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El envejecimiento de la población aumenta la prevalencia de enfermedades crónicas como la diabetes mellitus (DM) y la enfermedad pulmonar obstructiva crónica (EPOC). Diferentes estudios realizados con un diseño de casos y controles y de cohortes confirman la asociación existente entre DM y EPOC. Existen diferentes explicaciones plausibles que relacionan la EPOC y la DM (tabaco, menor actividad física, presencia de un estado pro-inflamatorio y el uso de corti- coides) y también que relacionan y explican el deterioro de la función pulmonar en pacientes con DM, tratándose de una complicación principalmente microvascular. La presente revisión bibliográfica, sin ser una revisión sistemática de la literatura, pretende aproximar la relación existente entre ambas patologías a todos los profesionales implicados en su manejo práctico y aporta una serie de consejos prácticos de manejo del paciente con ambas patologías.

Mitochondrial dysfunction is a hallmark of cancer cachexia (CC). Mitochondrial reactive oxygen species (ROS) are elevated in muscle shortly after tumor onset. Targeting mitochondrial ROS may be a viable option to prevent CC. The aim of this study was to evaluate the efficacy of a mitochondria-targeted antioxidant, SkQ1, to mitigate CC in both biological sexes. Male and female Balb/c mice were injected bilaterally with colon 26 adenocarcinoma (C26) cells (total 1 × 10 6 cells) or PBS (equal volume control). SkQ1 was dissolved in drinking water (∼250 nmol/kg body wt/day) and administered to mice beginning 7 days following tumor induction, whereas control groups consumed normal drinking water. In vivo muscle contractility of dorsiflexors, deuterium oxide-based protein synthesis, mitochondrial respiration and mRNA content of mitochondrial, protein turnover, and calcium channel-related markers were assessed at endpoint (25 days following tumor induction). Two-way ANOVAs, followed by Tukey's post hoc test when interactions were significant ( P ≤ 0.05), were performed. SkQ1 attenuated cancer-induced atrophy, promoted protein synthesis, and abated Redd1 and Atrogin induction in gastrocnemius of C26 male mice. In female mice, SkQ1 decreased muscle mass and increased catabolic signaling in the plantaris of tumor-bearing mice, as well as reduced mitochondrial oxygen consumption, regardless of tumor. However, in females, SkQ1 enhanced muscle contractility of the dorsiflexors with concurrent induction of Ryr1 , Serca1 , and Serca2a in TA. In conclusion, the mitochondria-targeted antioxidant SkQ1 may attenuate CC-induced muscle loss in males, while improving muscle contractile function in tumor-bearing female mice, suggesting sexual dimorphism in the effects of this mitochondrial therapy in CC. NEW & NOTEWORTHY Herein, we assess the efficacy of the mitochondria-targeted antioxidant SkQ1 to mitigate cancer cachexia (CC) in both biological sexes. We demonstrate that SkQ1 administration attenuates muscle wasting induced by C26 tumors in male, but not female, mice. Conversely, we identify that in females, SkQ1 improves muscle contractility. These phenotypic adaptations to SkQ1 are aligned with respective responses in muscle protein synthesis, mitochondrial respiration, and mRNA content of protein turnover, as well as mitochondrial and calcium handling-related markers.

Studies suggest heterogeneity in cancer cachexia (CC) among models and biological sexes, yet examinations comparing models and sexes are scarce. We compared the transcriptional landscape of skeletal muscle across murine CC models and biological sexes during early and late CC. Global gene expression analyses were performed on gastrocnemius (LLC-Lewis Lung Carcinoma), quadriceps (KPC-pancreatic), and tibialis anterior (C26-colorectal and Apc Min/+ ) muscles across biological sexes. Differentially expressed genes (DEGs) were identified using an adj-p-value of <0.05, followed by pathway and computational cistrome analyses. Integrating all controls, early, and late-stage of all models and sexes revealed up to 68% of DEGs and pathways were enriched at early and late CC, indicating a conserved transcriptional profile during CC development. Comparing DEGs and pathways within sexes and across models, in early-CC, the transcriptional response was highly heterogeneous. At late-stage, 11.5% of upregulated and 10% of downregulated genes were shared between models in males, while 18.9% of upregulated and 7% of downregulated DEGs were shared in females. Shared DEGs were enriched in proteasome and mitophagy/autophagy pathways (upregulated), and downregulation of energy metabolism pathways in males only. Between sexes, though proportion of shared DEGs was low (<16%), similar pathway enrichment was observed, including proteasome and mitophagy at late-stage CC. In early-CC, Osmr upregulation was the only commonality across all models and sexes, while CLOCK and ARNTL/BMAL1 were predicted transcriptional factors associated with dysregulations in all three male models. This study highlights sex and model differences in CC progression and suggests conserved transcriptional changes as potential therapeutic targets.

Orchard bees of the genus Osmia Panzer are important pollinators of fruit trees in various regions of the world, with some species commercially available in the United States and Europe. In addition to their pollination services, Osmia lignaria, Osmia cornifrons, Osmia bicornis, and Osmia cornuta have been identified as potential model species for solitary bees in pesticide risk assessment and have been used for the development of new methods to test acute lethal effects via contact and oral routes of exposure. Our goal was to expand the available methodology to characterize the toxicity of pesticides for these solitary bees through a chronic oral test for adult bees. Chronic oral toxicity of pesticides to orchard bees has been reported, but methods differ among research groups. In our study, O. lignaria, O. cornifrons, O. bicornis, and O. cornuta female bees had access to sucrose solution ad libitum in separate, species-specific 10-day tests. Mean body mass, mean daily consumption, and survival differed among the studied bee species. The dose-response test design was validated with dimethoate, a reference toxic compound, and chronic toxicity endpoints were estimated for the 4 Osmia species. The median lethal daily doses normalized by weight for O. lignaria, O. bicornis, O. cornuta, and O. cornifrons were within the same order of magnitude at 0.23, 0.26, 0.49, and 0.61 µg dimethoate/g bee/day, respectively. The methodology described here was aligned as much as possible with the available honey bee and bumble bee standard methods to facilitate the comparison of chronic toxicity profiles among bee species., (© The Author(s) 2024. Published by Oxford University Press on behalf of Entomological Society of America.)

Cancer cachexia (CC) is a multifactorial and complex syndrome experienced by up to 80% of patients with cancer and implicated in ∼40% of cancer-related deaths. Given its significant impact on patients' quality of life and prognosis, there has been a growing emphasis on elucidating the underlying mechanisms of CC using preclinical models. However, the mechanisms of cachexia appear to differ across several variables including tumor type and model and biologic variables such as sex. These differences may be exacerbated by variance in experimental approaches and data reporting. This review examines literature spanning from 2011 to March 2024, focusing on common preclinical models of CC, including Lewis Lung Carcinoma, pancreatic KPC, and colorectal colon-26 and Apc min/+ models. Our analysis reveals considerable heterogeneity in phenotypic outcomes, and investigated mechanisms within each model, with particular attention to sex differences that may be exacerbated through methodological differences. Although searching for unified mechanisms is critical, we posit that effective treatment approaches are likely to leverage the heterogeneity presented by the tumor and pertinent biological variables to direct specific interventions. In exploring this heterogeneity, it becomes critical to consider methodological and data reporting approaches to best inform further research.

Arrestin domain containing 2 and 3 ( Arrdc2/3 ) are genes whose mRNA contents are decreased in young skeletal muscle following mechanical overload. Arrdc3 is linked to the regulation of signaling pathways in nonmuscle cells that could influence skeletal muscle size. Despite a similar amino acid sequence, Arrdc2 function remains undefined. The purpose of this study was to further explore the relationship of Arrdc2 / Arrdc3 expression with changes in mechanical load in young and aged muscle and define the effect of Arrdc2/3 expression on C2C12 myotube diameter. In young and aged mice, mechanical load was decreased using hindlimb suspension whereas mechanical load was increased by reloading previously unloaded muscle or inducing high-force contractions. Arrdc2 and Arrdc3 mRNAs were overexpressed in C2C12 myotubes using adenoviruses. Myotube diameter was determined 48-h posttransfection, and RNA sequencing was performed on those samples. Arrdc2 and Arrdc3 mRNA content was higher in the unloaded muscle within 1 day of disuse and remained higher up through 10 days. The induction of Arrdc2 mRNA was more pronounced in aged muscle than young muscle in response to unloading. Reloading previously unloaded muscle of young and aged mice restored Arrdc2 and Arrdc3 levels to ambulatory levels. Increasing mechanical load beyond normal ambulatory levels lowered Arrdc2 mRNA, but not Arrdc3 mRNA, in young and aged muscle. Arrdc2 overexpression only was sufficient to lower myotube diameter in C2C12 cells in part by altering the transcriptome favoring muscle atrophy. These data are consistent with Arrdc2 contributing to disuse atrophy, particularly in aged muscle. NEW & NOTEWORTHY We establish Arrdc2 as a novel mechanosensitive gene highly induced in response to mechanical unloading, particularly in aged muscle. Arrdc2 induction in C2C12 myotubes is sufficient to produce thinner myotubes and a transcriptional landscape consistent with muscle atrophy and disuse.

