Tumour resistance to radiotherapy remains a barrier to improving cancer patient outcomes. To overcome radioresistance, certain drugs have been found to sensitize cells to ionizing radiation (IR). In ...theory, more potent radiosensitizing drugs should increase tumour kill and improve patient outcomes. In practice, clinical utility of potent radiosensitizing drugs is curtailed by off-target side effects. Here we report potent anti-tubulin drugs conjugated to anti-ErbB antibodies selectively radiosensitize to tumours based on surface receptor expression. While two classes of potent anti-tubulins, auristatins and maytansinoids, indiscriminately radiosensitize tumour cells, conjugating these potent anti-tubulins to anti-ErbB antibodies restrict their radiosensitizing capacity. Of translational significance, we report that a clinically used maytansinoid ADC, ado-trastuzumab emtansine (T-DM1), with IR prolongs tumour control in target expressing HER2+ tumours but not target negative tumours. In contrast to ErbB signal inhibition, our findings establish an alternative therapeutic paradigm for ErbB-based radiosensitization using antibodies to restrict radiosensitizer delivery.
We present a mid-infrared (IR) sample study of nearby ultraluminous X-ray sources (ULXs) using multiepoch observations with the Infrared Array Camera (IRAC) on the Spitzer Space Telescope. ...Spitzer/IRAC observations taken after 2014 were obtained as part of the Spitzer Infrared Intensive Transients Survey. Our sample includes 96 ULXs located within 10 Mpc. Of the 96 ULXs, 12 have candidate counterparts consistent with absolute mid-IR magnitudes of supergiants, and 16 counterparts exceeded the mid-IR brightness of single supergiants and are thus more consistent with star clusters or non-ULX background active galactic nuclei. The supergiant candidate counterparts exhibit a bimodal color distribution in a Spitzer/IRAC color-magnitude diagram, where "red" and "'blue" ULXs fall in IRAC colors 3.6 - 4.5 ∼ 0.7 and 3.6 - 4.5 ∼ 0.0, respectively. The mid-IR colors and absolute magnitudes of four "red" and five "blue" ULXs are consistent with those of supergiant Be (sgBe) and red supergiant (RSG) stars, respectively. Although "blue," RSG-like mid-IR ULX counterparts likely host RSG mass donors; we propose that "red" counterparts are ULXs exhibiting the "Be phenomenon" rather than hosts of sgBe mass donors. We show that the mid-IR excess from the "red" ULXs is likely due to thermal emission from circumstellar or circumbinary dust. Using dust as a probe for total mass, we estimate mass-loss rates of M ˙ ∼ 1 × 10 − 4 M yr−1 in dust-forming outflows of red ULXs. Based on the transient mid-IR behavior and its relatively flat spectral index, = −0.19 0.1, we suggest that the mid-IR emission from Holmberg IX X-1 originates from a variable jet.
Basal protein turnover, which largely relies on the degradation of ubiquitinated substrates, is instrumental for maintenance of muscle mass and function. However, the regulation of ubiquitinated ...protein degradation in healthy, nonatrophying skeletal muscle is still evolving, and potential tissue‐specific modulators remain unknown. Using an unbiased expression analysis of 34 putative autophagy genes across mouse tissues, we identified unc‐51 like autophagy activating kinase (Ulk)2, a homolog of the yeast autophagy related protein 1, as particularly enriched in skeletal muscle. Subsequent experiments revealed accumulations of insoluble ubiquitinated protein aggregates associated with the adaptors sequestosome 1 (SQSTM1, also known as p62) and next to breast cancer type 1 susceptibility protein gene 1 protein (NBR1) in adult muscles with ULK2 deficiency. ULK2 deficiency also led to impaired muscle force and caused myofiber atrophy and degeneration. These features were not observed in muscles with deficiency of the ULK2 paralog, ULK1. Furthermore, short‐term ULK2 deficiency did not impair autophagy initiation, autophagosome to lysosome fusion, or protease activities of the lysosome and proteasome. Altogether, our results indicate that skeletal muscle ULK2 has a unique role in basal selective protein degradation by stimulating the recognition and proteolytic sequestration of insoluble ubiquitinated protein aggregates associated with p62 and NBR1. These findings have potential implications for conditions of poor protein homeostasis in muscles as observed in several myopathies and aging.—Fuqua, J. D., Mere, C. P., Kronemberger, A., Blomme, J., Bae, D., Turner, K. D., Harris, M. P., Scudese, E., Edwards, M., Ebert, S. M., de Sousa, L. G. O., Bodine, S. C., Yang, L., Adams, C. M., Lira, V. A. ULK2 is essential for degradation of ubiquitinated protein aggregates and homeostasis in skeletal muscle. FASEB J. 33, 11735‐11745 (2019). www.fasebj.org
