Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation.

ABSTRACT: Teclistamab and other B-cell maturation antigen (BCMA)-targeting bispecific antibodies (BsAbs) have substantial activity in patients with heavily pretreated multiple myeloma (MM) but are associated with a high rate of infections. BCMA is also expressed on normal plasma cells and mature B cells, which are essential for the generation of a humoral immune response. The aim of this study was to improve the understanding of the impact of BCMA-targeting BsAbs on humoral immunity. The impact of teclistamab on polyclonal immunoglobulins and B cell counts was evaluated in patients with MM who received once-weekly teclistamab 1.5 mg/kg subcutaneously. Vaccination responses were assessed in a subset of patients. Teclistamabinduced rapid depletion of peripheral blood B cells in patients with MM and eliminated normal plasma cells in ex vivo assays. In addition, teclistamab reduced the levels of polyclonal immunoglobulins (immunoglobulin G [IgG], IgA, IgE, and IgM), without recovery over time while receiving teclistamab therapy. Furthermore, response to vaccines against Streptococcus pneumoniae, Haemophilus influenzae type B, and severe acute respiratory syndrome coronavirus 2 was severely impaired in patients treated with teclistamab compared with vaccination responses observed in patients with newly diagnosed MM or relapsed/refractory MM. Intravenous immunoglobulin (IVIG) use was associated with a significantly lower risk of serious infections among patients treated with teclistamab (cumulative incidence of infections at 6 months: 5.3% with IVIG vs 54.8% with observation only [P < .001]). In conclusion, our data show severe defects in humoral immunity induced by teclistamab, the impact of which can be mitigated by the use of immunoglobulin supplementation. This trial was registered at www.ClinicalTrials.gov as #NCT04557098.

Preclinical Activity of JNJ-7957, a Novel BCMA×CD3 Bispecific Antibody for the Treatment of Multiple Myeloma, Is Potentiated by Daratumumab.

PURPOSE: Multiple myeloma (MM) patients with disease refractory to all available drugs have a poor outcome, indicating the need for new agents with novel mechanisms of action. EXPERIMENTAL DESIGN: We evaluated the anti-MM activity of the fully human BCMA×CD3 bispecific antibody JNJ-7957 in cell lines and bone marrow (BM) samples. The impact of several tumor- and host-related factors on sensitivity to JNJ-7957 therapy was also evaluated. RESULTS: We show that JNJ-7957 has potent activity against 4 MM cell lines, against tumor cells in 48 of 49 BM samples obtained from MM patients, and in 5 of 6 BM samples obtained from primary plasma cell leukemia patients. JNJ-7957 activity was significantly enhanced in patients with prior daratumumab treatment, which was partially due to enhanced killing capacity of daratumumab-exposed effector cells. BCMA expression did not affect activity of JNJ-7957. High T-cell frequencies and high effector:target ratios were associated with improved JNJ-7957-mediated lysis of MM cells. The PD-1/PD-L1 axis had a modest negative impact on JNJ-7957 activity against tumor cells from daratumumab-naïve MM patients. Soluble BCMA impaired the ability of JNJ-7957 to kill MM cells, although higher concentrations were able to overcome this negative effect. CONCLUSIONS: JNJ-7957 effectively kills MM cells ex vivo, including those from heavily pretreated MM patients, whereby several components of the immunosuppressive BM microenvironment had only modest effects on its killing capacity. Our findings support the ongoing trial with JNJ-7957 as single agent and provide the preclinical rationale for evaluating JNJ-7957 in combination with daratumumab in MM.

Changes in the soil environment from excessive application of fertilizers and manures to two contrasting intensive cropping systems on the North China Plain.

