Impact of insecticide programs on pests, the predatory mite Phytoseiulus persimilis, and staked tomato profitability.

BACKGROUND: Various insecticides are available to manage diverse pest complexes in commercial vegetable production, but knowledge gaps exist regarding their overall performance in pest suppression, profitability, and compatibility with biological control. We conducted trials in staked tomatoes in western North Carolina in 2017-2018 to compare how different insecticide programs managed key pests and their interactions with Phytoseiulus persimilis Athias-Henriot, a predator of the twospotted spider mite (TSSM, Tetranychus urticae Koch). Treatments compared no insecticides to broad-spectrum ('hard') foliar applications, selective ('soft') foliar applications, and to chemigation of selective systemic insecticides. Treatment efficacy was based on pest control, net profitability, and Environmental Impact Quotient (EIQ) ratings comparing environmental and human health risks. RESULTS: All programs similarly suppressed aphids, while flower thrips and flea beetle populations were low and unaffected by program. Only the 'hard' foliar program suppressed TSSM (including P. persimilis), which quickly rebounded. This program inhibited biological control, and eventual TSSM suppression was likely caused by P. persimilis immigrating from nearby plots. All programs were generally equivalent in reducing fruit damage. Net profits were similar among insecticide programs, which were significantly greater than in untreated plots. Yield and profit trends were similar both years, but impacted by record flooding in 2018. CONCLUSION: Safer and more selective chemigation and 'soft' foliar programs were as effective and economical as the 'hard' foliar program, while also conserving biological control. These results support existing research demonstrating that improved insecticide use can be integrated with biological control for more profitable and environmentally sustainable vegetable production. © 2022 Society of Chemical Industry.

Banks Grass Mite (Acari: Tetranychidae) Suppression May Add to the Benefit of Drought-Tolerant Corn Hybrids Exposed to Water Stress.

Spider mite (Acari: Tetranychidae) outbreaks are common on corn grown in the arid West. Hot and dry conditions reduce mite development time, increase fecundity, and accelerate egg hatch. Climate change is predicted to increase drought incidents and produce more intense temperature patterns. Together, these environmental shifts may cause more frequent and severe spider mite infestations. Spider mite management is difficult as many commercially available acaricides are ineffective due to the development of resistance traits in field mite populations. Therefore, alternative approaches to suppress outbreaks are critically needed. Drought-tolerant plant hybrids alleviate the challenges of growing crops in water-limited environments; yet, it is unclear if drought-tolerant hybrids exposed to water stress affect mite outbreaks under these conditions. We conducted a greenhouse experiment to evaluate the effect of drought-tolerant corn hybrids on Banks grass mite [Oligonychus pratensis Banks (Acari: Tetranychidae)], a primary pest of corn, under optimal irrigation and water-stress irrigation. This was followed by a 2-yr field study investigating the effect of drought-tolerant corn hybrids exposed to the same irrigation treatments on Banks grass mite artificially infested on hybrids and resident spider mite populations. Results showed that water-stressed drought-tolerant hybrids had significantly lower Banks grass mite and resident spider mite populations than water-stressed drought-susceptible hybrids. Interestingly, water-stressed drought-tolerant hybrids had equal Banks grass mite populations to drought-susceptible and drought-tolerant hybrids under optimal irrigation. We posit that planting drought-tolerant hybrids may suppress spider mite outbreaks in water-challenged areas.

Cerambycid Communities and Their Associated Hymenopteran Parasitoids From Major Hardwood Trees in Delaware: Implications for Biocontrol of Invasive Longhorned Beetles.