Diverse stresses including starvation and muscle disuse cause skeletal muscle atrophy. However, the molecular mechanisms of muscle atrophy are complex and not well understood. Here, we demonstrate ...that growth arrest and DNA damage-inducible 45a protein (Gadd45a) is a critical mediator of muscle atrophy. We identified Gadd45a through an unbiased search for potential downstream mediators of the stress-inducible, pro-atrophy transcription factor ATF4. We show that Gadd45a is required for skeletal muscle atrophy induced by three distinct skeletal muscle stresses: fasting, muscle immobilization, and muscle denervation. Conversely, forced expression of Gadd45a in muscle or cultured myotubes induces atrophy in the absence of upstream stress. We show that muscle-specific ATF4 knock-out mice have a reduced capacity to induce Gadd45a mRNA in response to stress, and as a result, they undergo less atrophy in response to fasting or muscle immobilization. Interestingly, Gadd45a is a myonuclear protein that induces myonuclear remodeling and a comprehensive program for muscle atrophy. Gadd45a represses genes involved in anabolic signaling and energy production, and it induces pro-atrophy genes. As a result, Gadd45a reduces multiple barriers to muscle atrophy (including PGC-1α, Akt activity, and protein synthesis) and stimulates pro-atrophy mechanisms (including autophagy and caspase-mediated proteolysis). These results elucidate a critical stress-induced pathway that reprograms muscle gene expression to cause atrophy.
Background: In skeletal muscle, diverse stresses induce the transcription factor ATF4, which promotes muscle atrophy by an unknown mechanism.
Results: ATF4 causes muscle atrophy by inducing Gadd45a, which reprograms myonuclear gene expression to repress anti-atrophy mechanisms and induce pro-atrophy mechanisms.
Conclusion: Gadd45a is a critical stress-induced mediator of muscle atrophy.
Significance: The ATF4/Gadd45a pathway is a potential therapeutic target in atrophic muscle.
•Machine learning-based textual analysis is a viable tool for police survey research•Analyzing large numbers of police free-text responses provides more nuanced understanding of police perceptions of ...the public•Officers' attention to professionalism guards against de-policing, while attention to perceived unfair criticism increases it•The public's integrity has a stronger effect on propensity to de-police than the public's knowledge about police work
The initial interaction between rape victims and police officers affects how cases progress through the criminal justice system. In one US state capitol, the police agency determined its initial ...response to rape victims was sub-par. Victim engagement was low, and officer-written reports often endorsed negative stereotypes about rape victims. A four-hour training to enhance police response was developed and implemented. Within four months, all sworn officers (n ~ 600) completed an in-person, four-hour training. We first test the effects of training on the percentage of rape victims who stay engaged in the investigative process following their initial contact with officers. We then use a machine-learning-based text analysis of all written reports (77 pre-training, and 55 post-training cases) of initial contacts between officers and victims. Compared to the six months before training, victim engagement improved 32% in the post-training period. Written reports by officers also improved, with increased victim-supportive language and improved focus on victim services.
•A sexual assault training program was administered department-wide•Victim engagement improved 32% following the training•Written reports improved, suggesting improved focus on victim services•Police behaviors, not attitudes, should be the focus when evaluating training
Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine Hammer, Scott M; Sobieszczyk, Magdalena E; Janes, Holly ...
New England journal of medicine/The New England journal of medicine,
11/2013, Letnik:
369, Številka:
22
Journal Article
Recenzirano
Odprti dostop
In an efficacy trial, 2504 persons at high risk for HIV-1 acquisition received either a DNA prime–recombinant adenovirus type 5 boost (DNA/rAd5) vaccine or placebo. The vaccine regimen did not reduce ...either HIV-1 acquisition or viral load.
The epidemic infection caused by the human immunodeficiency virus type 1 (HIV-1) is now in its fourth decade, with an estimated 2.5 million new infections occurring annually worldwide.
1
The number of newly infected persons, although diminishing, outpaces the number of patients who initiate antiretroviral therapy. Despite a number of successful prevention interventions that have been reported, including preexposure prophylaxis and treatment as prevention,
2
–
9
ultimate control of the HIV epidemic will most likely come only with the development of a safe and effective preventive vaccine.
This goal has proved to be elusive. Of the efficacy trials of HIV vaccines that . . .
