Search

Objective The aim of this study was to assess the clinical benefit value of approved antibody drug conjugates (ADCs) for solid tumours using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) V.1.1.Design Systematic descriptive analysis.Data sources PubMed was searched for publications from 1 January 2000 to 18 October 2023.Eligibility criteria We included the phase III randomised controlled trials or phase II pivotal trials leading to approval of ADCs in solid tumours.Data extraction and synthesis Two independent reviewers extracted data and discrepancies were resolved by consensus in the presence of a third investigator.Results ESMO-MCBS Scores were calculated for 16 positive clinical trials of eight ADCs, which were first approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration and the Japanese Pharmaceuticals and Medical Devices Agency for solid cancers. Among 16 trials, 4 (25%) met the ESMO-MCBS benefit threshold grade, while 12 (75%) of the regimens did not meet the ESMO-MCBS benefit threshold grade. 5 (31%) of the 16 trials had no published scorecard on the ESMO website due to the approval by other jurisdictions but not by the FDA or EMA. Discrepancies between our results and the ESMO scorecard were observed in 4 (36%) of 11 trials, mostly owing to integration of more recent data.Conclusions ESMO-MCBS is an important tool for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold.

Abstract Background As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). Methods/design In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). Results Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1–13.8%) and 42.1% (16/38, 95% CI 26.3–59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4–99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9–3.7) and 10.3 months (95% CI 7.3–not evaluable [NE]), respectively. Conclusion BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. Trial registration Clinicaltrials.gov NCT02929290 (11/10/2016).

The psyllid Bactericera gobica is a serious pest in goji berry orchards. The current primary psyllid control methods involve chemical pesticides, which pose potential risks to human health and the environment. The implementation and promotion of biological control agents should receive increased attention as an alternative approach to safeguarding goji berry orchards. To compare the predatory performance of three potential biocontrol agents of psyllids, including Harmonia axyridis, Coccinella septempunctata and Hippodamia variegata, the functional response and intraspecific interactions of adult ladybirds were studied under laboratory conditions. We observed a significantly higher searching efficiency (0.84 ± 0.09) in H. axyridis when preying on psyllids compared to H. variegata (0.55 ± 0.05), whereas the handling time for psyllids was considerably longer in H. axyridis (7.33 ± 0.83 min) than in H. variegata (5.67 ± 0.97 min). The impact of intraspecific interactions on H. variegata (0.44 ± 0.04) was significantly greater than that on C. septempunctata (0.29 ± 0.03), whereas the maximum consumption by C. septempunctata (223.35 ± 41.3) significantly exceeded that of H. variegata (133.4 ± 26.9). Our study suggests that each of these three ladybird species possesses distinct advantages as a potential predator of psyllids. However, further field studies are required to determine the most promising ladybird species for rapid impact through inundative biological control, taking into consideration the specific environmental adaptability of each ladybird species. The present study is expected to provide evidence that supports the potential of incorporating promising ladybird species as an effective biological control agent in goji berry orchard management programs.

The aphid, Aphis gossypii Glover, is identified as a significant pest that causes severe damage to goji berries in China. To analyze the ladybird consumption of aphids, the functional responses of three ladybird species, Harmonia axyridis, Coccinella septempunctata, and Hippodamia variegata, and intraspecific competition among ladybird individuals were evaluated under laboratory conditions. Moreover, the practical impact of ladybirds on aphid population reduction was investigated in semi-field conditions. We found that all adult ladybirds of the three species exhibited a type II functional response toward aphids. According to Holling’s disc equation, H. axyridis exhibited the highest searching efficiency (a = 0.79), while C. septempunctata had the shortest handling time (Th = 5.07 min) among the three ladybird species studied. Additionally, intraspecific competition had a greater impact on H. variegata (m = 0.41) compared to the other two ladybird species. The semi-field study demonstrated that H. axyridis (83.9% reduction) and C. septempunctata (78.7% reduction) exhibited higher efficacy in reducing aphid populations compared to H. variegata (27.3% reduction). This study suggests that H. axyridis and C. septempunctata exhibit potential as effective biological control agents against aphids on goji berry plants and highlights the importance of considering intraspecific competition. However, the results obtained from laboratory and semi-field studies cannot be directly extrapolated to field conditions due to the simplification of these experimental systems. Future field studies are crucial in ensuring the effective implementation of a biological control program.