Effects of excessive fertilizer and manure applications on the soil environment were compared in greenhouse vegetable systems shifted from wheat-maize rotations 5-15years previously and in wheat-maize rotations. N, P and K surpluses to the greenhouses were 4328, 1337 and 1466kgha(-1)year(-1), respectively compared to 346, 65 and -163kgha(-1)year(-1) to wheat-maize fields. Subsequently, substantial mineral N and available P and K accumulated in the soil and leaching occurred down the soil profile in the greenhouses. Soil pH under vegetables was significantly lower than in the wheat-maize fields, while the EC was significantly higher in the vegetable soils. The mean Cd concentration in the vegetable soils was 2.8 times that in the wheat-maize rotations. Due to excessive fertilizer application in greenhouse vegetable production in northeast China, excessive salt and nitrate concentrations may accumulate and soil quality may deteriorate faster than in conventional wheat-maize rotations.

Interception of residual nitrate from a calcareous alluvial soil profile on the North China Plain by deep-rooted crops: a 15N tracer study.

15N-labeled nitrate was injected into different depths of an alluvial calcareous soil profile on the North China Plain. Subsequent movement of NO3- -N and its recovery by deep-rooted maize (Zea mays L.) and shallow-rooted eggplant (Solanum melongena L.) were studied. Under conventional water and nutrient management the mean recoveries of 15N-labeled nitrate from K(15)NO3 injected at depths 15, 45, and 75 cm were 22.4, 13.8, and 7.8% by maize and 7.9, 4.9, and 2.7% by eggplant. The recovery rate by maize at each soil depth was significantly higher than by eggplant. The deeper the injection of nitrate the smaller the distance of its downward movement and this corresponded with the movement of soil water during crop growth. Deeper rooting crops with high root length density and high water consumption may therefore be grown to utilize high concentrations of residual nitrate in the subsoil from previous intensive cropping and to protect the environment.

Sequestration of As by iron plaque on the roots of three rice (Oryza sativa L.) cultivars in a low-P soil with or without P fertilizer.

A pot experiment was carried out in a greenhouse to investigate the sequestration of As in iron plaques on root surface of three rice (Oryza sativa L.) cultivars. Phosphate (P) fertilization increased both plant biomass and tissue P concentrations significantly, indicating that the soils used in this study was highly P-deficient. Results from this study confirmed that low P supply improved the formation of iron plaque on rice roots. As a consequence, arsenic (As) concentrations in DCB-extracts with no P addition were significantly higher than those with P fertilization. Arsenic was highly sequestrated in iron plaque; arsenic concentration in iron was up to nearly 120 mg kg(-1), while arsenic concentrations in roots were just several mg kg(-1). Both arsenic and phosphate concentrations in iron plaque were highly positively correlated with the amounts of iron plaque (DCB-extractable Fe). Contrary to normal understanding that increasing P supply could reduced As accumulation in plants, results from the present study showed that P fertilization did not inhibit the As uptake by plants (As accumulation in aboveground), which was probably due to the fact that iron plaque formation was improved under low P conditions, thus leading to more As sequestration in the iron plaque. Thus results obtained in this study indicated that the iron plaque may inhibit the transfer of As from roots to shoots, and thus alter the P-As interaction in plant As uptake processes.

Yield and arsenate uptake of arbuscular mycorrhizal tomato colonized by Glomus mosseae BEG167 in As spiked soil under glasshouse conditions.

A glasshouse pot experiment was conducted to study the effect of arbuscular mycorrhizal (AM) colonization by Glomus mosseae BEG167 on the yield and arsenate uptake of tomato plants in soil experimentally contaminated with five As levels (0, 25, 50, 75 and 150 mg kg(-1)). Mycorrhizal colonization (50-70% of root length) was little affected by As application and declined only in soil amended with 150 mg As kg(-1). Mycorrhizal colonization increased plant biomass at As application rates of 25, 50 and 75 mg kg(-1). Shoot As concentration increased with increasing As addition up to 50 mg kg(-1) but decreased with mycorrhizal colonization at As addition rates of 75 and 150 mg kg(-1). Shoot As uptake increased with mycorrhizal colonization at most As addition levels studied, but tended to decrease with addition of 150 mg As kg(-1). Total P uptake by mycorrhizal plants was elevated at As rates of 25, 50 and 75 mg kg(-1), and more P was allocated to the roots of mycorrhizal plants. Mycorrhizal plants had higher shoot and root P/As ratios at higher As application rates than did non-mycorrhizal controls. The soil of inoculated treatments had higher available As than uninoculated controls, and higher pH values at As addition levels of 25, 50 and 75 mg kg(-1). Mycorrhizal colonization may have increased plant resistance to potential As toxicity at the highest level of As contamination studied. Mycorrhizal tomato plants may have potential for phytoextraction of As from moderately contaminated soils or phytostabilization of more highly polluted sites.