Skeletal muscle atrophy is a common and debilitating condition that lacks an effective therapy. To address this problem, we used a systems-based discovery strategy to search for a small molecule ...whose mRNA expression signature negatively correlates to mRNA expression signatures of human skeletal muscle atrophy. This strategy identified a natural small molecule from tomato plants, tomatidine. Using cultured skeletal myotubes from both humans and mice, we found that tomatidine stimulated mTORC1 signaling and anabolism, leading to accumulation of protein and mitochondria, and ultimately, cell growth. Furthermore, in mice, tomatidine increased skeletal muscle mTORC1 signaling, reduced skeletal muscle atrophy, enhanced recovery from skeletal muscle atrophy, stimulated skeletal muscle hypertrophy, and increased strength and exercise capacity. Collectively, these results identify tomatidine as a novel small molecule inhibitor of muscle atrophy. Tomatidine may have utility as a therapeutic agent or lead compound for skeletal muscle atrophy.
Skeletal muscle atrophy is a common and serious condition that lacks a pharmacologic therapy.
We used a systems-based strategy to identify tomatidine, a natural compound from tomato plants, as a novel small molecule inhibitor of muscle atrophy.
Tomatidine may have utility as a therapeutic agent or lead compound for muscle atrophy.
These results suggest new therapeutic strategies for muscle atrophy.
Objectives: Several reports indicate that the body fat compartments, especially ip fat, predict metabolic risk better than total body fat. The objective of the study was to determine whether this can ...be confirmed and generalized throughout the population.
Participants: A representative sample of 1934 Black and White women and men of the Dallas Heart Study participated in the study.
Design: We measured the fat in total body, trunk, and lower body with dual-energy x-ray absorptiometry and in abdominal compartments (sc, ip, and retroperitoneal) with magnetic resonance imaging. Other measurements included body mass index (BMI), waist circumference, blood pressure, plasma lipids, glucose, insulin (including homeostasis model), and C-reactive protein.
Results: In all groups, total body fat correlated positively with key metabolic risk factors, i.e. homeostasis model, triglyceride/high-density lipoprotein-cholesterol ratios, C-reactive protein, and blood pressure; however, it explained less than one third of the variability of all the risk factors. After adjustment for total body fat, truncal fat conferred additional positive correlation with risk factors. Furthermore, with multivariable regression analysis, ip fat conferred independent correlation with plasma lipids beyond a combination of other compartments including truncal fat. Still, except for insulin levels, all combinations including ip fat still explained less than one third of the variability in risk-factor levels. Conversely, lower body fat correlated negatively with risk factors; i.e. lower body fat appeared to offer some protection against risk factors.
Conclusions: Body fat distribution has some influence on risk factors beyond total body fat content. Both waist circumference and BMI significantly predicted risk factors after adjustment for total body fat, and for clinical purposes, most of the predictive power for men was contained in waist circumference, whereas for women, BMI and waist circumference were similarly predictive. Finally, even though the correlations between combined body fat parameters and risk factors explained only a portion of the variation in the latter, the average number of categorical metabolic risk factors increased progressively with increasing obesity. Hence, obesity seemingly has more clinical impact than revealed in these correlative studies.
We present the discovery by the SPitzer InfraRed Intensive Transients Survey (SPIRITS) of a likely supernova (SN) in NGC 3556 (M108) at only 8.8 Mpc that was not detected by optical searches. A ...luminous infrared (IR) transient at M4.5 = −16.7 mag (Vega), SPIRITS 16tn is coincident with a dust lane in the inclined, star-forming disk of the host. Using observations in the IR, optical, and radio, we attempt to determine the nature of this event. We estimate AV 8-9 mag of extinction, placing it among the three most highly obscured IR-discovered SNe. The 4.5 light curve declined at a rate of 0.013 mag day−1, and the 3.6-4.5 color increased from 0.7 to 1.0 mag by 184.7 days post discovery. Optical/IR spectroscopy shows a red continuum but no clearly discernible features, preventing a definitive spectroscopic classification. Radio observations constrain the radio luminosity of SPIRITS 16tn to L 1024 erg s−1 Hz−1 between 3 and 15 GHz, excluding many varieties of core-collapse SNe. An SN Ia is ruled out by the observed IR color and lack of spectroscopic features from Fe-peak elements. SPIRITS 16tn was fainter at 4.5 than typical stripped-envelope SNe by 1 mag. Comparison of the spectral energy distribution to SNe II suggests that SPIRITS 16tn was both highly obscured and intrinsically dim, possibly akin to the low-luminosity SN 2005cs. We infer the presence of an IR dust echo powered by an initial peak luminosity of the transient of 5 × 1040 erg s−1 Lpeak 4 × 1043 erg s−1, consistent with the observed range for SNe II. This discovery illustrates the power of IR surveys to overcome the compounding effects of visible extinction and optically subluminous events in completing the inventory of nearby SNe.
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