Soil ecosystems are far more functionally valuable than previously thought, so soil biodiversity conservation deserves more attention. Soil animals are less visible and often overlooked, so maintaining ecosystem function is essential to reducing species loss. In contrast to aboveground communities, the susceptibility to extinction in the belowground world to data has been dealt with only cursorily. Here, we surveyed population sizes of different animal orders in both urban and rural Beijing from 2013 to 2016, to study the impact of increasing urbanization on the ecology of soil fauna. We found 9 orders had less than 1% of soil-animal population in both urban and rural areas. The populations of 6 orders in urban areas were far smaller than those in rural areas. Between 2013 and 2016, both urban (46.9%) and rural (61.2%) areas had experienced a substantial long-term population decrease, and soil animals in Beijing suffered a 52.8% loss of population. Our study indicates 40.9% of orders may be in danger of local extinction, and 27.3% of orders seem highly susceptible to urbanization. Over just four years the soil-animal population in Beijing is shrinking fast thanks largely to increasing urbanization. This raises the worrying prospect of a future soil fauna that may be at risk of local extinction in cities. It is therefore necessary to provide a pragmatic approach to soil-animal diversity conservation. Moreover, the deeper understanding of soil extinction ecology opens up an exciting frontier of opportunities for future research.

The gall mite Aceria pallida and the psyllid Bactericera gobica are serious Goji berry pests. The mite can be phoretic on the psyllid to overwinter, but it is unclear whether the vector can obtain benefits from the phoront during the growing season. After detachment, the mite shares the same habitat with its vector, so there are very likely to be interspecific interactions. To better understand whether the interactions are positive or negative, information on relationships between abundances of A. pallida and B. gobica on leaves is needed. Here, B. gobica abundance was represented by the egg abundance because the inactive nymphs develop on the same sites after hatching. (1) We found a positive linear relationship between the gall diameter and the mite abundance in the gall (one more millimeter on gall diameter for every 30 mites increase), which provided a way to rapidly estimate mite abundances in the field by measuring gall diameters. (2) There was a positive relationship between the abundance of mites and psyllid eggs on leaves. (3) Both species had positive effects on each other’s habitat selections. More importantly, the interactions of the two species prevented leaf abscission induced by B. gobica (leaf lifespan increased by 62.9%), increasing the continuation of the psyllid population. Our study suggests positive interactions between two pests during the growing season. The positive relationship between A. pallida and B. gobica egg abundances highlights the increasing need for novel methods for Goji berry pest management. In practice, A. pallida control can be efficient by eliminating its vector B. gobica. Both pests can be controlled together, which reduces chemical usage.

Functional responses at each developmental stage of predators and intraspecific competition associated with direct interactions among them provide insights into developing biological control strategies for pests. The functional responses of Harmonia axyridis (Pallas) at each developmental stage of Melanaphis sacchari (Zehntner) and intraspecific competition among predators were evaluated under laboratory conditions. The results showed that all stages of H. axyridis displayed a type II functional response to M. sacchari. Based on Holling's disc equation, the instantaneous searching rates were highest (a) and handling time was shortest (Th) of fourth instar larvae (a = 0.8818; Th = 3.9 min) and female adults (a = 0.9881; Th = 3.0 min) at larval and adult stages, respectively. The coefficients of mutual interference (m) assessed by the intraspecific competition equation were higher for fourth instar larvae (m = 0.4764) and female adults (m = 0.4183). The present study indicates that fourth instar and female adult were more effective stages of H. axyridis in the context of biological control but suitable predator densities need to be considered before natural enemy release.