Nutrients can enhance phytoremediation of copper-polluted soil by Indian mustard.

An orthogonally designed experiment was conducted to study the single and combined effects of N, P and K on phytoremediation of Cu-polluted soil by Indian mustard. Addition of fertilizer N and P significantly increased Indian mustard shoot yield. Two high treatments combined with N resulted in the highest yields, followed by low-P combined with N. In contrast, high P with no N gave no yield increase and K had no effect on yield of Indian mustard. Nitrogen and P increased the amount of chlorophyll in the leaves, indicating that the yield increases were due to enhanced photosynthesis. Nitrogen application had no effect on plant Cu concentrations but addition of P slightly decreased plant Cu concentrations, likely a dilution effect resulting from the increase in yield. Among the treatments, N and P applied at 100 and 200 mg kg(-1) respectively with no K application resulted in the highest Cu uptake. Thus, a combination of low N and high P produced a yield increase in Indian mustard that was more than adequate to compensate for a slight decrease in Cu concentration, resulting in the highest Cu removal from the contaminated soil.

Influence of early stages of arbuscular mycorrhiza on uptake of zinc and phosphorus by red clover from a low-phosphorus soil amended with zinc and phosphorus.

In a pot experiment, red clover (Trifolium pratense) was grown in sterilized Zn-amended low available P soil (0, 50 or 400 mg Zn kg(-1)) with or without 100 mg kg(-1) added P and with or without inoculation with the arbuscular mycorrhizal (AM) fungus G. mosseae. When the plants were harvested after 40 days, AM colonization of the roots was still at an early stage, with only 14-38% of total root length colonized on average. AM colonization was highest in low-P soil, and was lowest in soil amended with 400 mg Zn kg(-1). Shoot yields were highest in AM plants with added P, but root yields were unaffected by AM inoculation. Shoot and root yields were higher with 100 mg added P kg(-1) soil, but lower with 400 mg Zn kg(-1) than 50 mg Zn kg(-1) or controls unamended with Zn. Shoot and root P concentrations were seldom higher in AM plants, but shoot P offtakes were higher in AM plants with added P. Concentrations of Zn and Cu were much higher in the roots than in the shoots. Shoot and root Zn and shoot Cu were lower, but root Cu was higher, in AM plants. Soil residual pH after plant growth was higher in AM treatments, and residual total Zn was also higher, indicating lower Zn uptake by AM plants. Soil solution pH was higher in AM treatments, and soil solution Zn was lower in the presence of mycorrhiza. The results are discussed in terms of AM protection of the plants against excessive shoot Zn uptake.

The role of arbuscular mycorrhiza in zinc uptake by red clover growing in a calcareous soil spiked with various quantities of zinc.

Three pot experiments were conducted to investigate the role of arbuscular mycorrhiza (AM) in Zn uptake by red clover. Plants inoculated with Glomus mosseae and uninoculated controls were grown in a sterile calcareous soil in 'Plexiglas' (Acrylic) containers with two nylon net partitions (30 microm mesh) to separate the central root zone from the two outer hyphal zones. The effects of mycorrhiza on plant growth and Zn uptake changed dramatically with increasing Zn addition level (range 0-1200 mg kg(-1)) in the root zone. With Zn addition levels <300 mg kg(-1), added Zn did not affect plant yield and above the critical level plant yield gradually decreased but was always higher for mycorrhizal than for controls. Below the critical Zn application rate (50 mg kg(-1)), Zn uptake was enhanced while above this level Zn translocation to the shoots decreased. At all Zn addition levels, mycorrhizal colonization increased Zn absorption and accumulation in the roots, and this may help to explain the alleviation of Zn toxicity at high Zn application rates. As expected, AM colonization enhanced P nutrition and hence yield at all added Zn levels studied. Efforts were made to obtain direct evidence for hyphal contribution to Zn uptake by applying both Zn to the hyphal growth zone and additional P to the root zone to avoid the 'growth dilution effect'. The data demonstrate that mycorrhizal hyphae could absorb Zn directly from the soil and then transfer it to the plant roots. The hyphal contribution to Zn uptake by the host plant reached its maximum value at the Zn addition level of 50 mg kg(-1), in which Zn uptake via the extramatrical hyphae comprised 22% of total uptake, thus confirming the critical Zn application level found previously.