An unusual series of germylenes and stannylenes stabilized by new tetradentate bis(amidine) ligands RNC(R')N-linker-NC(R')NR with a rigid naphthalene backbone has been prepared by protonolysis reaction of Lappert's metallylenes [M(HMDS) 2 ] (M = Ge or Sn). Germylenes and stannylenes were fully characterized by NMR spectroscopy and X-ray diffraction analysis. DFT calculations have been performed to clarify the structural and electronic properties associated with tetradentate bis(amidine) ligands. Stannylene L 1 Sn shows reactivity through oxidation, oxidative addition, and transmetalation reactions, affording the corresponding gallium and aluminum derivatives.

In this work, we report on the synthesis and characterization of six new iridium(III) complexes of the type [Ir(C^N) 2 (N^N)] + using 2-phenylpyridine ( C1 - 3 ) and its fluorinated derivative ( C4 - 6 ) as cyclometalating ligands (C^N) and R-phenylimidazo(4,5- f )1,10-phenanthroline (R = H, CH 3 , F) as the ancillary ligand (N^N). These luminescent complexes have been fully characterized through optical and electrochemical studies. In solution, the C4 - 6 series exhibits quantum yields (Ф) twice as high as the C1 - 3 series, exceeding 60% in dichloromethane and where 3 MLCT/ 3 LLCT and 3 LC emissions participate in the phenomenon. These complexes were employed in the active layer of light-emitting electrochemical cells (LECs). Device performance of maximum luminance values of up to 21.7 Lx at 14.7 V were observed for the C2 complex and long lifetimes for the C1 - 3 series. These values are counterintuitive to the quantum yields observed in solution. Thus, we established that the rigidity of the system and the structure of the solid matrix dramatically affect the electronic properties of the complex. This research contributes to understanding the effects of the modifications in the ancillary and cyclometalating ligands, the photophysics of the complexes, and their performance in LEC devices.

A series of four novel heteroleptic Cu(I) complexes, bearing bis(1 H -indazol-1-yl)methane analogues as N , N ligands and DPEPhos as the P,P ligand, were synthesised in high yields under mild conditions and characterised by spectroscopic and spectrometric techniques. In addition, the position of the carboxymethyl substituent in the complexes and its effect on the electrochemical and photophysical behaviour was evaluated. As expected, the homoleptic copper (I) complexes with the N , N ligands showed air instability. In contrast, the obtained heteroleptic complexes were air- and water-stable in solid and solution. All complexes displayed green-yellow luminescence in CH 2 Cl 2 at room temperature due to ligand-centred (LC) phosphorescence in the case of the Cu(I) complex with an unsubstituted N,N ligand and metal-to-ligand charge transfer (MLCT) phosphorescence for the carboxymethyl-substituted complexes. Interestingly, proper substitution of the bis(1 H -indazol-1-yl)methane ligand enabled the achievement of a remarkable luminescent yield (2.5%) in solution, showcasing the great potential of this novel class of copper(I) complexes for potential applications in luminescent devices and/or photocatalysis.

Disuse-induced muscle atrophy is a common clinical problem observed mainly in older adults, intensive care units patients, or astronauts. Previous studies presented biological sex divergence in progression of disuse-induced atrophy along with differential changes in molecular mechanisms possibly underlying muscle atrophy. The aim of this study was to perform transcriptomic profiling of male and female mice during the onset and progression of unloading disuse-induced atrophy. Male and female mice underwent hindlimb unloading (HU) for 24, 48, 72, and 168 h ( n = 8/group). Muscles were weighed for each cohort and gastrocnemius was used for RNA-sequencing analysis. Females exhibited muscle loss as early as 24 h of HU, whereas males after 168 h of HU. In males, pathways related to proteasome degradation were upregulated throughout 168 h of HU, whereas in females these pathways were upregulated up to 72 h of HU. Lcn2 , a gene contributing to regulation of myogenesis, was upregulated by 6.46- to 19.86-fold across all time points in females only. A reverse expression of Fosb , a gene related to muscle degeneration, was observed between males (4.27-fold up) and females (4.57-fold down) at 24-h HU. Mitochondrial pathways related to tricarboxylic acid (TCA) cycle were highly downregulated at 168 h of HU in males, whereas in females this downregulation was less pronounced. Collagen-related pathways were consistently downregulated throughout 168 h of HU only in females, suggesting a potential biological sex-specific protective mechanism against disuse-induced fibrosis. In conclusion, females may have protection against HU-induced skeletal muscle mitochondrial degeneration and fibrosis through transcriptional mechanisms, although they may be more vulnerable to HU-induced muscle wasting compared with males. NEW & NOTEWORTHY Herein, we have assessed the transcriptomic response across biological sexes during the onset and progression of unloading disuse-induced atrophy in mice. We have demonstrated an inverse expression of Fosb between males and females, as well as differentially timed patterns of expressing atrophy-related pathways between sexes that are concomitant to the accelerated atrophy in females. We also identified in females signs of mechanisms to combat disuse-induced mitochondrial degeneration and fibrosis.

Cancer cachexia (CC) is a multifactorial wasting syndrome characterized by a significant loss in lean and/or fat mass and represents a leading cause of mortality in cancer patients. Nutraceutical treatments have been proposed as a potential treatment strategy to mitigate cachexia-induced muscle wasting. However, contradictory findings warrant further investigation. The purpose of this study was to determine the effects of leucine supplementation on skeletal muscle in male and female Apc Min/+ mice (APC). APC mice and their wild-type (WT) littermates were given normal drinking water or 1.5% leucine-supplemented water (n = 4-10/group/sex). We measured the gene expression of regulators of inflammation, protein balance, and myogenesis. Leucine treatment lowered survival rates, body mass, and muscle mass in males, while in females, it had no effect on body or muscle mass. Leucine treatment altered inflammatory gene expression by lowering Il1b 87% in the APC group and decreasing Tnfa 92% in both WT and APC males, while it had no effect in females ( p < 0.05). Leucine had no effect on regulators of protein balance and myogenesis in either sex. We demonstrated that leucine exacerbates moribundity in males and is not sufficient for mitigating muscle or fat loss during CC in either sex in the Apc Min/+ mouse., Competing Interests: The authors declare no conflict of interest.

Cancer cachexia is clinically defined by involuntary weight loss >5% in <6 mo, primarily affecting skeletal muscle. Here, we aimed to identify sex differences in the onset of colorectal cancer cachexia with specific consideration to skeletal muscle contractile and metabolic functions. Eight-weeks old BALB/c mice (69 males, 59 females) received subcutaneous C26 allografts or PBS vehicle. Tumors were developed for 10-, 15-, 20-, or 25 days. Muscles and organs were collected, in vivo muscle contractility, protein synthesis rate, mitochondrial function, and protein turnover markers were assessed. One-way ANOVA within sex and trend analysis between sexes were performed, P < 0.05. Gastrocnemius and tibialis anterior (TA) muscles became atrophic in male mice at 25 days, whereas female mice exhibited no significant differences in muscle weights at endpoints despite presenting hallmarks of cancer cachexia (fat loss, hepatosplenomegaly). We observed lowered muscle contractility and protein synthesis concomitantly to muscle mass decay in males, with higher proteolytic markers in muscles of both sexes. mRNA of Opa1 was lower in TA, whereas Bnip3 was higher in gastrocnemius after 25 days in male mice, with no significant effect in female mice. Our data suggest relative protections to skeletal muscle in females compared with males despite other canonical signs of cancer cachexia and increased protein degradation markers; suggesting we should place onus upon nonmuscle tissues during early stages of cancer cachexia in females. We noted potential protective mechanisms relating to skeletal muscle contractile and mitochondrial functions. Our findings underline possible heterogeneity in onset of cancer cachexia between biological sexes, suggesting the need for sex-specific approaches to treat cancer cachexia. NEW & NOTEWORTHY Our study demonstrates biological-sex differences in phenotypic characteristics of cancer cachexia between male and female mice, whereby females display many common characteristics of cachexia (gonadal fat loss and hepatosplenomegaly), protein synthesis markers alterations, and common catabolic markers in skeletal muscle despite relatively preserved muscle mass in early-stage cachexia compared with males. Mechanisms of cancer cachexia appear to differ between sexes. Data suggest need to place onus of early cancer cachexia detection and treatment on nonmuscle tissues in females.