Cerambycidae provide important ecological services in forests yet cause economic damage when they infest living trees. Parasitoids can regulate woodborer populations, providing considerable control of pest cerambycids. Identifying parasitoids of native cerambycids may be useful in managing cerambycid outbreaks and aid in new-association biocontrol of exotic invasive cerambycids. We investigated Cerambycidae and associated hymenopteran parasitoid communities infesting Acer rubrum, Pinus virginiana, and Carya tomentosa from a forest in Delaware from 2005 to 2012. Cerambycid abundance, diversity, and richness, as well as parasitoid abundance, were measured by collecting trees in different conditions: felled, girdled, and naturally infested. Effect of edge or interior red maple on cerambycid abundance, diversity, and richness was examined. Over 14,500 cerambycids of 56 species and 38 genera were collected during the 7-yr period. Eleven species represented 95% of all cerambycids collected. Treatment only affected red maple, showing increased cerambycid richness and diversity from naturally infested trees. Cerambycid richness and diversity were two times greater on hickory than other species when combining girdled and felled treatments. Over 19,000 parasitic Hymenoptera of 12 families emerged from woodborer-infested wood with >70% of individuals belonging to Braconidae. Thirteen known species, and two unknown species, of Braconidae were identified from a subsample of 495 specimens; Ontsira mellipes (Ashmead) (Hymenoptera: Braconidae) and Rhoptrocentrus piceus Marshall (Hymenoptera: Braconidae) were the most abundant. This study provides fundamental information on native parasitoids associated with Cerambycidae, including cerambycid larval host associations. Parasitoids identified herein should be investigated for potential adaptation to invasive Cerambycidae to benefit invasive woodborer management.

Rational Design of 5-(4-(Isopropylsulfonyl)phenyl)-3-(3-(4-((methylamino)methyl)phenyl)isoxazol-5-yl)pyrazin-2-amine (VX-970, M6620): Optimization of Intra- and Intermolecular Polar Interactions of a New Ataxia Telangiectasia Mutated and Rad3-Related (ATR) Kinase Inhibitor.

The DNA damage response (DDR) is a DNA damage surveillance and repair mechanism that can limit the effectiveness of radiotherapy and DNA-damaging chemotherapy, commonly used treatment modalities in cancer. Two related kinases, ataxia telangiectasia mutated (ATM) and ATM and Rad3-related kinase (ATR), work together as apical proteins in the DDR to maintain genome stability and cell survival in the face of potentially lethal forms of DNA damage. However, compromised ATM signaling is a common characteristic of tumor cells, which places greater reliance on ATR to mediate the DDR. In such circumstances, ATR inhibition has been shown to enhance the toxicity of DNA damaging chemotherapy to many cancer cells in multiple preclinical studies, while healthy tissue with functional ATM can tolerate ATR inhibition. ATR therefore represents a very attractive anticancer target. Herein we describe the discovery of VX-970/M6620, the first ATR inhibitor to enter clinical studies, which is based on a 2-aminopyrazine core first reported by Charrier ( J. Med. Chem. 2011 , 54 , 2320 - 2330 , DOI: 10.1021/jm101488z ).

Effects of Legume Species and Plant Growth Stage on Attraction, Fecundity, and Development of the Kudzu Bug (Heteroptera: Plataspidae).

The kudzu bug, Megacopta cribraria (F.) (Heteroptera: Plataspidae), is an invasive pest of soybeans in the southeastern United States. Two greenhouse choice assays evaluated crop species and growth stage-specific orientation preference of kudzu bug adults to six different legume species (Fabales: Fabaceae) at four plant growth stages (V2, V4, R1, and R5). Adults had differential orientation to both legume species and plant growth stages tested. Adults preferred the R1 stage of soybean (Glycine max (L.) Merrill) and lima bean (Phaseolus lunatus (L.)), but preferred various growth stages of the other legumes tested. Given their respective attractive growth stages, adults significantly preferred lima bean (47.8%) to soybean (21.9%) and kidney bean (Phaseolus vulgaris (L.), 19.2%), and preferred mung bean (Vigna radiata (L.) Wilczek, 4.2%), black-eyed pea (Vigna unguiculata subsp. unguiculata (L.) Walp, 4.7%), and green bean (Phaseolus vulgaris (L.), 2.7%) the least. In no-choice assays, females deposited a similar number of eggs on each legume species, except for green bean and kidney bean, on which they deposited the fewest eggs. Eggs laid by females feeding on soybean (67.9%), lima bean (58.1%), and mung bean (42.6%) had significantly greater hatch rates than eggs laid by females feeding on the other legume species. No-choice assays also showed that nymphs completed development to adults on soybean, lima bean, and mung bean; yet, survival was greatest on soybean. Results show that females fed and oviposited on all of the legume species tested; however, plant species significantly affected egg hatch rates and nymphal survival.

