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2025
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ABSTRACT
Cullin-1 (Cul1), a cullin–RING ubiquitin ligase component, represses c-MYC activity in the nucleus.
Orientia tsutsugamushi
causes the potentially fatal rickettsiosis, scrub typhus. The obligate intracellular bacterium encodes an arsenal of ankyrin repeat-containing effectors (Anks), many of which carry a eukaryotic-like F-box motif that binds Cul1.
O. tsutsugamushi
reduces Cul1 levels in the nucleus. This phenomenon is not due to an alteration in Cul1 neddylation but is bacterial burden- and protein synthesis-dependent. Five of the 11 Anks capable of binding Cul1 (Ank1, Ank5, Ank6, Ank9, Ank17) sequester it in the cytoplasm when each is ectopically expressed. Ank1 and Ank6 proteins with alanine substitutions in their F-boxes that render them unable to bind Cul1 cannot exclude Cul1 from the nucleus. Coincident with the reduction of Cul1 in the nuclei of
Orientia
-infected cells, c-MYC nuclear levels are elevated, and Cul1 target genes are differentially expressed. Several of these genes regulate apoptosis. The resistance of
O. tsutsugamushi
-infected cells to staurosporine-induced apoptosis is recapitulated in uninfected cells expressing Ank1 or Ank6 but not alanine-substituted versions thereof that cannot bind Cul1. Other F-box-containing Anks that cannot bind or exclude Cul1 from the nucleus also fail to confer resistance to apoptosis. Overall,
O. tsutsugamushi
modulates the Cul1:c-MYC intranuclear balance as an anti-apoptotic strategy that is functionally linked to a subset of its F-box-containing Anks.
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ABSTRACTTo gain insight into biological mechanisms that cause resistance to DNA damage, we performed parallel pooled genetic CRISPR-Cas9 screening for survival in high risk HNSCC subtypes. Surprisingly, and in addition to ATM, DNAPK, and NFKB signaling, JAK1 was identified as a driver of tumor cell radiosensitivity. Knockout of JAK1 in HNSCC increases cell survival by enhancing the DNA damage-induced G2 arrest, and both knockout and JAK1 inhibition with abrocitinib prevent subsequent formation of radiation-induced micronuclei. Loss of JAK1 function does not affect canonical CDK1 signaling but does reduce activation of PLK1 and AURKA, kinases that regulate both G2 and M phase progression. Correspondingly, JAK1 KO was found to cause mitotic defects using both EdU labeling and live cell imaging techniques. Given this insight, we evaluated Kif18a inhibition as an approach to exacerbate mitotic stress and enhance the efficacy of radiation. These studies establish Kif18a inhibition as a novel strategy to counteract therapeutic resistance to DNA damage mediated by G2 cell cycle arrest.- Book : ()
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2025
Honey bees extract sticky material from the exudates of different plants which transform afterwards to propolis. Propolis from several global locations has been shown to contain a wide variety of polyphenolic chemicals. Recent studies have revealed that propolis possesses antioxidant, anti-inflammatory, and immunomodulatory abilities. In laboratory animal studies, it has been demonstrated that propolis can enhance the functioning of the antioxidant defense system and decrease the activity of nuclear factor-kappa B. As a result, they can effectively alleviate the damage caused by exercise. One of the main flavonoids found in propolis, quercetin, has been demonstrated to enhance muscle mitochondrial biogenesis and exercise capacity. Propolis may aid athletes in preventing oxidative and inflammatory damage to their muscles during exercise and enhance their athletic performance. The goal of the current review was to evaluate how propolis consumption affected the molecular signaling associated with antioxidant/oxidant state, pro/anti-inflammatory cytokines, and anaerobic/aerobic endurance.- Book : ()
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2025
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2025
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2025
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2025
Abstract
Objective
Survivors of pediatric head and neck rhabdomyosarcoma (HNRMS) are at risk of developing endocrinopathies following local treatment, resulting from radiation damage to the pituitary gland, hypothalamus, or thyroid gland, often at a young age. Our aim was to determine the prevalence of endocrine dysfunction in long-term HNRMS survivors and compare the prevalence of anterior pituitary insufficiency (API) among different local treatment strategies: external beam radiation with photons, external beam radiation with protons, microscopically radical surgery combined with external irradiation, and macroscopic radical surgery combined with brachytherapy.
Design and methods
Head and neck rhabdomyosarcoma survivors treated between 1993 and 2017, with ≥2 years of follow-up, without recurrent disease or secondary malignancy were eligible for this study. The presence of any endocrine dysfunction was assessed cross-sectionally using Common Terminology Criteria of Adverse Events grading, anthropometrics, and biochemical testing. Retrospective chart review was added to this clinical assessment.
Results
Ninety-six survivors with long follow-up time (median, 9 years) were included. Any endocrinopathy was present in 35% of survivors, with 88% having pituitary, 6% peripheral (thyroid), and 6% combined insufficiencies. None had gonadal insufficiency. Growth hormone deficiency was diagnosed in 31 (32%) survivors, with additional pituitary insufficiencies in 12 (39%). In 8%, central precocious puberty preceded API. None of the survivors given brachytherapy had API.
Conclusions
The prevalence of pituitary dysfunction in HNRMS survivors is high, emphasizing the importance of systematic endocrine assessment during follow-up, including pubertal development and growth. Efforts should be made to further reduce extraneous irradiation to endocrine organs to prevent dysfunction later in life.
- Book : 192(1)
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