZO had a favorable benefit-risk profile compared with O, and represents a potential combination therapy for patients with R/R FL.