Influence of Temperature on the Reproductive and Developmental Biology of Ontsira mellipes (Hymenoptera: Braconidae): Implications for Biological Control of the Asian Longhorned Beetle (Coleoptera: Cerambycidae).

Ontsira mellipes Ashmead (Hymenoptera: Braconidae) is a North American parasitoid species that develops on the invasive pest, Anoplophora glabripennis (Moltschulsky) (Coleoptera: Cerambycidae), under laboratory conditions and is currently being considered as a potential new-association biocontrol agent. To develop mass-rearing protocols and field-release strategies for this parasitoid, information on its reproductive biology in relation to temperature is needed. We determined the effect of temperature (10, 15, 20, 25, and 30 °C) on development, survivorship, and sex ratio, and its effect on the longevity, fecundity, and host attack rates (parasitism) of adults. Developmental time for parasitoid eggs to pupae decreased from 26.7 d to 6.1 d as temperature increased from 10 °C to 30 °C. While no pupae eclosed as adults at 10 °C, time of adult emergence from pupae decreased from 39.7 d to 12.2 d as temperature increased from 15 °C to 30 °C. Based on estimated lower development temperature threshold (11.1 °C), the degree-days required for one generation was estimated at 342.9. When female parasitoids were provided with host larvae, parasitism occurred at all temperatures and was maximized at 25 °C. Additionally, increasing temperatures significantly reduced the preoviposition period and longevity of female O. mellipes. In addition, combining these results with temperature data from areas in the United States currently infested with A. glabripennis, we estimated that O. mellipes can complete 1.2-3.7 generations per year. Findings from this study may be considered for the future development of effective mass rearing and augmentative release strategies of O. mellipes for biological control of A. glabripennis.

Clinical development of new drug-radiotherapy combinations.

In countries with the best cancer outcomes, approximately 60% of patients receive radiotherapy as part of their treatment, which is one of the most cost-effective cancer treatments. Notably, around 40% of cancer cures include the use of radiotherapy, either as a single modality or combined with other treatments. Radiotherapy can provide enormous benefit to patients with cancer. In the past decade, significant technical advances, such as image-guided radiotherapy, intensity-modulated radiotherapy, stereotactic radiotherapy, and proton therapy enable higher doses of radiotherapy to be delivered to the tumour with significantly lower doses to normal surrounding tissues. However, apart from the combination of traditional cytotoxic chemotherapy with radiotherapy, little progress has been made in identifying and defining optimal targeted therapy and radiotherapy combinations to improve the efficacy of cancer treatment. The National Cancer Research Institute Clinical and Translational Radiotherapy Research Working Group (CTRad) formed a Joint Working Group with representatives from academia, industry, patient groups and regulatory bodies to address this lack of progress and to publish recommendations for future clinical research. Herein, we highlight the Working Group's consensus recommendations to increase the number of novel drugs being successfully registered in combination with radiotherapy to improve clinical outcomes for patients with cancer.

Life History, Reproductive Biology, and Larval Development of Ontsira mellipes (Hymenoptera: Braconidae), a Newly Associated Parasitoid of the Invasive Asian Longhorned Beetle (Coleoptera: Cerambycidae).

The invasive Asian longhorned beetle, Anoplophora glabripennis (Motschulsky), is a destructive xylophagous forest pest species originating from Asia. Several endemic North American hymenopteran (Braconidae) species in the mid-Atlantic region were capable of attacking and reproducing on A. glabripennis larvae in laboratory bioassays. Ontsira mellipes Ashmead (Hymenoptera: Braconidae) has been continually reared on A. glabripennis larvae at USDA-ARS BIIRU since 2010, and has been identified as a potential new-association biocontrol agent. Two experiments were conducted to investigate parasitism, paralysis, reproductive biology, larval development, and longevity of adult O. mellipes In the first experiment, pairs of adult parasitoids were given single A. glabripennis larvae every 2 d (along with honey and water) over their lifetimes, while in the second experiment individual parasitoids were observed daily from egg to adult, and adults were subsequently starved. Adults in the first experiment parasitized ∼21% of beetle larvae presented to them throughout their life, and paralysis of larvae occurred 1-2 d after oviposition. More than half of the individual pairs parasitized A. glabripennis larvae, with each female producing around 26 offspring throughout her life. In the second experiment, median development time of O. mellipes from egg to adult was about 3 wk, with five larval instars. Adult O. mellipes that were provided with host larvae, honey, and water lived 9 d longer than host-deprived and starved adults. These findings indicate that mass-rearing procedures for O. mellipes may be developed using the new association host for development of effective biocontrol programs against A. glabripennis.

