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Alterations of fibroblast growth factor receptors (FGFRs) are common in bladder and other cancers and result in disrupted signalling via several pathways. Therapeutics that target FGFRs have now entered the clinic, but, in common with many cancer therapies, resistance develops in most cases. To model this, we derived resistant sublines of two FGFR‐driven bladder cancer cell lines by long‐term culture with the FGFR inhibitor PD173074 and explored mechanisms using expression profiling and whole‐exome sequencing. We identified several resistance‐associated molecular profiles. These included HRAS mutation in one case and reversible mechanisms resembling a drug‐tolerant persister phenotype in others. Upregulated IGF1R expression in one resistant derivative was associated with sensitivity to linsitinib and a profile with upregulation of a YAP/TAZ signature to sensitivity to the YAP inhibitor CA3 in another. However, upregulation of other potential therapeutic targets was not indicative of sensitivity. Overall, the heterogeneity in resistance mechanisms and commonality of the persister state present a considerable challenge for personalised therapy. Nevertheless, the reversibility of resistance may indicate a benefit from treatment interruptions or retreatment following disease relapse in some patients. © 2022 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland. [ABSTRACT FROM AUTHOR]

Purpose: The impact of gamma radiation on the reproductive biology of the spotted pod borer, Maruca vitrata (Fabr.) (Lepidoptera: Crambidae) was ascertained to explore the potential of the radio-genetic 'Inherited (F1) Sterility' technique (modified Sterile Insect technique) to control this serious pigeonpea pest in India. Materials and methods: Radio-biological investigations involved dose–response studies, at a range of 100–250 Gy, with respect to radiation induced adverse effects on reproductive behavior in substerilized parent (P1) moths, inheritance of sterility and associated metamorphic disruption in F1 progeny. The reproductive competence of P1 male moths and their F1 progeny was evaluated by ascertaining the survival, mating success, sperm transfer and amphimixis of gametes from irradiated male parents and their F1 progeny. Daily ovipositional and egg fertility profile were evaluated as crucial parameters for simulation modeling for this radio-genetic technique. Results: Radiation-induced check in insemination rate and sterility in P1 and F1 generation had a positive correlation with gamma dose. The metamorphic adverse effects in F1 progeny of substerilized P1 males were influenced by P1 irradiation. A higher dose of 200 Gy that resulted in 21.1% fertility in parent cross (P1♂x N♀) could form only 14.4% F1 adults that were all malformed. A gamma dose of 150 Gy (administered to P1 males) could be considered as a suitable dose for F1 sterility, that induced 57.4% control of reproduction in parent generation, followed by 72–85% control of reproduction in F1 progeny involved in three crosses -F1♂xN♀, N♂xF1♀, F1♂xF1♀. Daily fertility profile of the eggs laid indicated a marked reduction on 4th day onwards during the ovipositional span in P1 and F1 generation. High degree of mating competitiveness value (CV) was noticed for 150 Gy irradiated male P1 moths (0.78–0.93), and their F1 male progeny (0.70–0.89), released in different sex ratios in the field cages having untreated moths. Reduced relative damage to the pigeon pea plants by the released F1 progeny in the field cages was observed in comparison to control. Conclusion: The present study indicated the potential use of a dose of 150 Gy to apply the 'F1 sterility' technique for parabiological suppression of the pigeon pea pod borer. The present findings and reproductive performance of the irradiated moths in F2 generation along with other compatible biorational pest control tactics (that are in progress), might help in formulating an effective integrated pest management module, including the F1 sterility technique as an integral component. [ABSTRACT FROM AUTHOR]

Sperm behavior represents one of the attributes in the radiogenetic technique called inherited sterility crucial for its effectiveness to suppress populations of Spodoptera litura (F.) (Lepidoptera: Noctuidae). Quantitative and qualitative assessments of S. litura sperm behavior (production, descent, activation, movement and transfer to females) were made in parental (P) males that received sub-sterilizing irradiation doses of either 100 or 130 Gy and in their F1 generation males. Age dependent production of eupyrene and apyrene spermatozoa in the testes were not affected by such irradiation in the P males, nonetheless a slight but significant effect occurred in the F1 generation. During the rhythmic cycles of sperm descent in the photophase and scotophase, the profile and proportion of sperm descent from the testes to the upper vas deferens (UVD), seminal vesicle (SV) and duplex were not significantly influenced by irradiation in P and F1 males. Sperm activation-assessed as percent active apyrene sperm and their intensity of motility-was not diminished in irradiated P males, while in F1 males it showed a slight but significant reduction. Mating status was not a markedly pronounced factor in eliciting the motility of irradiated sperm. Sub-sterilized P males and their F1 progeny were nearly as competitive as non-irradiated males in terms of sperm transfer from male to female. Successful amphimixis occurred between the altered genomes of either irradiated P males or F1 males and the non-irradiated female genome; consequently dose dependent reductions in percent egg hatch were observed in the hatching of F1 and F2 eggs. Irradiation with either 100 or 130 Gy did not adversely influence the sperm characteristics in the irradiated P males and their F1 male progeny, and this study validated the sperm' viability and performance in irradiated P males and of their F1 sons. The findings indicated that these genetically altered sperm would fertilize the eggs of wild females and lead to effective control of this tropical pest. [ABSTRACT FROM AUTHOR]