Multidrug-resistant bacteria, such as ESBL producing-Klebsiella pneumoniae, have increased substantially, encouraging the development of complementary therapies such as photodynamic inactivation (PDI). PDI uses photosensitizer (PS) compounds that kill bacteria using light to produce reactive oxygen species. We test Ru-based PS to inhibit K. pneumoniae and advance in the characterization of the mode of action. The PDI activity of PSRu-L2, and PSRu-L3, was determined by serial micro dilutions exposing K. pneumoniae to 0.612 J/cm 2 of light dose. PS interaction with cefotaxime was determined on a collection of 118 clinical isolates of K. pneumoniae. To characterize the mode of action of PDI, the bacterial response to oxidative stress was measured by RT-qPCR. Also, the cytotoxicity on mammalian cells was assessed by trypan blue exclusion. Over clinical isolates, the compounds are bactericidal, at doses of 8 µg/mL PSRu-L2 and 4 µg/mL PSRu-L3, inhibit bacterial growth by 3 log 10 (>99.9%) with a lethality of 30 min. A remarkable synergistic effect of the PSRu-L2 and PSRu-L3 compounds with cefotaxime increased the bactericidal effect in a subpopulation of 66 ESBL-clinical isolates to > 6 log 10 with an FIC-value of 0.16 and 0.17, respectively. The bacterial transcription response suggests that the mode of action occurs through Type II oxidative stress. The upregulation of the extracytoplasmic virulence factors mrkD, magA, and rmpA accompanied this response. Also, the compounds show little or no toxicity in vitro on HEp-2 and HEK293T cells. Through the type II effect, PSs compounds are bactericidal, synergistic on K. pneumoniae, and have low cytotoxicity in mammals., Competing Interests: Declaration of Competing Interest The authors declare no conflict of interest., (Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.)

Background: Cancer-cachexia (CC) is a debilitating condition affecting up to 80% of cancer patients and contributing to 40% of cancer-related deaths. While evidence suggests biological sex differences in the development of CC, assessments of the female transcriptome in CC are lacking, and direct comparisons between sexes are scarce. This study aimed to define the time course of Lewis lung carcinoma (LLC)-induced CC in females using transcriptomics, while directly comparing biological sex differences., Results: We found the global gene expression of the gastrocnemius muscle of female mice revealed biphasic transcriptomic alterations, with one at 1 week following tumor allograft and another during the later stages of cachexia development. The early phase was associated with the upregulation of extracellular-matrix pathways, while the later phase was characterized by the downregulation of oxidative phosphorylation, electron transport chain, and TCA cycle. When DEGs were compared to a known list of mitochondrial genes (MitoCarta), ~ 47% of these genes were differently expressed in females exhibiting global cachexia, suggesting transcriptional changes to mitochondrial gene expression happens concomitantly to functional impairments previously published. In contrast, the JAK-STAT pathway was upregulated in both the early and late stages of CC. Additionally, we observed a consistent downregulation of Type-II Interferon signaling genes in females, which was associated with protection in skeletal muscle atrophy despite systemic cachexia. Upregulation of Interferon signaling was noted in the gastrocnemius muscle of cachectic and atrophic male mice. Comparison of female tumor-bearing mice with males revealed ~ 70% of DEGs were distinct between sexes in cachectic animals, demonstrating dimorphic mechanisms of CC., Conclusion: Our findings suggest biphasic disruptions in the transcriptome of female LLC tumor-bearing mice: an early phase associated with ECM remodeling and a late phase, accompanied by the onset of systemic cachexia, affecting overall muscle energy metabolism. Notably, ~ 2/3 of DEGs in CC are biologically sex-specific, providing evidence of dimorphic mechanisms of cachexia between sexes. Downregulation of Type-II Interferon signaling genes appears specific to CC development in females, suggesting a new biological sex-specific marker of CC not reliant on the loss of muscle mass, that might represent a protective mechanism against muscle loss in CC in female mice., (© 2023. The Author(s).)

Cancer cachexia (CC) accounts for 20%-40% of cancer-related deaths. Mitochondrial aberrations have been shown to precede muscle atrophy in different atrophy models, including cancer. Therefore, this study investigated potential protection from the cachectic phenotype through overexpression of peroxisome proliferator-activated receptor γ coactivator-1 α (PGC-1α). First, to establish potential of mitochondria-based approaches we showed that the mitochondrial antioxidant MitoTEMPO (MitoT) attenuates myotube atrophy induced by Lewis lung carcinoma (LLC) cell conditioned media. Next, cachexia was induced in muscle-specific PGC-1α overexpressing (MCK-PCG1α) or wildtype (WT) littermate mice by LLC implantation. MCK-PCG1α did not protect LLC-induced muscle mass loss. In plantaris, Atrogin mRNA content was 6.2-fold and ∼11-fold greater in WT-LLC vs WT-phosphate-buffered saline (PBS) for males and females, respectively ( p  < 0.05). MitoTimer red:green ratio for male PGC was ∼65% higher than WT groups ( p  < 0.05), with ∼3-fold more red puncta in LLC than PBS ( p  < 0.05). Red:green ratio was ∼56% lower in females WT-LLC vs PGC-LLC ( p  < 0.05). In females, no change in red puncta was noted across conditions. Lc3 mRNA content was ∼73% and 2-fold higher in male and female LLC mice, respectively, vs PBS ( p  < 0.05). While MitoT could mitigate cancer-induced atrophy in vitro, PGC-1α overexpression was insufficient to protect muscle mass and mitochondrial health in vivo despite mitigation of cachexia-associated signaling pathways.

Purpose: This guideline provides updated evidence-based recommendations addressing recent developments in the management of patients with brain metastases, including advanced radiation therapy techniques such as stereotactic radiosurgery (SRS) and hippocampal avoidance whole brain radiation therapy and the emergence of systemic therapies with central nervous system activity., Methods: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on the radiotherapeutic management of intact and resected brain metastases from nonhematologic solid tumors. The guideline is based on a systematic review provided by the Agency for Healthcare Research and Quality. Recommendations were created using a predefined consensus-building methodology and system for grading evidence quality and recommendation strength., Results: Strong recommendations are made for SRS for patients with limited brain metastases and Eastern Cooperative Oncology Group performance status 0 to 2. Multidisciplinary discussion with neurosurgery is conditionally recommended to consider surgical resection for all tumors causing mass effect and/or that are greater than 4 cm. For patients with symptomatic brain metastases, upfront local therapy is strongly recommended. For patients with asymptomatic brain metastases eligible for central nervous system-active systemic therapy, multidisciplinary and patient-centered decision-making to determine whether local therapy may be safely deferred is conditionally recommended. For patients with resected brain metastases, SRS is strongly recommended to improve local control. For patients with favorable prognosis and brain metastases receiving whole brain radiation therapy, hippocampal avoidance and memantine are strongly recommended. For patients with poor prognosis, early introduction of palliative care for symptom management and caregiver support are strongly recommended., Conclusions: The task force has proposed recommendations to inform best clinical practices on the use of radiation therapy for brain metastases with strong emphasis on multidisciplinary care., (Copyright © 2022. Published by Elsevier Inc.)