The role of arbuscular mycorrhizal fungi in the transfer of nutrients between white clover and perennial ryegrass.

A glasshouse experiment was conducted in which 15N was used as a tracer applied as (15NH4)2SO4 to donor plants of white clover and perennial ryegrass. Nitrogen transfer via hyphae of arbuscular mycorrhizal fungi (AMF) or by other routes was studied by separating the root systems of the two plant species, as donors and receivers, when growing in the same pot, with selective mesh barriers of varying pore sizes in the presence and absence of AMF. Inoculation with AMF increased DM production and nitrogen (N) yield of clover plants. Transfer of 15N occurred between white clover and grass plants but was independent of AMF. Pore size of the mesh barriers controlled the degree of 15N enrichment in the grass, suggesting that transfer was mediated by mass flow and/or diffusion. Additional experiments showed that grass roots could pass through pores of 60-microm diameter, and hyphal links could not be detected by autoradiography, thus supporting the conclusions of the tracer experiment.

A modified glass bead compartment cultivation system for studies on nutrient and trace metal uptake by arbuscular mycorrhiza.

A modified glass bead compartment cultivation system is described in which glass beads continue to be used in the hyphal compartment but are replaced by coarse river sand in the compartments for host plant roots and mycorrhizal hyphae. Arbuscular mycorrhizal (AM) associations were established using two host plant species, maize (Zea mays L.) and red clover (Trifolium pratense L.) and two AM fungi, Glomus mosseae and G. versiforme. When the standard and modified cultivation systems were compared, the new method yielded much more fungal tissue in the hyphal compartment. Using G. versiforme as the fungal symbiont, up to 30 mg of fungal dry matter (DM) was recovered from the hyphal compartment of mycorrhizal maize and about 6 mg from red clover. Multi-element analysis was conducted on samples of host plant roots and shoots and on harvested fungal biomass. Concentrations of P, Cu and Zn were much higher in the fungal biomass than in the roots or shoots of the host plants but fungal concentrations of K, Ca, Mg, Fe and Mn were similar to or lower than those in the plants. There were also significant differences in nutrient concentrations between the two AM fungi and these may be related to differences in their proportions of extraradical mycelium to spores. The high affinity of the fungal mycelium for Zn was very striking and is discussed in relation to the potential use of arbuscular mycorrhiza in the phytoremediation of Zn-polluted soils.

Uptake of Zn by arbuscular mycorrhizal white clover from Zn-contaminated soil.

A randomised block glasshouse pot experiment compared the growth and Zn uptake of mycorrhizal and nonmycorrhizal white clover plants grown in a sterile soil/sand mixture containing 25 mg Zn kg(-1) to which five application rates of Zn (as ZnSO4) from 0 to 400 mg kg(-1) were made. Two mycorrhizal inocula infected roots from the field and from clover trap cultures, were compared. Mycorrhizal infection (ranging from 33% to 46% of total root length) and Zn application had little effect on plant growth. Increasing Zn application rate led to increased uptake of Zn in roots and shoots (especially roots), but the increases were significantly greater in non-mycorrhizal controls than in mycorrhizal treatments. In contrast, P uptake was higher in mycorrhizal than in non-mycorrhizal plants. Plants that received trap culture inoculum had significantly lower Zn uptake than those that received field inoculum. The results indicate that mycorrhizal infection may have exerted some protective effect against plant Zn accumulation at the range of soil Zn concentrations studied and may have immobilised Zn in or near the roots to some extent. However, this mycorrhizal effect cannot be explained simply by tissue dilution, hyphal sequestration or root immobilisation of Zn.