The dose of radiation applied to the Oriental leafworm (also known as the common cutworm), Spodoptera litura (F.) (Lepidoptera: Noctuidae) for use in inherited sterility (IS) sterility programs must not materially reduce the quality and competitiveness of the released males. To assess the quality of sub-sterilized male moths and their F1 progeny, their flight and mating behaviors were investigated. Thus, parental (P) generation S. litura males that had been irradiated with either 100 or 130 Gy and their F1 male descendants were subjected to flight assay tests to assess flight ability, orientation towards a pheromone source and mating behavior, i.e., mating performance using various sex ratios, sequential matings, and effect of female age. The orientation behavior of either P or F1 males towards pheromone-baited traps was not different from that of non-irradiated males. Mating abilities of irradiated P generation males and their F1 male progeny with non-irradiated females were studied using several sex ratios, but large differences were not found even when the sex ratio was increased from 1:1 to 5:1. A study on sperm use patterns revealed the precedence of sperm of the last male to mate, for example, when a non-irradiated female was sequentially mated with a non-irradiated P male, followed by an irradiated P male and finally by an F1 male, as well as in all other possible sequences of such males. Mating success, remating propensity and fertility were significantly influenced by mating sequences that included irradiated males. Further, the age of the female at the first mating influenced fertility in matings with F1 males, and mating success and remating propensity were reduced in several of sequences of matings involving non-irradiated and irradiated males and F1 males, with reductions being more apparent when females were aged 5-6 d. The present study indicates that gamma doses of either 100 or 130 Gy are suitable for the suppression of S. litura using an IS approach. [ABSTRACT FROM AUTHOR]

Purpose: To investigate age-correlated radiosensitivity in highly radioresistant lepidopteran pest, Helicoverpa armigera, upon exposure to ionizing radiation and to examine the irradiation impact on stress-molecular responses in F1 (first-filial) progeny of irradiated (100 Gy) male moths in relation to its reproductive behavior. Materials and methods: Efficacy of sub-lethal gamma radiation was evaluated on two markedly apart ontogenic stages, neonates and adult moths. Differential growth, reproductive behavior and stress-indicating molecular responses were examined upto F1 progeny of sub-sterilized moths. Free-radical scavenging enzymes, superoxide dismutase (SOD), catalase (CAT) and Phenoloxidase cascade enzymes, pro-phenoloxidase (PPO), its activating enzyme (PPAE) were studied in irradiated and irradiated plus microbial challenge regimen (dual-stress) by Real-time RT-PCR (reverse-transcription-polymerase-chain-reaction). Results: An inverse correlation of radiosensitivity with developmental age of insect was observed. F1 sterility was higher than parent sterility. F1 progeny exhibited protraction in development and decreased survival upon irradiation. Sex ratio in F1 progeny was skewed towards males. PPO, PPAE, SOD and CAT transcripts were downregulated upon neonate irradiation resulting in enhanced vulnerability of larvae to incidental microbial challenge. These transcripts were upregulated in F1 progeny of sub-sterilized male moths (100 Gy) upon dual-stress. Conclusions: Irradiation impact on stress-indicating molecular responses in F1 progeny is correlated with its reproductive performance. These observations will permit defining regimen having pragmatic viability of 'F1 sterility technique' for pest suppression. Gamma dose of 100 Gy would ensure balance between induced sterility of males and their field competitiveness. These parameters would facilitate integration of biocontrol strategy with parabiological 'Sterile Insect Release Technique'. [ABSTRACT FROM AUTHOR]