Potentiation of tumor responses to DNA damaging therapy by the selective ATR inhibitor VX-970.

Platinum-based DNA-damaging chemotherapy is standard-of-care for most patients with lung cancer but outcomes remain poor. This has been attributed, in part, to the highly effective repair network known as the DNA-damage response (DDR). ATR kinase is a critical regulator of this pathway, and its inhibition has been shown to sensitize some cancer, but not normal, cells in vitro to DNA damaging agents. However, there are limited in vivo proof-of-concept data for ATR inhibition. To address this we profiled VX-970, the first clinical ATR inhibitor, in a series of in vitro and in vivo lung cancer models and compared it with an inhibitor of the downstream kinase Chk1. VX-970 markedly sensitized a large proportion of a lung cancer cell line and primary tumor panel in vitro to multiple DNA damaging drugs with clear differences to Chk1 inhibition observed. In vivo VX-970 blocked ATR activity in tumors and dramatically enhanced the efficacy of cisplatin across a panel of patient derived primary lung xenografts. The combination led to complete tumor growth inhibition in three cisplatin-insensitive models and durable tumor regression in a cisplatin-sensitive model. These data provide a strong rationale for the clinical evaluation of VX-970 in lung cancer patients.

Structure of human Bloom's syndrome helicase in complex with ADP and duplex DNA.

Bloom's syndrome is an autosomal recessive genome-instability disorder associated with a predisposition to cancer, premature aging and developmental abnormalities. It is caused by mutations that inactivate the DNA helicase activity of the BLM protein or nullify protein expression. The BLM helicase has been implicated in the alternative lengthening of telomeres (ALT) pathway, which is essential for the limitless replication of some cancer cells. This pathway is used by 10-15% of cancers, where inhibitors of BLM are expected to facilitate telomere shortening, leading to apoptosis or senescence. Here, the crystal structure of the human BLM helicase in complex with ADP and a 3'-overhang DNA duplex is reported. In addition to the helicase core, the BLM construct used for crystallization (residues 640-1298) includes the RecQ C-terminal (RQC) and the helicase and ribonuclease D C-terminal (HRDC) domains. Analysis of the structure provides detailed information on the interactions of the protein with DNA and helps to explain the mechanism coupling ATP hydrolysis and DNA unwinding. In addition, mapping of the missense mutations onto the structure provides insights into the molecular basis of Bloom's syndrome.

Selective killing of ATM- or p53-deficient cancer cells through inhibition of ATR.

Here we report a comprehensive biological characterization of a potent and selective small-molecule inhibitor of the DNA damage response (DDR) kinase ATR. We show a profound synthetic lethal interaction between ATR and the ATM-p53 tumor suppressor pathway in cells treated with DNA-damaging agents and establish ATR inhibition as a way to transform the outcome for patients with cancer treated with ionizing radiation or genotoxic drugs.

Discovery of potent and selective inhibitors of ataxia telangiectasia mutated and Rad3 related (ATR) protein kinase as potential anticancer agents.

DNA-damaging agents are among the most frequently used anticancer drugs. However, they provide only modest benefit in most cancers. This may be attributed to a genome maintenance network, the DNA damage response (DDR), that recognizes and repairs damaged DNA. ATR is a major regulator of the DDR and an attractive anticancer target. Herein, we describe the discovery of a series of aminopyrazines with potent and selective ATR inhibition. Compound 45 inhibits ATR with a K(i) of 6 nM, shows >600-fold selectivity over related kinases ATM or DNA-PK, and blocks ATR signaling in cells with an IC(50) of 0.42 µM. Using this compound, we show that ATR inhibition markedly enhances death induced by DNA-damaging agents in certain cancers but not normal cells. This differential response between cancer and normal cells highlights the great potential for ATR inhibition as a novel mechanism to dramatically increase the efficacy of many established drugs and ionizing radiation.

