Three-year follow-up analysis of axicabtagene ciloleucel in relapsed/refractory indolent non-Hodgkin lymphoma (ZUMA-5).

ABSTRACT: Axicabtagene ciloleucel (axi-cel) is an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy approved for relapsed/refractory (R/R) follicular lymphoma (FL). Approval was supported by the phase 2, multicenter, single-arm ZUMA-5 study of axi-cel for patients with R/R indolent non-Hodgkin lymphoma (iNHL; N = 104), including FL and marginal zone lymphoma (MZL). In the primary analysis (median follow-up, 17.5 months), the overall response rate (ORR) was 92% (complete response rate, 74%). Here, we report long-term outcomes from ZUMA-5. Eligible patients with R/R iNHL after ≥2 lines of therapy underwent leukapheresis, followed by lymphodepleting chemotherapy and axi-cel infusion (2 × 106 CAR T cells per kg). The primary end point was ORR, assessed in this analysis by investigators in all enrolled patients (intent-to-treat). After median follow-up of 41.7 months in FL (n = 127) and 31.8 months in MZL (n = 31), ORR was comparable with that of the primary analysis (FL, 94%; MZL, 77%). Median progression-free survival was 40.2 months in FL and not reached in MZL. Medians of overall survival were not reached in either disease type. Grade ≥3 adverse events of interest that occurred after the prior analyses were largely in recently treated patients. Clinical and pharmacokinetic outcomes correlated negatively with recent exposure to bendamustine and high metabolic tumor volume. After 3 years of follow-up in ZUMA-5, axi-cel demonstrated continued durable responses, with very few relapses beyond 2 years, and manageable safety in patients with R/R iNHL. The ZUMA-5 study was registered at www.clinicaltrials.gov as #NCT03105336.

Biochar alleviating heavy metals phytotoxicity in sludge-amended soil varies with plant adaptability.

Recycling sewage sludge (SS) to soil potentially causes soil heavy metal (HM) pollution and plant phytotoxicity. Biochar plays an important role in alleviating HM phytotoxicity, and responses vary with the feedstocks and usage of biochar. However, the effect of plant adaptability on biochar-mediated alleviation is poorly understood. Here, SS-derived biochar (SB) and rice straw-derived biochar (RB) applied at rates of 1.5% and 3% (W/W, SB1.5, SB3, RB1.5, and RB3) were used to improve the properties of soil amended with SS at 50% (W/W). Alleviation of phytotoxicity by biochar was further analyzed with SS-sensitive plant Monstera deliciosa and SS-resistant plant Ruellia simplex. Results revealed that both SB and RB significantly decreased the soil's bulk density and increased water retention. They also changed soil organic matter content and HMs fractionation. The addition of SB or RB alleviated the SS phytotoxicity, and they significantly promoted the growth and the root morphology and physiological index of M. deliciosa. But for R. simplex, these significant changes only synchronously occurred in SB3 treatment. The alleviation in M. deliciosa was more prominent and more closely connected with soil property changes than in R. simplex. Also, more soil property predictors were observed to play an important role in M. deliciosa growth than in R. simplex growth. These results indicated that biochar alleviating HMs phytotoxicity in SS-amended soil is associated with the changes of soil property. Moreover, the alleviation varies more prominently with plant adaptability than with biochar feedstocks and usage.

Effects of sewage sludge and other wastes application on the growth and element uptake of Jatropha curcas in abandoned rare-earth mine soil.

The wastes such as sewage sludge (SS) can be used to amend soil of abandoned rare-earth mine land (ARL). The energy plant Jatropha curcas could be used as a pioneer tree species in the ARL. In a pot experiment to address the responses of growth and element uptake of J. curcas, three treatments were established: adding SS to the soil of ARL (T1), adding SS and bagasse to the soil of ARL (T2), adding SS, bagasse and passivator to the soil of ARL (T3), with the untreated soil of the ARL as the control (CK). The results showed that compared with CK, T1 only significantly increased the plant height of J. curcas, T2 and T3 significantly increased the plant height, ground diameter and dry biomass of J. curcas, of which the total dry biomass increased by more than 184.7%. All the three treatments significantly increased the contents of N, P, K and Cu in J. curcas. T1 and T2 significantly increased the proportion of exchangeable Zn, Cd and Ni in the substrates, while T3 showed the opposite effects. T3 significantly decreased the migration factor (M) and mobility factor (MF) of Zn, Cd, Ni in the substrates, and significantly reduced the contents of Zn, Pb, Cd, Ni in J. curcas, with an inhibition rate of over 36.1%. The comprehensive evaluation of the membership function showed that the order of growth promotion effects on J. curcas was T2>T3>T1>CK, while the order of capacity of inhibiting J. curcas to accumulate Cu, Zn, Pb, Cd, Ni was T3>CK>T2>T1. The combined application of SS and bagasse significantly promoted the growth and element accumulation of J. curcas, and the addition of passivator significantly reduced heavy metals uptake without affecting the growth of J. curcas.

Temperature and historical land connectivity jointly shape the floristic relationship between Hainan Island and the neighbouring landmasses.