The present investigation was carried out to create a scientific foundation on which to establish a phytosanitary irradiation regimen against the quarantine pest, the papaya mealybug, Paracoccus marginatus Williams and Granara de Willink (Hemiptera: Pseudococcidae). All of the ontogenetic stages of P. marginatus were irradiated with a range of doses of gamma radiation intended to completely prevent reproduction either by inducing sterility of the adults or by metamorphic arrest of the immatures stages. Effective gamma doses (ED99.9) ranged from 26 Gy for the egg—the most sensitive pre-imaginal stage—to 258 Gy for the N3-female—the most resistant pre-imaginal stage in which induced lethality—caused by metamorphic arrest to prevent adult formation—was used as the measure of efficacy against the various irradiated pre-imaginal stages. Further, an ED99.9 dose in the range of 27–62 Gy applied to various immature stages was sufficient to induce reproductive sterility in parent (P) generation adults as a consequence of carry-over effects induced by sub-lethal irradiation of the pre-imaginal immature stages. ED99.9 doses applied to adult females for the induction of complete sterility were in the range of 56–165 Gy depending on the age of the irradiated adult females. In addition, sub-sterilizing doses administered to P generation adults were efficacious in inducing either metamorphic arrest or reproductive sterility in their F1 progeny. The prevention of development of F1 N2 nymphs from F1 N1 crawlers—another important threshold for efficacy of phytosanitary irradiation—was feasible with the ED99.9 dose of 91 Gy administered to the most radio-tolerant stage of P generation, i.e., gravid females. ED99.9 values in the range of 35–62 Gy administered to P generation adult females belonging to different age groups were sufficient to completely prevent the formation of F1 adult females. ED99.9 sub-sterilizing gamma radiation doses in the range of 27–37 Gy given to P adult males and females—irradiated in different age groups—were sufficient to induce complete F1 sterility. Further, irradiation with either 200 Gy or 400 Gy did not degrade the sensory indices of papaya, Carica papaya L. (Brassicales: Caricaceae)—a major host of P. marginatus—such as color and weight, and vital physico-chemical attributes, thus assuring phytosanitary irradiation as an acceptable method safeguarding this fresh food. The present investigation indicated that gamma radiation in the range of 165–258 Gy applied against P. marginatus could be used as an effective and safe phytosanitary irradiation measure, because these doses induce lethality in developing stages, sterility in adults of this pest and do not degrade the quality of papaya fruits as a human food. Since the magnitude of the adult sterilizing dose was less than the dose causing pre-imaginal metamorphic disruption, a gamma dose of 200 Gy might be considered as an effective phytosanitary treatment to enable infestation-free agricultural commerce with respect to this quarantine pest. [ABSTRACT FROM AUTHOR]

Phytosanitary irradiation (PI) has great potential to disinfest agricultural commodities of quarantine pests. Efficacy of gamma irradiation (5–500 Gy) was studied on various ontogenetic stages of the solenopsis mealybug, Phenacoccus solenopsis Tinsley (Hemiptera: Pseudococcidae), which is an economic tropical postharvest pest. As P. solenopsis showed a parthenogenetic mode of reproduction, studies were focused on female adults to estimate the minimum dose required for sterilization by gamma radiation. The radiosensitivity of the insect decreased as its age and developmental stage increased. The most radiotolerant stage, the 11-12 d-old gravid females required 500 Gy to completely prevent F1 egg hatch, whereas 200 Gy prevented molting of all F1 first instar nymphs to the second instar. The next lowest dose attempted was 100 Gy, whereupon 43 F1 first instar nymphs— hatched from 500 eggs laid by irradiated gravid females,— molted to the F1 second instar. Therefore, a dose of ~200 Gy might suffice as a phytosanitary treatment against P. solenopsis. Large-scale confirmatory testing would be required to confirm a dose that could be used against this insect. Radiotolerance of potato (Solanum tuberosum L.; Solanales: Solanaceae)—a major host of P. solenopsis—was studied at 200 and 400 Gy. Color, weight, total soluble solids, titratable acidity, pH, vitamin C and ß-carotene content were not affected compared with non-irradiated controls after 7 d storage at 5 °C. [ABSTRACT FROM AUTHOR]