Statement of Problem: A silicon carbide (SiC) protective coating has been developed for dental ceramics, but whether the coated ceramics can match the classical VITA shades is unclear., Purpose: The purpose of this observational in vitro study was to evaluate the color adaptability of SiC-coated dental ceramics by testing the hypotheses that SiC-coated disks can be fabricated to match standard tooth shades and have a perceptible color match rate of at least 50% for disks with a color difference (ΔE)<2.0. The effects of ΔE, shade hue, shade value, observer sex, years of experience, profession, and shade guide orientation on color perception were studied., Material and Methods: SiC-coated disks were fabricated to color match (ΔE ab <3.3) all 16 VITA classical shades. Uncoated disks of each VITA shade were used as the reference materials to determine whether the SiC-coated disks were color matched to the classical VITA shade guide. Three ΔE formulas (76, 94, and 2000) were applied and compared. Participants (N=120) with an average of 22 years of experience included dental school students, dental faculty members, and dental assistants. Pseudoisochromatic plate and the Farnsworth D-15 Panel test for assessing color deficiency and color blindness were administered. Participants then attempted to match SiC-coated disks to standard shade guides arranged by value or hue. All spectrophotometer readings and color matching were conducted in a light booth with standardized daylight illumination. Statistical analysis used the Fisher's exact test to determine factors associated with improved matching performance (α=.05)., Results: A significant difference in color match rate was found between disks with ΔE<2.0 (63.9%) and ΔE≥2.0 (41.7%) (P<.001). Arranging shade by value (72.2%) instead of hue (67.2%) produced better color matching (P<.001). Sex (P=.430), profession (P=.708), and years of experience (P=.902) had no significant influence on color matching., Conclusions: SiC-coated disks were successfully fabricated to match all VITA classical shades, and clinical visual color matching results confirmed that ΔE was a useful metric in optimizing color matching for the SiC-coated dental ceramics., (Copyright © 2020 Editorial Council for the Journal of Prosthetic Dentistry. Published by Elsevier Inc. All rights reserved.)

The risk of honey bee (Apis mellifera L.) exposure to pesticide residues while foraging for nectar and pollen is commonly explored in the context of agroecosystems. However, pesticides are also used in urban and suburban areas for vegetation management, vector control, and the management of ornamental plants in public and private landscapes. The extent to which pesticides pose a health risk to honey bees in these settings remains unclear. We addressed this at a landscape scale by conducting pesticide residue screening analyses on 768 nectar and 862 pollen samples collected monthly over 2 years from honey bee colonies located in urban and suburban areas in eight medium to large cities in California, Florida, Michigan, and Texas (USA). A risk assessment was performed using the US Environmental Protection Agency's BeeREX model whenever an oral toxicity value was available for a compound. Chemical analyses detected 17 pesticides in nectar and 60 in pollen samples during the survey. Approximately 73% of all samples contained no detectable pesticide residues. Although the number of detections varied among the sampled regions, fewer pesticides were detected in nectar than in pollen. Per BeeREX, four insecticides showed a potential acute risk to honey bees: imidacloprid, chlorpyrifos, and esfenvalerate in nectar, and deltamethrin in nectar and pollen. In general, exposure of honey bees to pesticides via nectar and pollen collection was low in urban and suburban areas across the United States, and no seasonal or spatial trends were evident. Our data suggest that honey bees are exposed to fewer pesticides in developed areas than in agricultural ones. Environ Toxicol Chem 2022;41:991-1003. © 2022 SETAC., (© 2022 SETAC.)

microRNAs (miRs) are linked to various human diseases including type 2 diabetes mellitus (T2DM) and emerging evidence suggests that miRs may serve as potential therapeutic targets. Lower miR-16 content is consistent across different models of T2DM; however, the role of miR-16 in muscle metabolic health is still elusive. Therefore, the purpose of this study was to investigate how deletion of miR-16 in mice affects skeletal muscle metabolic health and contractile function in both sexes. This study was conducted using both 1 ) in vitro and 2 ) in vivo experiments. In in vitro experiments, we used C2C12 myoblasts to test if inhibition or overexpression of miR-16 affected insulin-mediated glucose handling. In in vivo experiments, we generated muscle-specific miR-16 knockout (KO) mice fed a high-fat diet (HFD) to assess how miR-16 content impacts metabolic and contractile properties including glucose tolerance, insulin sensitivity, muscle contractile function, protein anabolism, and mitochondrial network health. In in vitro experiments, although inhibition of miR-16 induced impaired insulin signaling ( P = 0.002) and glucose uptake ( P = 0.014), overexpression of miR-16 did not attenuate lipid overload-induced insulin resistance using the diacylglycerol analog 1-oleoyl-2-acetyl- sn -glycerol. In in vivo experiments, miR-16 deletion induced both impaired muscle contractility ( P = 0.031-0.033), and mitochondrial network health ( P = 0.008-0.018) in both sexes. However, although males specifically exhibited impaired insulin sensitivity following miR-16 deletion ( P = 0.030), female KO mice showed pronounced glucose intolerance ( P = 0.046), corresponding with lower muscle weights ( P = 0.015), and protein hyperanabolism ( P = 0.023). Our findings suggest distinct sex differences in muscle adaptation in response to miR-16 deletion and miR-16 may serve as a key regulator for metabolic dysregulation in T2DM. NEW & NOTEWORTHY We set to investigate the role of miR-16 in skeletal muscle during diet-induced insulin resistance. Our data provide novel evidence that the lack of miR-16 induced multiple aberrations in insulin sensitivity, muscle contractility, mitochondrial network health, and protein turnover in a sex-dependent manner. Interestingly, miR-16 deletion leads to insulin resistance in males and exacerbated glucose intolerance in females, suggesting different mechanisms of metabolic dysregulation with a lack of miR-16 between sexes.

Cancer cachexia (CC) results in impaired muscle function and quality of life and is the primary cause of death for ∼20%-30% of patients with cancer. We demonstrated mitochondrial degeneration as a precursor to CC in male mice; however, whether such alterations occur in females is currently unknown. The purpose of this study was to elucidate muscle alterations in CC development in female tumor-bearing mice. Sixty female C57BL/6J mice were injected with PBS or Lewis lung carcinoma at 8 wk of age, and tumors developed for 1, 2, 3, or 4 wk to assess the time course of cachectic development. In vivo muscle contractile function, protein fractional synthetic rate (FSR), protein turnover, and mitochondrial health were assessed. Three- and four-week tumor-bearing mice displayed a dichotomy in tumor growth and were reassigned to high tumor (HT) and low tumor (LT) groups. HT mice exhibited lower soleus, tibialis anterior, and fat weights than PBS mice. HT mice showed lower peak isometric torque and slower one-half relaxation time than PBS mice. HT mice had lower FSR than PBS mice, whereas E3 ubiquitin ligases were greater in HT than in other groups. Bnip3 (mitophagy) and pMitoTimer red puncta (mitochondrial degeneration) were greater in HT mice, whereas Pgc1α1 and Tfam (mitochondrial biogenesis) were lower in HT mice than in PBS mice. We demonstrate alterations in female tumor-bearing mice where HT exhibited greater protein degradation, impaired muscle contractility, and mitochondrial degeneration compared with other groups. Our data provide novel evidence for a distinct cachectic development in tumor-bearing female mice compared with previous male studies. NEW & NOTEWORTHY Our study demonstrates divergent tumor development and tissue wasting within 3- and 4-wk mice, where approximately half the mice developed large tumors and subsequent cachexia. Unlike previous male studies, where metabolic perturbations precede the onset of cachexia, females appear to exhibit protections from the metabolic perturbations and cachexia development. Our data provide novel evidence for divergent cachectic development in tumor-bearing female mice compared with previous male CC studies, suggesting different mechanisms of CC between sexes.