Present-day biodiversity in insular biota results from the interplay among geographical barriers, environmental filtering, and historical biogeography, but how these factors interact on insular biodiversity patterns is poorly understood. Here, we analysed the geographical patterns of beta diversity of seed plants between Hainan Island and the neighbouring landmasses in relation to space and the environmental factors to assess the relative effects of historical processes and ecological gradients on community assembly. We assessed beta diversity patterns by quantifying the turnover and nestedness components and used clustering and ordination to investigate the relationships between local floras from Hainan and the neighbouring landmasses. Utilising simple linear regression and linear mixed effect models, we evaluated the importance of historical processes and environmental gradients in shaping these beta diversity patterns. Our results show that the contributions of nestedness and turnover components to the total beta diversity vary across space. The flora of Hainan predominantly nests with the flora of Vietnam but shows larger species turnover with Guangdong, Guangxi, and Taiwan. Clustering and ordination analyses indicate that Hainan is first merged with Vietnam, after which it is grouped with mainland China and finally with Taiwan and the Philippines. The results of the linear mixed effect models consistently reveal that temperature, followed by the historical land connectivity, has the most important role in shaping the floristic dissimilarity. We conclude that the flora of Hainan is of continental origin and has the highest floristic affinity with Vietnam. The periodic emergence of a land bridge during Quaternary glacial cycles determines the origin of Hainan's flora, and temperature shapes the floristic dissimilarities via environmental filtering. Our study highlights the critical roles of historical sea level change and current environmental limitation in structuring the plant communities on Southeast Asian islands.

Diversified effects of co-planting landscape plants on heavy metals pollution remediation in urban soil amended with sewage sludge.

Recycling sewage sludge (SS) as a soil amendment potentially causes soil heavy metals (HMs) contamination. This study investigated the potential roles of landscape plants co-planting in SS-amended soil remediation. Three landscape trees Mangifera persiciforma, Bischofia javanica, and Neolamarckia cadamba (NC), and three ground cover plants Dianella ensifolia, Syngonium podophyllum, and Schefflera odorata (SO) were selected for the tree-ground cover co-planting. Species in different co-planting treatments exhibited diversified effects on the growth, root morphology, HMs uptake, and HMs accumulation. Five plant characteristics including total root length, total surface of roots (diameter <2 mm), specific root length, shoot dry weight and root dry weight played crucial roles in plant HMs uptake. Structural equation modeling analysis revealed that different co-planting treatments drive species to develop an active, passive, or avoidance strategy to accumulate HMs, resulting in a diversity of HMs removal efficiency. Co-planting of NC with SO promoted NC and SO HMs accumulation and resulted in the greatest HMs contents decline (48.0% for Cd, 24.9% for Cu, 33.8% for Zn, and 27.2% for Ni) and the lowest potential ecological risk. Co-planting of landscape tree and ground cover plants with an active strategy can be a potential candidate for HMs phytoremediation of SS-amended soil.

Burden of neurological and neurocognitive impairment in pediatric sickle cell anemia in Uganda (BRAIN SAFE): a cross-sectional study.

BACKGROUND: Children with sickle cell anemia (SCA) are highly susceptible to stroke and other manifestations of pediatric cerebral vasculopathy. Detailed evaluations in sub-Saharan Africa are limited. METHODS: We aimed to establish the frequency and types of pediatric brain injury in a cross-sectional study at a large SCA clinic in Kampala, Uganda in a randomly selected sample of 265 patients with HbSS ages 1-12 years. Brain injury was defined as one or more abnormality on standardized testing: neurocognitive impairment using an age-appropriate test battery, prior stroke by examination or transcranial Doppler (TCD) velocities associated with stroke risk in children with SCA (cerebral arterial time averaged mean maximum velocity ≥ 170 cm/second). RESULTS: Mean age was 5.5 ± 2.9 years; 52.3% were male. Mean hemoglobin was 7.3 ± 1.01 g/dl; 76.4% had hemoglobin < 8.0 g/dl. Using established international standards, 14.7% were malnourished, and was more common in children ages 5-12. Overall, 57 (21.5%) subjects had one to three abnormal primary testing. Neurocognitive dysfunction was found in 27, while prior stroke was detected in 15 (5.7%). The most frequent abnormality was elevated TCD velocity 43 (18.1%), of which five (2.1%) were in the highest velocity range of abnormal. Only impaired neurocognitive dysfunction increased with age (OR 1.44, 95%CI 1.23-1.68), p < 0.001). In univariate models, malnutrition defined as wasting (weight-for-height ≤ -2SD), but not sex or hemoglobin, was modestly related to elevated TCD (OR 1.37, 95%CI 1.01-1.86, p = 0.04). In adjusted models, neurocognitive dysfunction was strongly related to prior stroke (OR 6.88, 95%CI 1.95-24.3, p = .003) and to abnormal TCD (OR 4.37, 95%CI 1.30, p = 0.02). In a subset of 81 subjects who were enriched for other abnormal results, magnetic resonance imaging and angiography (MRI/MRA) detected infarcts and/or arterial stenosis in 52%. Thirteen subjects (25%) with abnormal imaging had no other abnormalities detected. CONCLUSIONS: The high frequency of neurocognitive impairment or other abnormal results describes a large burden of pediatric SCA brain disease in Uganda. Evaluation by any single modality would have underestimated the impact of SCA. Testing the impact of hydroxyurea or other available disease-modifying interventions for reducing or preventing SCA brain effects is warranted.