As larval cannibalism is common under intensive rearing conditions, leg regeneration can help ladybugs adapt to the competitive environment, but whether the leg regeneration leads to side effects on development remains unclear. To analyze the potentially developmental cost of leg regeneration, the developmental period and weight of leg-regenerated Coccinella septempunctata were studied in the laboratory. The results showed that, when the time intervals between the emergency of 4th-instar larva and leg amputation increased, the developmental period of leg-regenerated 4th-instar larvae was gradually prolonged. Significantly developmental delay were also examined at prepupal and pupal stages, and various timings of leg amputation affected the periods of leg-regenerated prepupae/pupae similarly. After the leg was amputated at different larval instars, the developmental delay only occurred at the larval instar when the leg was amputated, whereas other larval instars failed to be extended, and the developmental periods of leg-regenerated prepupae/pupae were affected similarly by the instars of leg amputation. Developmental delays possibly resulted in more consumption by leg-regenerated larvae, and then weight gains at prepupal/pupal stages, but different larval instars of leg amputation affected the weight gain similarly. Both the developmental delay (at 4th-instar larval, prepupal and pupal stages) and weight gain (at pupal and adult stages) in complete/bilateral amputation were longer or greater than those in half/unilateral amputation. However, the thoracic locations of leg amputation impacted the developmental delay and weight gain similarly. Our study indicates that although leg regeneration triggers the developmental cost decreasing the competitive superiority or agility, C. septempunctata larvae still choose to completely regenerate the leg to adapt to complex environments. Thus, in order to remain competitive at adult stages, leg-impaired larvae may make an investment tradeoff between leg regeneration and developmental cost.

Tonic immobility (TI) is a well-known anti-predator strategy adopted by diverse preys. Numerous studies on the cost–benefit involve in TI have been reported. Although, some studies have reported the effect of mating behavior on TI, few studies highlight the phases of mate search. In the present study, we investigated the relationship between mate search and TI behavior in the sweetpotato weevil (SPW), Cylas formicarius (Coleoptera: Brentidae). First, we found the most active mate search period of male SPW within 24 h. Then, we measured whether the duration of TI of virgin male and female were affected during the mate search. In the end, the Y-tube olfactometer was used to compare the duration of mate search and the proportion of orientation towards the females in two artificial selection groups of the male SPW with longer and shorter duration of TI. Our study confirmed that male mate searching increase after 3 h at night, and up to 73% at midnight, TI was affected by mate search in male, because the duration of TI of the male during mate search (Mean ± SE = 214.53 ± 22.74 s) was significantly shorter duration than the control (679.64 ± 69.77 s). However, mate search did not affect the strength of TI in the females tested. This study determined that mate search was affected by TI due to males from the group with shorter duration of TI who had 28% higher proportion of orientation towards the females than the males with longer duration of TI. Investment trade-off between TI and mate search was confirmed in the males of the SPW.

Functional responses of the fall armyworm (FAW) larvae at each stage, and their intraspecific competition associated with cannibalism, provide insights into developing pest management strategies for the FAW. To help use insecticides more sparingly, the functional response and intraspecific competition of the FAW larvae were evaluated under the laboratory conditions. The results showed that all stages of the FAW larvae displayed a type II functional response to diet. Based on Holling’s disc equation, the search rate (a) and handling time (Th) of sixth instar larvae (a = 0.493; Th = 0.37 min) were the highest, and the shortest of all larval stages, respectively. Intraspecific competition curves fitted the data for fourth to sixth larval stages of the FAW, and the coefficient of intraspecific competition (m) assessed by the intraspecific competition equation were highest for fifth instar larvae (m = 0.48). The present study indicates that 5th and 6th instar larvae can cause the most plant damage (accounted for 88.9% of larval consumption), and these stages should be the focus of any pest management strategy. Intraspecific competition, especially cannibalism, impacts the feeding patterns of the FAW larvae and needs close attention. Understanding the functional response and intraspecific competition of the FAW larvae contributes greatly to practical applications of insecticides, increasing the effectiveness of chemical sprays and decreasing ecological damage.