Risk assessment for chemicals in the United States relies upon the honey bee (Apis meliffera L. [Hymenoptera: Apidae]) as a surrogate for other bee species. There is uncertainty in extrapolating honey bee toxicity data to bumble bees due to differences in life history strategies, food consumption, and nest structure. Here we evaluated the design of a queenless bumble bee microcolony test that could be considered for generating larval toxicity data. Three microcolony studies were conducted with Bombus impatiens to evaluate the effects of exposure to 1) diflubenzuron in pollen, 2) dimethoate in pollen, and 3) dimethoate in sucrose. Immature drone bee emergence, worker survival, pollen, and sucrose utilization were measured throughout the study duration. For dimethoate, a 10-d chronic adult bumble bee study was also conducted to compare microcolony endpoints to toxicity endpoints on individual adults. Microcolonies exposed to 10 mg diflubenzuron/kg pollen produced fewer adult drones despite no effects on worker survival. Microcolonies treated with dimethoate at ≥3 mg a.i./kg pollen and ≥0.1 mg a.i./kg sucrose solution produced fewer drones. Exposure to dimethoate in the 10-d chronic adult study resulted in direct mortality to the adult workers at ≥0.1 mg a.i./kg diet. Results from the 10-d study suggest direct effects of dimethoate on workers in the microcolony will alter provisioning of diet to the brood, resulting in lower drone production in the microcolony. Our data suggest that the microcolony study is only appropriate to assess brood effects to bumble bees for substances with low toxicity to adults, as demonstrated with diflubenzuron., (© The Author(s) 2021. Published by Oxford University Press on behalf of Entomological Society of America.)

Purpose: Several sentinel phase III randomized trials have recently been published challenging traditional radiation therapy (RT) practices for small cell lung cancer (SCLC). This American Society for Radiation Oncology guideline reviews the evidence for thoracic RT and prophylactic cranial irradiation (PCI) for both limited-stage (LS) and extensive-stage (ES) SCLC., Methods: The American Society for Radiation Oncology convened a task force to address 4 key questions focused on indications, dose fractionation, techniques and timing of thoracic RT for LS-SCLC, the role of stereotactic body radiation therapy (SBRT) compared with conventional RT in stage I or II node negative SCLC, PCI for LS-SCLC and ES-SCLC, and thoracic consolidation for ES-SCLC. Recommendations were based on a systematic literature review and created using a consensus-building methodology and system for grading evidence quality and recommendation strength., Results: The task force strongly recommends definitive thoracic RT administered once or twice daily early in the course of treatment for LS-SCLC. Adjuvant RT is conditionally recommended in surgically resected patients with positive margins or nodal metastases. Involved field RT delivered using conformal advanced treatment modalities to postchemotherapy volumes is also strongly recommended. For patients with stage I or II node negative disease, SBRT or conventional fractionation is strongly recommended, and chemotherapy should be delivered before or after SBRT. In LS-SCLC, PCI is strongly recommended for stage II or III patients who responded to chemoradiation, conditionally not recommended for stage I patients, and should be a shared decision for patients at higher risk of neurocognitive toxicities. In ES-SCLC, radiation oncologist consultation for consideration of PCI versus magnetic resonance surveillance is strongly recommended. Lastly, the use of thoracic RT is strongly recommended in select patients with ES-SCLC after chemotherapy treatment, including a conditional recommendation in those responding to chemotherapy and immunotherapy., Conclusions: RT plays a vital role in both LS-SCLC and ES-SCLC. These guidelines inform best clinical practices for local therapy in SCLC., (Copyright © 2020. Published by Elsevier Inc.)

The honey bee, Apis mellifera L. (Hymenoptera: Apidae), is a model organism for pollinators in risk assessment frameworks globally. The acute toxicity tests with adult honey bees for contact and oral exposure are part of the requirements for pesticide registration and are typically conducted with the active ingredient. A question often asked is if the typical end-use product (TEP) is more toxic than the technical grade active ingredient (TGAI) to honey bees. We explored this question by mining publicly available databases from regulatory agencies worldwide, where testing with the TEP is required. The objective of this study was to determine whether TEPs are comparable in toxicity to the TGAI. The dataset was analyzed via a 3 × 3 contingency table with toxicity categories, as the data cannot be computed for regression analysis. Of the 151 active ingredients with reported endpoints for contact exposure, 28 were classified as either moderately or highly toxic, 123 were classified as practically nontoxic, and 3 were inconclusive. Only two (1.3%) were reclassified from nontoxic to moderately toxic as the TEP. Of the 141 active ingredients with reported endpoints for oral exposure, 23 were classified as moderately or highly toxic, 113 were classified as practically nontoxic, and 5 were inconclusive. Only five (3.6%) were reclassified from nontoxic to moderately toxic as the TEP. Fewer than 5% of the total TEPs evaluated (contact and oral) were shown to be more toxic than the TGAI, suggesting that the risk assessments of TGAIs would be sufficiently protective to pollinators at the screening laboratory level., (© The Author(s) 2019. Published by Oxford University Press on behalf of Entomological Society of America.)

We designed, synthesized, and evaluated novel 2,6,9-trisubstituted purine derivatives for their prospective role as antitumor compounds. Using simple and efficient methodologies, 31 compounds were obtained. We tested these compounds in vitro to draw conclusions about their cell toxicity on seven cancer cells lines and one non-neoplastic cell line. Structural requirements for antitumor activity on two different cancer cell lines were analyzed with SAR and 3D-QSAR. The 3D-QSAR models showed that steric properties could better explain the cytotoxicity of compounds than electronic properties (70% and 30% of contribution, respectively). From this analysis, we concluded that an arylpiperazinyl system connected at position 6 of the purine ring is beneficial for cytotoxic activity, while the use of bulky systems at position C-2 of the purine is not favorable. Compound 7h was found to be an effective potential agent when compared with a currently marketed drug, cisplatin, in four out of the seven cancer cell lines tested. Compound 7h showed the highest potency, unprecedented selectivity, and complied with all the Lipinski rules. Finally, it was demonstrated that 7h induced apoptosis and caused cell cycle arrest at the S-phase on HL-60 cells. Our study suggests that substitution in the purine core by arylpiperidine moiety is essential to obtain derivatives with potential anticancer activity.

For honey bees (Apis mellifera), colony maintenance and growth are highly dependent on worker foragers obtaining sufficient resources from flowering plants year round. Despite the importance of floral diversity for proper bee nutrition, urban development has drastically altered resource availability and diversity for these important pollinators. Therefore, understanding the floral resources foraged by bees in urbanized areas is key to identifying and promoting plants that enhance colony health in those environments. In this study, we identified the pollen foraged by bees in four developed areas of the U.S., and explored whether there were spatial or temporal differences in the types of floral sources of pollen used by honey bees in these landscapes. To do this, pollen was collected every month for up to one year from colonies located in developed (urban and suburban) sites in California, Texas, Florida, and Michigan, except during months of pollen dearth or winter. Homogenized pollen samples were acetolyzed and identified microscopically to the lowest taxonomic level possible. Once identified, each pollen type was classified into a frequency category based on its overall relative abundance. Species richness and diversity indices were also calculated and compared across states and seasons. We identified up to 64 pollen types belonging to 39 plant families in one season (California). Species richness was highest in CA and lowest in TX, and was highest during spring in every state. In particular, "predominant" and "secondary" pollen types belonged to the families Arecaceae, Sapindaceae, Anacardiaceae, Apiaceae, Asteraceae, Brassicaceae, Fabaceae, Fagaceae, Lythraceae, Myrtaceae, Rhamnaceae, Rosaceae, Rutaceae, Saliaceae, and Ulmaceae. This study will help broaden our understanding of honey bee foraging ecology and nutrition in urban environments, and will help promote the use of plants that serve the dual purpose of providing aesthetic value and nutritious forage for honey bee colonies placed in developed landscapes., Competing Interests: We have the following interests: This study was funded in part by Bayer Crop Science and Syngenta Crop Protection LLC and by the Texas Beekeepers Association. Daniel R. Schmehl and Ana R. Cabrera are employed by Bayer CropScience LP. Joseph Sullivan is employed by Ardea Consulting. There are no patents, products in development or marketed products to declare. This does not alter our adherence to all the PLOS ONE policies on sharing data and materials.