Changes in soil solution Zn and pH and uptake of Zn by arbuscular mycorrhizal red clover in Zn-contaminated soil.

Red clover plants inoculated with Glomus mosseae were grown in a sterile pasture soil containing 50 mg Zn kg(-1) in 'Plexiglas' (acrylic) containers with nylon net partitions (30 microm mesh) designed to separate the soil into a central root zone and two outer zones for hyphal growth with no root penetration. Two porous plastic soil moisture samplers were installed in each pot, one in the root compartment and the other in one of the hyphal compartments. The soil in the outer compartments was amended with one of the four application rates of Zn (as ZnSO4) ranging from 0 to 1000 mg kg(-1). Non-mycorrhizal controls were included, and there were five replicates of each treatment in a randomised block in a glasshouse. Uninoculated plants received supplementary P to avoid yield limitation due to low soil P status. Plants grew in the central compartment for nine weeks. Soil moisture samples were collected 4, 24 and 62 days after sowing to monitor changes in the Zn concentration and pH of the soil solution. At harvest, the mean mycorrhizal infection rate of inoculated plants ranged from 29% to 34% of total root length and was little affected by Zn application. Root and shoot yields were not affected by mycorrhizal infection. Plant Zn concentration and uptake were lower in mycorrhizal plants than non-mycorrhizal controls, and this effect was more pronounced with increasing Zn application rate to the soil. Soil solution Zn concentrations were lower and pH values were higher in mycorrhizal treatments than non-mycorrhizal controls and the mycorrhiza effect was more pronounced at higher Zn application rates. The protective effect of mycorrhiza against plant Zn uptake may have been associated with changes in Zn solubility mediated by changes in the soil solution pH, or by immobilisation of Zn in the extraradical mycelium.

Surface water phosphorus dynamics in rice fields receiving fertiliser and manure phosphorus.

A long-term randomised block field experiment was established in 1997 to study the dynamics of total P and dissolved P in the surface waters of rice fields receiving two application rates of fertiliser P and one rate of combined fertiliser and manure P. Preliminary results from the first two crops show that concentrations of both total P and dissolved P in the surface waters increased significantly following P application, especially during the first 2 weeks after application. P concentrations subsequently declined sharply within about 10 days, then declined steadily and remained almost constant from about 1 month after application. The initial increase in P concentration of surface waters was higher with increasing rate of fertiliser P, and the P concentration at the highest fertiliser rate peaked within about 1 week of application. The elevated P concentrations following fertiliser P application declined more rapidly than those following the combined application of fertiliser and manure P. When fertiliser and manure P were applied together, about 7 days later the surface water P concentrations were significantly higher than when the same rate of P (or double) was applied as fertiliser only. Disturbance of the surface soil by hand harrowing further increased the P concentrations in surface waters, with a subsequent decline to a steady value after about 1 week. Application of P fertiliser to the high P status soil in this experiment gave no crop yield response and may have increased the risk of pollution of adjacent surface waters through drainage from heavy rainfall events during the rice growing season. Therefore, fertiliser P should not be applied to such soils. If, however, fertiliser or manure P is applied, the application should be made during the dry winter to reduce P losses. Manure should be applied with particular care because of the higher risk of P losses to surface water arising from the relatively long period of high P concentrations in surface waters and the potential for greater release of P to field surface waters from the soil. Hand harrowing should also be avoided during wet weather to protect water quality.

The use of 0.2% chlorhexidine in the absence of a structured mechanical regimen of oral hygiene following the non-surgical treatment of periodontitis.