The purpose of this research was to determine the efficacy of ionizing irradiation as a phytosanitary treatment against the pink hibiscus mealybug, Maconellicoccus hirsutus Green (Hemiptera: Pseudococcidae), a species having major pest status in the Indian subcontinent and elsewhere. Various ontogenetic stages of M. hirsutus were exposed to gamma radiation at different doses to assess the metamorphic disruptions leading to lethality and/ or adult sterility. Effective treatment doses (ED99.9) ranged from 28 to 371 Gy where induced lethality due to metamorphic arrest and prevention of adult formation were used as the measure of efficacy against the various irradiated pre-imaginal stages. Further, ED99.9 doses ranging from 30 Gy for the radio-sensitive egg stage to 88 Gy for the N3-female—the most resistant pre-imaginal stage—were sufficient to induce sexual sterility in the parent generation (P) adults due to a carry-over effect of sub-lethal doses administered to the pre-imaginal stages. The ED99.9 values to induce sterility in adult females ranged from 112 to 235 Gy depending on the age of the irradiated adult females. Further, the effect of sub-sterilizing irradiation doses given to P generation adults was ascertained on the viability of their F1 progeny. ED99.9 doses in the range of 37–79 Gy administered to P adult females belonging to various age groups were sufficient to induce the complete prevention of F1 female adult formation. A gamma radiation ED99.9 dose in the range of 30–52 Gy administered to P adults—depending on which of the various age groups was irradiated—induced complete F1 sterility. In addition, this study also examined sensory characteristics like color and weight loss, and physico-chemical features like total soluble solids, titratable acidity, pH, vitamin C and β-carotene contents of irradiated table grapes, Vitis vinifera L.(Vitales: Vitaceae)—a major host of Maconellicoccus hirsutus—that were found to be unaffected by phytosanitary irradiation at the highest dose tested, 400 Gy. The results indicated that at least 371 Gy would be required to cause metamorphic inhibition in the most radio-resistant pre-imaginal N3 female stage and ~240 Gy to completely sterilize the most radioresistant adult gravid female stage. However, the phytosanitary dose could be further reduced to less than 200 Gy if the criterion of efficacy would be the prevention of the formation of F1 N2 nymphs. This criterion warrants pilot testing to validate the final gamma irradiation dose to be employed for phytosanitary irradiation. This range of quarantine doses would also ensure no damage to the nutritional quality of irradiated foods. [ABSTRACT FROM AUTHOR]

Purpose: The impact of gamma radiation on the reproductive biology of the spotted pod borer, Maruca vitrata (Fabr.) (Lepidoptera: Crambidae) was ascertained to explore the potential of the radio-genetic 'Inherited (F 1 ) Sterility' technique (modified Sterile Insect technique) to control this serious pigeonpea pest in India. Materials and methods: Radio-biological investigations involved dose-response studies, at a range of 100-250 Gy, with respect to radiation induced adverse effects on reproductive behavior in substerilized parent (P 1 ) moths, inheritance of sterility and associated metamorphic disruption in F 1 progeny. The reproductive competence of P 1 male moths and their F 1 progeny was evaluated by ascertaining the survival, mating success, sperm transfer and amphimixis of gametes from irradiated male parents and their F 1 progeny. Daily ovipositional and egg fertility profile were evaluated as crucial parameters for simulation modeling for this radio-genetic technique. Results: Radiation-induced check in insemination rate and sterility in P 1 and F 1 generation had a positive correlation with gamma dose. The metamorphic adverse effects in F 1 progeny of substerilized P 1 males were influenced by P 1 irradiation. A higher dose of 200 Gy that resulted in 21.1% fertility in parent cross (P 1 ♂x N♀) could form only 14.4% F 1 adults that were all malformed. A gamma dose of 150 Gy (administered to P 1 males) could be considered as a suitable dose for F 1 sterility, that induced 57.4% control of reproduction in parent generation, followed by 72-85% control of reproduction in F 1 progeny involved in three crosses -F 1 ♂xN♀, N♂xF 1 ♀, F 1 ♂xF 1 ♀. Daily fertility profile of the eggs laid indicated a marked reduction on 4th day onwards during the ovipositional span in P 1 and F 1 generation. High degree of mating competitiveness value (CV) was noticed for 150 Gy irradiated male P 1 moths (0.78-0.93), and their F 1 male progeny (0.70-0.89), released in different sex ratios in the field cages having untreated moths. Reduced relative damage to the pigeon pea plants by the released F 1 progeny in the field cages was observed in comparison to control. Conclusion: The present study indicated the potential use of a dose of 150 Gy to apply the 'F 1 sterility' technique for parabiological suppression of the pigeon pea pod borer. The present findings and reproductive performance of the irradiated moths in F 2 generation along with other compatible biorational pest control tactics (that are in progress), might help in formulating an effective integrated pest management module, including the F 1 sterility technique as an integral component.