To date, regulatory pesticide risk assessments have relied on the honey bee (Apis mellifera L.) (Hymenoptera: Apidae) as a surrogate test species for estimating the risk of pesticide exposure to all bee species. However, honey bees and non-Apis bees may differ in their susceptibility and exposure to pesticides. In 2017, a workshop ('Pesticide Exposure Assessment Paradigm for Non-Apis Bees') was held to assess if honey bee risk assessment frameworks are reflective of non-Apis bee pesticide exposure. In this article, we summarize the workshop discussions on bumble bees (Bombus spp.). We review the life history and foraging behavior of bumble bees and honey bees and discuss how these traits may influence routes and levels of exposure for both taxa. Overall, the major pesticide exposure routes for bumble bees and honey bees are similar; however, bumble bees face additional exposure routes (direct exposure of foraging queens and exposure of larvae and adults to soil residues). Furthermore, bumble bees may receive comparatively higher pesticide doses via contact or oral exposure. We conclude that honey bee pesticide risk assessments may not always be protective of bumble bees, especially queens, in terms of exposure. Data needed to reliably quantify pesticide exposure for bumble bees (e.g., food consumption rates, soil residue levels) are lacking. Addressing these knowledge gaps will be crucial before bumble bee exposure can be incorporated into the pesticide risk assessment process. Because bumble bees exhibit appreciable interspecific variation in colony and behavioral characteristics, data relevant to pesticide exposure should be generated for multiple species.

We describe the syntheses of nine new angucyclinone 6-aza-analogues, achieved through a hetero Diels-Alder reaction between the shikimic acid derivative-azadiene 13 , with different naphthoquinones. The cytotoxic activity of the new synthesized compounds and five angucyclinones, previously reported, was evaluated in vitro against three cancer cell lines: PC-3 (prostate cancer), HT-29 (colon cancer), MCF-7 (breast cancer), and one non-tumoral cell line, human colon epithelial cells (CCD841 CoN). Our results showed that most 6-azadiene derivatives exhibited significant cytotoxic activities, which was demonstrated by their IC 50 values (less than 10 μM), especially for the most sensitive cells, PC-3 and HT-29. From a chemical point of view, depending on the protected group of ring A and the pattern of substitution on ring D, cytotoxicity elicited these compounds, in terms of their potency and selectivity. Therefore, according to these chemical features, the most promising agents for every cancer cell line were 7a , 17, and 19c for PC-3 cells; 7a , 17, and 20 for HT-29 cells, and 19a for MCF-7 cells.

The demographic aging in Cuba has caused considerable changes in mortality and morbidity; its growing trend and high speed affect the attention of the elderly, posing a challenge to public health. This article focuses on years 1950-2015, and aims to present the situation of this population phenomenon from a positive view, according to three aspects: aging as an achievement, challenge and development opportunity; demographic and epidemiological transitions; and policies and strategies to address aging. The general fertility rate has decreased from 4.01 to 1.45, and the life expectancy at birth and the life expectancy at third age have increased from 59.40 to 78.45 years and from 16.04 to 22.58, respectively. The proportion of people aged 60 and over in Cuba amounts to 19.8%. Causes of morbidity and mortality have changed from infectious diseases to non-communicable diseases. In Cuba, aging is the result of a sustained reduction in fertility and mortality, and a negative migratory balance. The challenge of the dependency of the elderly person and the need for care is discussed. Although this demographic indicator represents an achievement and a development opportunity, population aging poses a challenge for development and public health, for which comprehensive and cross-sectional policies and strategies aimed at mitigating its negative effects have been established., Competing Interests: Conflicto de intereses. Ninguno.

Four new neutral N,N imidoyl-indazole ligands (L1, L3, L6, L7) and six new Pt(II)-based complexes (C1-5 and C7) were synthesized and characterized by spectroscopic and spectrometric techniques. Additionally, compounds L6, L7, C3, C5 and C7 were analyzed using X-ray diffraction. An evaluation of cytotoxicity and cell death in vitro for both ligands and complexes was performed by colorimetric assay and flow cytometry, in four cancer cell lines and VERO cells as the control, respectively. Cytotoxicity and selectivity demonstrated by each compound were dependent on the cancer cell line assayed. IC 50 values of complexes C1-5 and C7 were lower than those exhibited for the reference drug cisplatin, and selectivity of these complexes was in general terms greater than cisplatin on three cancer cell lines studied. In HL60 cells, complexes C1 and C5 exhibited the lowest values of IC 50 and were almost five times more selective than cisplatin. Flow cytometry results suggest that each complex predominantly induced necrosis, and its variant necroptosis, instead of apoptosis in all cancer cell lines studied. DNA binding assays, using agarose gel electrophoresis and UV-visible spectrophotometry studies, displayed a strong interaction only between C4 and DNA. In fact, theoretical calculations showed that C4-DNA binding complex was the most thermodynamic favorable interaction among the complexes in study. Overall, induction of cell death by dependent and independent-DNA-metal compound interactions were possible using imidoyl-indazole Pt(II) complexes as anticancer agents., (Copyright © 2017 Elsevier Inc. All rights reserved.)

In this paper, we explored the fluorescence properties of eight aurone derivatives bearing methoxy groups and bromine atoms as substituents in the benzene rings. All derivatives showed strong solvatochromic absorption and emission properties in solvents of different polarities. Some of them showed high fluorescence quantum yields, which make them potential compounds for sensing applications. The position of the methoxy groups in the benzofuranone moiety and the presence of bromine atoms in the benzene ring had a strong influence on the fluorescence behaviour of the aurones. DFT calculations allowed us to explain the emission properties of aurones and their solvatochromism, which was related to an excited state with strong charge-transfer character. Aurone 4 has the most promising characteristics showing a large difference in the quantum yields and large Stokes shifts depending on the solvent polarities. These results prompted us to explore some preliminary biological applications for aurone 4 such as the sensing of hydrophobic pockets of a protein and its thermotropic behaviour in liposomes.

A novel feeding protocol for delivery of bio-active agents to Varroa mites was developed by providing mites with honey bee larva hemolymph supplemented with cultured insect cells and selected materials delivered on a fibrous cotton substrate. Mites were starved, fed on treated hemolymph to deliver selected agents and then returned to bee larvae. Transcript levels of two reference genes, actin and glyceraldehyde 3-phosphate dehydrogenase (GAPDH), as well as for nine selected genes involved in reproductive processes showed that the starvation and feeding protocol periods did not pose a high level of stress to the mites as transcript levels remained comparable between phoretic mites and those completing the protocol. The feeding protocol was used to deliver molecules such as hormone analogs or plasmids. Mites fed with Tebufenozide, an ecdysone analog, had higher transcript levels of shade than untreated or solvent treated mites. In order to extend this feeding protocol, cultured insect cells were incorporated to a final ratio of 1 part cells and 2 parts hemolymph. Although supplementation with Bombyx mori Bm5 cells increased the amount of hemolymph consumed per mite, there was a significant decrease in the percentage of mites that fed and survived. On the other hand, Drosophila melanogaster S2 cells reduced significantly the percentage of mites that fed and survived as well as the amount of hemolymph consumed. The feeding protocol provides a dynamic platform with which to challenge the Varroa mite to establish efficacy of control agents for this devastating honey bee pest.

Flupyradifurone (Sivanto) is a novel systemic insecticide from the butenolide class developed by Bayer. Based on available data (USEPA 2014), this insecticide appears to have a favorable safety profile for honey bee colonies. As a result, the label permits the product to be applied during prebloom and bloom in various crops, including citrus, except when mixed with azole fungicides during the blooming period. We placed 24 honey bee (Apis mellifera L.) colonies adjacent to eight flowering buckwheat (Fagopyrum esculentum Moench) fields that either had been sprayed with the maximum label rate of flupyradifurone or with water only (control fields), with three colonies placed adjacent to each field. We conducted colony strength assessments during which the number of adult bees, eggs, uncapped brood cells, capped brood cells, food storage cells, and weights of honey supers and brood chambers were determined prior to, during, and after the flowering period. We also analyzed bee-collected pollen and nectar for flupyradifurone residues. Overall, there were no differences in any colony strength parameter for colonies placed at control and flupyradifurone-treated buckwheat fields. Residue analyses showed that pollen (x =  565.8 ppb) and nectar (x  =  259.4 ppb) gathered by bees on fields treated with flupyradifurone contained significantly higher flupyradifurone residues than did bee bread and unprocessed nectar collected by bees from control fields (75% of samples 