The aim of the present study was to evaluate a 0.2% chlorhexidine mouthrinse following the non-surgical treatment of advanced human periodontitis in the absence of a structured mechanical oral hygiene regimen. 10 patients and a total of 1483 sites were used. Recordings for plaque, bleeding, pocket depth and attachment levels were made at baseline and at 3, 6, 9, and 12 months. Debridement was performed under local anaesthesia. No instruction or reinforcement in mechanical oral hygiene procedures was given at any time. However, at each visit the patients were instructed in the 2x daily use of 0.2% chlorhexidine mouthwash. The plaque indices, scored as % of sites with removable deposits, showed negligible improvement from baseline scores of 80%-100% for all categories of initial probing depth. Mean bleeding score was reduced to 10-20% irrespective of initial probing pocket depth, site location or tooth surface location. Sites > or = 7 mm at baseline demonstrated a reduction in mean probing pocket depth of 3.9 mm and a gain in mean probing attachment level of 2.5 mm. Moderately deep sites (4-6.5 mm) demonstrated a reduction in mean probing pocket depth of 2 mm and a gain in mean probing attachment level of 0.8 mm. Shallow sites (< or = 3.5 mm) demonstrated a reduction in mean probing pocket depth of 0.5 mm and a loss in mean probing attachment level of 0.2 mm. Site-specific attachment level analysis demonstrated that over 80% of losing sites were shallow with low bleeding frequency, indicating that the loss of attachment may have occurred for reasons other than inflammatory periodontal disease. The results indicate that chlorhexidine can be used as an adjunct to inadequate mechanical oral hygiene over an observation period of 1 year.

Therapeutic use of cannabis: clarifying the debate.

The debate regarding therapeutic use of cannabis is being confused by a lack of distinction between therapeutic and social use of cannabis. Separate consideration of therapeutic and social use would enable strategies to minimise any negative social impact of therapeutic use. For therapeutic use of cannabis to be considered on its own merits, greater emphasis needs to be placed on scientific evidence of therapeutic efficacy. At present the evidence is limited, it mostly relates to the use of synthetic cannabinoids, and much of it fails to compare cannabis with the best therapies available for the conditions of interest. Claims of therapeutic efficacy tend to be based on opinion and anecdote rather than the results of controlled studies. Further research is needed to clarify the potential therapeutic benefits, to enable claims of therapeutic use to be objectively assessed and to enable informed decisions to be made about the relative risks and benefits for any individual using cannabis for therapeutic purposes. Further research is required to clarify the efficacy of pure, synthetic cannabinoids compared to cannabis, the most effective route of administration, and the importance of delivering a known dose. The most likely value of cannabis is as an adjunct, rather than a replacement for, current medical approaches. The potential therapeutic benefits of cannabis will be greatest for those conditions where long-term cannabis use, with its attendant health risks, is not an issue and where the patient has the capacity to titrate dose against symptoms. There is sufficient evidence of potential therapeutic benefit to justify the facilitation of further research.

Initial effects of the grounding of the tanker Braer on health in Shetland. The Shetland Health Study Group.

OBJECTIVE: To determine if the oil spillage from the tanker Braer had any immediate health effects on the exposed resident population. DESIGN: Cohort study with a comparison against controls, exposure status being assigned on the basis of geographical location. SETTING: Rural Shetland. SUBJECTS: All those resident on or after 5 January 1993 (day 0) within 4.5 km of the site of tanker's grounding. Controls matched for sex and age were drawn from a general practice list 95 km distant. OUTCOME MEASURES: Demographic details; smoking and alcohol consumption; perception of health and reported presence or absence of specific symptoms; peak expiratory flow; results of haematology, liver and renal function tests, and blood and urine toxicology. RESULTS: Of subjects contacted, 420 (66%) exposed people and 92 (68%) controls were studied; 56 non-attenders were surveyed. Principal health effects arose on days 1 and 2 and were headache, throat irritation, and itchy eyes. No significant differences between those exposed and controls were found for any of the biological markers. Toxicological studies did not show any exposures that are known to affect human health. CONCLUSIONS: The study confirmed the anecdotal reports of certain acute symptoms. No evidence of pulmonary, haematological, renal, or hepatic damage was detected at the population level. Toxicological samples from exposed people did not find levels known to affect human health. Further studies are required to ascertain whether there have been any long term effects on the population.