VX-166: a novel potent small molecule caspase inhibitor as a potential therapy for sepsis.

INTRODUCTION: Prevention of lymphocyte apoptosis by caspase inhibition has been proposed as a novel treatment approach in sepsis. However, it has not been clearly demonstrated that caspase inhibitors improve survival in sepsis models when dosed post-insult. Also, there are concerns that caspase inhibitors might suppress the immune response. Here we characterize VX-166, a broad caspase inhibitor, as a novel potential treatment for sepsis. METHODS: VX-166 was studied in a number of enzymatic and cellular assays. The compound was then tested in a murine model of endotoxic shock (lipopolysaccharide (LPS), 20 mg/kg IV) and a 10 d rat model of polymicrobial sepsis by caecal ligation and puncture (CLP). RESULTS: VX-166 showed potent anti-apoptotic activity in vitro and inhibited the release of interleukin (IL)-1beta and IL-18. In the LPS model, VX-166 administered 0, 4, 8 and 12 h post-LPS significantly improved survival in a dose-dependent fashion (P < 0.0028). In the CLP model, VX-166 continuously administered by mini-osmotic pump significantly improved survival when dosed 3 h after insult, (40% to 92%, P = 0.009). When dosed 8 h post-CLP, VX-166 improved survival from 40% to 66% (P = 0.19). Mode of action studies in the CLP model confirmed that VX-166 significantly inhibited thymic atrophy and lymphocyte apoptosis as determined by flow cytometry (P < 0.01). VX-166 reduced plasma endotoxin levels (P < 0.05), suggesting an improved clearance of bacteria from the bloodstream. Release of IL-1beta in vivo or T-cell activation in vitro were moderately affected. CONCLUSIONS: Our studies enhance the case for the use of caspase inhibitors in sepsis. VX-166 itself has promise as a therapy for the treatment of sepsis in man.

The discovery of the potent aurora inhibitor MK-0457 (VX-680).

The identification of a novel series of Aurora kinase inhibitors and exploitation of their SAR is described. Replacement of the initial quinazoline core with a pyrimidine scaffold and modification of substituents led to a series of very potent inhibitors of cellular proliferation. MK-0457 (VX-680) has been assessed in Phase II clinical trials in patients with treatment-refractory chronic myelogenous leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) containing the T315I mutation.

VX-680, a potent and selective small-molecule inhibitor of the Aurora kinases, suppresses tumor growth in vivo.

The Aurora kinases are essential for the regulation of chromosome segregation and cytokinesis during mitosis. Aberrant expression and activity of these kinases occur in a wide range of human tumors, and lead to aneuploidy and tumorigenesis. Here we report the discovery of a highly potent and selective small-molecule inhibitor of Aurora kinases, VX-680, that blocks cell-cycle progression and induces apoptosis in a diverse range of human tumor types. This compound causes profound inhibition of tumor growth in a variety of in vivo xenograft models, leading to regression of leukemia, colon and pancreatic tumors at well-tolerated doses. Our data indicate that Aurora kinase inhibition provides a new approach for the treatment of multiple human malignancies.

Novel inhibitors of plasminogen activator inhibitor-1: development of new templates from diketopiperazines.

Several isoquinoline-based templates were identified from the studies of the conformational effects of the diketopiperazine structures for PAI-1 inhibition. Moderate to good activity was retained with the elimination of unattractive characteristics in the diketopiperazine template.

Design, synthesis and in vitro evaluation of potent, novel, small molecule inhibitors of plasminogen activator inhibitor-1.

We have synthesized and evaluated a series of tetramic acid-based and hydroxyquinolinone-based inhibitors of plasminogen activator inhibitor-1 (PAI-1). These studies resulted in the identification of several compounds which showed excellent potency against PAI-1. The design, synthesis and SAR of these compounds are described.