Purpose: To present evidence-based guidelines for radiation therapy in treating glioblastoma not arising from the brainstem., Methods and Materials: The American Society for Radiation Oncology (ASTRO) convened the Glioblastoma Guideline Panel to perform a systematic literature review investigating the following: (1) Is radiation therapy indicated after biopsy/resection of glioblastoma and how does systemic therapy modify its effects? (2) What is the optimal dose-fractionation schedule for external beam radiation therapy after biopsy/resection of glioblastoma and how might treatment vary based on pretreatment characteristics such as age or performance status? (3) What are ideal target volumes for curative-intent external beam radiation therapy of glioblastoma? (4) What is the role of reirradiation among glioblastoma patients whose disease recurs following completion of standard first-line therapy? Guideline recommendations were created using predefined consensus-building methodology supported by ASTRO-approved tools for grading evidence quality and recommendation strength., Results: Following biopsy or resection, glioblastoma patients with reasonable performance status up to 70 years of age should receive conventionally fractionated radiation therapy (eg, 60 Gy in 2-Gy fractions) with concurrent and adjuvant temozolomide. Routine addition of bevacizumab to this regimen is not recommended. Elderly patients (≥70 years of age) with reasonable performance status should receive hypofractionated radiation therapy (eg, 40 Gy in 2.66-Gy fractions); preliminary evidence may support adding concurrent and adjuvant temozolomide to this regimen. Partial brain irradiation is the standard paradigm for radiation delivery. A variety of acceptable strategies exist for target volume definition, generally involving 2 phases (primary and boost volumes) or 1 phase (single volume). For recurrent glioblastoma, focal reirradiation can be considered in younger patients with good performance status., Conclusions: Radiation therapy occupies an integral role in treating glioblastoma. Whether and how radiation therapy should be applied depends on characteristics specific to tumor and patient, including age and performance status., (Copyright © 2016 American Society for Radiation Oncology. Published by Elsevier Inc. All rights reserved.)

Global declines of bumble bees and other pollinator populations are of concern because of their critical role for crop production and maintenance of wild plant biodiversity. Although the consensus among scientists is that the interaction of many factors, including habitat loss, forage scarcity, diseases, parasites, and pesticides, potentially plays a role in causing these declines, pesticides have received considerable attention and scrutiny. In response, regulatory agencies have introduced more stringent pollinator testing requirements for registration and reregistration of pesticides, to ensure that the risks to pollinators are minimized. In this context, guidelines for testing bumble bees (Bombus spp.) in regulatory studies are not yet available, and a pressing need exists to develop suitable protocols for routine higher-tier studies with these non-Apis sp., social bees. To meet this need, Bayer CropScience LP, Syngenta Crop Protection LLC US, and Valent USA. Corporation organized a workshop bringing together a group of global experts on bumble bee behavior, ecology, and ecotoxicology to discuss and develop draft protocols for both semi-field (Tier II) and field (Tier III) studies. The workshop was held May 8-9, 2014, at the Bayer Bee Care Center, North Carolina, USA. The participants represented academic, consulting, and industry scientists from Europe, Canada, the United States, and Brazil. The workshop identified a clear protection goal and generated proposals for basic experimental designs, relevant measurements, and endpoints for both semifield (tunnel) and field tests. These initial recommendations are intended to form the basis of discussions to help advance the development of appropriate protocol guidelines., (© 2015 The Authors. Integrated Environmental Assessment and Management Published by SETAC.)

The syntheses of the new asymmetric substituted boron amidines [N'-(2,6-diisopropylphenyl)-N-(pentafluorophenyl)acetimidamide]bis(pentafluorophenyl)borate () and [N'-(2,6-diisopropylphenyl)-N-(4-cyanophenyl)acetimidamide]bis(pentafluorophenyl)borate () were achieved by reaction of one equivalent of HB(C6F5)2 and the respective amidines and . These adducts, bearing electron withdrawing groups, showed thermally induced H2 elimination forming the four-membered cyclic diazaborate derivatives and . These new species were characterized by spectroscopic methods. X-ray diffraction studies have been carried out on , and . To prevent undesired reactions at the nitrile group, one equivalent of B(C6F5)3 was added to yielding the -B(C6F5)3 nitrile adduct . Compound underwent thermally induced dehydrogenation to give the four-membered cyclic diazaborate derivative . CO was inserted into the ring systems of and forming the five-membered diazaborolone derivatives and . Phenylacetylene reacted stoichiometrically with the asymmetric substituted boron amidines , and to give styrene by double H transfer.

The ecdysteroid biosynthetic pathway involves sequential enzymatic hydroxylations by a group of enzymes collectively known as Halloween gene proteins. Complete sequences for three Halloween genes, spook (Vdspo), disembodied (Vddib) and shade (Vdshd), were identified in varroa mites and sequenced. Phylogenetic analyses of predicted amino acid sequences for Halloween orthologues showed that the acarine orthologues were distantly associated with insect and crustacean clades indicating that acarine genes had more ancestral characters. The lack of orthologues or pseudogenes for remaining genes suggests these pathway elements had not evolved in ancestral arthropods. Vdspo transcript levels were highest in gut tissues, while Vddib transcript levels were highest in ovary-lyrate organs. In contrast, Vdshd transcript levels were lower overall but present in both gut and ovary-lyrate organs. All three transcripts were present in eggs removed from gravid female mites. A brood cell invasion assay was developed for acquiring synchronously staged mites. Mites within 4 h of entering a brood cell had transcript levels of all three that were not significantly different from mites on adult bees. These analyses suggest that varroa mites may be capable of modifying 7-dehydro-cholesterol precursor and hydroxylations of other steroid precursors, but whether the mites directly produce ecdysteroid precursors and products remains undetermined., (Published 2014. This article is a U.S. Government work and is in the public domain in the USA.)

Tomato (Solanum lycopersicum L.) is among the most valuable agricultural products, but Meloidogyne spp. (root-knot nematode) infestations result in serious crop losses. In tomato, resistance to root-knot nematodes is controlled by the gene Mi-1, but heat stress interferes with Mi-1-associated resistance. Inconsistent results in published field and greenhouse experiments led us to test the effect of short-term midday heat stress on tomato susceptibility to Meloidogyne incognita race 1. Under controlled day/night temperatures of 25°C/21°C, 'Amelia', which was verified as possessing the Mi-1 gene, was deemed resistant (4.1 ± 0.4 galls/plant) and Rutgers, which does not possess the Mi-1 gene, was susceptible (132 ± 9.9 galls/plant) to M. incognita infection. Exposure to a single 3 hr heat spike of 35°C was sufficient to increase the susceptibility of 'Amelia' but did not affect Rutgers. Despite this change in resistance, Mi-1 gene expression was not affected by heat treatment, or nematode infection. The heat-induced breakdown of Mi-1 resistance in 'Amelia' did recover with time regardless of additional heat exposures and M. incognita infection. These findings would aid in the development of management strategies to protect the tomato crop at times of heightened M. incognita susceptibility.

Background and Purpose: FaDu human squamous cell carcinoma (FaDu-hSCC) demonstrates accelerated tumor repopulation during fractionated irradiation with pathological validation (Ki-67 and BrdUrd makers) in a xenograft model system. However, these and other functional assays must be performed ex vivo and post hoc. We propose a novel, in vivo, real-time assay utilizing (18)F-FLT PET., Material and Methods: Nude mice with FaDu-hSCC were irradiated with 12 or 18 fractions of 1.8 Gy ([Dm]=3.0 Gy), either daily or every second day. (18)F-FLT micro-PET scans were performed at different time points, FLT parameters (SUVmax, SUVmean, and T/NT) were measured. Tumor sections were stained for Ki-67 and BrdUrd, a labeling index (LI) was calculated. Imaging-pathology correlation was determined by comparing FLT parameters and immunohistochemical results., Results: Measured SUVmax, SUVmean and T/NT decreased significantly after daily irradiation with 12 fractions in 12 days (P<0.05) and 18 fractions in 18 days (P<0.05). In contrast, these parameters increased in mice treated with 12 fractions in 24 days (P>0.05) and 18 fractions in 36 days (P>0.05), suggesting accelerated repopulation. Similarly, Ki-67 and BrdUrd LIs demonstrated significant decreases with daily irradiation (P<0.05), and increases with every-second-day irradiation (P>0.05). (18)F-FLT parameters correlated strongly with proliferation markers (r(2): 0.679-0.879, P<0.001)., Conclusions: (18)F-FLT parameters were in good agreement with Ki-67 and BrdUrd Li. These results may support a potential role for (18)F-FLT PET in real-time detection of tumor repopulation during fractionated radiotherapy., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Stereotactic body radiotherapy (SBRT) involves the treatment of extracranial primary tumors or metastases with a few, high doses of ionizing radiation. In SBRT, tumor kill is maximized and dose to surrounding tissue is minimized, by precise and accurate delivery of multiple radiation beams to the target. This is particularly challenging, because extracranial lesions often move with respiration and are irregular in shape, requiring careful treatment planning and continual management of this motion and patient position during irradiation. This review presents the rationale, process workflow, and technology for the safe and effective administration of SBRT, as well as the indications, outcome, and limitations for this technique in the treatment of lung cancer, liver cancer, and metastatic disease., (© 2013 American Cancer Society.)