The fall armyworm, Spodoptera frugiperda (J.E. Smith) is a serious agricultural pest. The species originates from the tropical and subtropical regions of the Americas and has now become established in many countries. Its strong migratory ability is the key factor in the rapidly expanding range of S. frugiperda in Africa, where food security faces unprecedented challenges. Exploring potential distributions and niche differentiation of S. frugiperda could provide new insights into the nature of climate niche shifts and our ability to anticipate further invasions. In this study, the occurrence population records (native, source, global, and African) and environmental variables of S. frugiperda were selected to fit ecological niche models (ENMs), with an evaluation of niche conservatism during its invasion of Africa. The results showed that the potential distributions of S. frugiperda are mainly in tropical and subtropical areas in Africa. The climate spaces occupied by its native population and introduced African population broadly overlap. Although, climate niches were conserved during invasion of Africa, many climate spaces were unoccupied, suggesting a high remaining invasion potential in Africa. The selection of the biogeographic realm is an important factor in model construction, and has a great influence on the transferability of the models. Indeed, the global model produced the best performance, following the source and native models.

A lack of specificity is restricting the further application of conotoxin from Conus bullatus (BuIA). In this study, an analogue library of BuIA was established and virtual screening was used, which identified high α7 nicotinic acetylcholine receptor (nAChR)-selectivity analogues. The analogues were synthesized and tested for their affinity to functional human α7 nAChR and for the regulation of intracellular calcium ion capacity in neurons. Immunofluorescence, flow cytometry, and patch clamp results showed that the analogues maintained their capacity for calcium regulation. The results of the hot-plate model and paclitaxel-induced peripheral neuropathy model indicated that, when compared with natural BuIA, the analgesia activities of the analogues in different models were maintained. To analyze the adverse effects and toxicity of BuIA and its analogues, the tail suspension test, forced swimming test, and open field test were used. The results showed that the safety and toxicity of the analogues were significantly better than BuIA. The analogues of BuIA with an appropriate and rational mutation showed high selectivity and maintained the regulation of Ca2+ capacity in neurons and activities of analgesia, whereas the analogues demonstrated that the adverse effects of natural α-conotoxins could be reduced.

Numerous studies focus on food-for-protection ant-aphid mutualism while ignoring the potential aphid’s protection for ants. To obtain a comprehensive understanding of bidirectional services in ant-aphid mutualism in goji berry, we manipulated the presence and abundance of ladybugs or mites, analyzing their impact on the ant-aphid mutualism persistence. We found that ants provided aphid protection from ladybugs and aphids provided anti-mite measures for protecting ants. For aphid protection by ants, 1) ant presence eroded the positive aphid-ladybug abundance relationship by reducing ladybug attendance. 2) Aphid-infested plants with more ants were less acceptable to ladybugs (ant-ladybug ratio above 1.75). 3) Ant presence impacted consumption traits of ladybugs, including aphid consumption (43.5% less), handling time (220.3% more), and theoretical maximum consumption (68.8% less). For ant protection by aphids, 4) aphid presence alleviated negative impacts on ants caused by mites by reducing mite abundance. 5) High-abundance mites (mite-ant ratio above 70) significantly reduced ant attendance. 6) The substantial volume of aphid honeydew had remarkable anti-mite effects by trapping mites (above 0.7 ml per leaf). Besides food-for-protection mutualism, our study indicates that anti-mite measures of aphids for protecting ants could promote the persistence of ant-aphid mutualism. Both protections were density-dependent, suggesting in practical applications of ladybugs, inundative biological control based on density advantage could be a promising option for rapid impact on aphids. Effective control strategies should focus on reducing the aphid abundance below the economic threshold rather than attempting eradication, allowing aphids to naturally suppress mite populations. This could effectively reduce the dosage of pesticide products. [ABSTRACT FROM AUTHOR]