When a female varroa mite, Varroa destructor (Anderson & Trueman), invades a honey bee brood cell, the physiology rapidly changes from feeding phoretic to reproductive. Changes in foraging and malvolio transcript levels in the brain have been associated with modulated intra-specific food searching behaviors in insects and other invertebrates. Transcription profiles for both genes were examined during and immediately following brood cell invasion to assess their role as potential control elements. Vdfor and Vdmvl transcripts were found in all organs of varroa mites with the highest Vdfor transcript levels in ovary-lyrate organs and the highest Vdmvl in Malpighian tubules. Changes in transcript levels of Vdfor and Vdmvl in synganglia were not associated with the cell invasion process, remaining comparable between early reproductive mites (collected from the pre-capping brood cells) and phoretic mites. However, Vdfor and Vdmvl transcript levels were lowered by 37 and 53%, respectively, in synganglia from reproductive mites compared to early reproductive mites, but not significantly different to levels in synganglia from phoretic mites. On the other hand, in whole body preparations the Vdfor and Vdmvl had significantly higher levels of transcript in reproductive mites compared to phoretic and early reproductive, mainly due to the presence of both transcripts accumulating in the eggs carried by the ovipositing mite. Varroa mites are a critical component for honey bee population decline and finding varroa mite genes associated with brood cell invasion, reproduction, ion balance and other physiological processes will facilitate development of novel control avenues for this honey bee parasite., (© 2013 Wiley Periodicals, Inc.)

The complete genomic region and corresponding transcript of the most abundant protein in phoretic varroa mites, Varroa destructor (Anderson & Trueman), were sequenced and have homology with acarine hemelipoglycoproteins and the large lipid transfer protein (LLTP) super family. The genomic sequence of VdLLTP included 14 introns and the mature transcript coded for a predicted polypeptide of 1575 amino acid residues. VdLLTP shared a minimum of 25% sequence identity with acarine LLTPs. Phylogenetic assessment showed VdLLTP was most closely related to Metaseiulus occidentalis vitellogenin and LLTP proteins of ticks; however, no heme binding by VdLLTP was detected. Analysis of lipids associated with VdLLTP showed that it was a carrier for free and esterified C12 -C22 fatty acids from triglycerides, diacylglycerides and monoacylglycerides. Additionally, cholesterol and β-sitosterol were found as cholesterol esters linked to common fatty acids. Transcript levels of VdLLTP were 42 and 310 times higher in phoretic female mites when compared with males and quiescent deutonymphs, respectively. Coincident with initiation of the reproductive phase, VdLLTP transcript levels declined to a third of those in phoretic female mites. VdLLTP functions as an important lipid transporter and should provide a significant RNA interference target for assessing the control of varroa mites., (Published 2013. This article is a U.S. Government work and is in the public domain in the USA.)

Purpose: Virtually all patients with malignant glioma (MG) eventually recur. This study evaluates the safety of concurrent stereotactic radiosurgery (SRS) and bevacizumab (BVZ), an antiangiogenic agent, in treatment of recurrent MG., Methods and Materials: Fifteen patients with recurrent MG, treated at initial diagnosis with surgery and adjuvant radiation therapy/temozolomide and then at least 1 salvage chemotherapy regimen, were enrolled in this prospective trial. Lesions <3 cm in diameter were treated in a single fraction, whereas those 3 to 5 cm in diameter received 5 5-Gy fractions. BVZ was administered immediately before SRS and 2 weeks later. Neurocognitive testing (Mini-Mental Status Exam, Trail Making Test A/B), Functional Assessment of Cancer Therapy-Brain (FACT-Br) quality-of-life assessment, physical exam, and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) were performed immediately before SRS and 1 week and 2 months following completion of SRS. The primary endpoint was central nervous system (CNS) toxicity. Secondary endpoints included survival, quality of life, microvascular properties as measured by DCE-MRI, steroid usage, and performance status., Results: One grade 3 (severe headache) and 2 grade 2 CNS toxicities were observed. No patients experienced grade 4 to 5 toxicity or intracranial hemorrhage. Neurocognition, quality of life, and Karnofsky performance status did not change significantly with treatment. DCE-MRI results suggest a significant decline in tumor perfusion and permeability 1 week after SRS and further decline by 2 months., Conclusions: Treatment of recurrent MG with concurrent SRS and BVZ was not associated with excessive toxicity in this prospective trial. A randomized trial of concurrent SRS/BVZ versus conventional salvage therapy is needed to establish the efficacy of this approach., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Radiotherapy plays an integral role in the management of most patients with cancers of the head and neck. Better understanding of radiobiology and radiation physics has allowed radiation oncologists to enhance the tumoricidal effects of radiation and reduce the severity of normal tissue toxicities. This article reviews the biologic foundation of head and neck radiotherapy, the physical principles and technological innovations that enable delivery of highly conformal radiation, the acute and late complications of radiation-based treatments, and the clinical evidence supporting contemporary practice., (Copyright © 2013 Elsevier Inc. All rights reserved.)

This manuscript reviews the clinical evidence for hypofractionation in prostate cancer, focusing on data from prospective trials. For the purposes of this manuscript, we categorize hypofractionation as moderate (2.4-4 Gy per fraction) or extreme (6.5-10 Gy per fraction). Five randomized controlled trials have evaluated moderate hypofractionation in >1500 men, with most followed for >4-5 years. The results of these randomized trials are inconsistent. No randomized trials or other rigorous comparisons of extreme hypofractionation with conventional fractionation have been reported. Prospective single-arm studies of extreme hypofractionation appear favorable, but small sample sizes preclude precise estimates of efficacy and short follow-up prevents complication estimates beyond 3-5 years. Over the next several years, the results of 3 large noninferiority trials of moderate hypofractionation and 2 randomized trials of extreme hypofractionation should help clarify the role of hypofractionation in prostate cancer therapy., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Background: Resistance monitoring is an important aspect of insect resistance management and the preservation of insecticide efficacy. The adult vial test (AVT) is most often used for resistance monitoring for a variety of insects. A potential alternative method is feeding disruption where resistant insects are distinguished from susceptible insects on the basis of their ability to feed on insecticide in nectar containing a colorimetric marker to measure feeding. The advantages of a feeding disruption test (FDT) for lepidopteran adults might include a more rapid assay than AVT, an assay format easier to prepare, a bioassay applicable to both oral and contact insecticides and the provision of food and water during the course of the test. The objective of the present work was to determine the feasibility of an adult FDT., Results: Heliothis virescens moths fed permethrin and spinosad in dyed nectar yielded dose-dependent ingestion, fecal production and mortality data. A permethrin diagnostic dose distinguished pyrethroid-resistant from pyrethroid-susceptible moths, based on fecal production., Conclusion: Proof of concept was demonstrated for an adult FDT in which resistant moths were distinguished from susceptible moths on the basis of the ability of the insect to feed on insecticide in dyed nectar and produce dyed feces., (© 2012 Society of Chemical Industry.)

Despite contemporary surgery, image-guided radiotherapy, and chemotherapy, glioblastoma multiforme (GBM) persists or relapses in nearly all patients, and tumors almost always recur locally. Management of recurrent GBM is variable, but approaches include best supportive care, reoperation, reirradiation, and/or systemic therapy. Promising novel therapies include antiangiogenic agents and stereotactic radiosurgery, which have cytotoxic effects on tumor microvasculature. Emerging data suggest the safety and efficacy of bevacizumab and radiosurgery either alone or in combination. This report presents the case of a man with locally recurrent GBM treated with stereotactic radiosurgery and concurrent bevacizumab, and reviews the preclinical and clinical data supporting this approach.