Epidermal growth factor receptor (EGFR) regulates many crucial cellular programs, with seven different activating ligands shaping cell signaling in distinct ways. Using crystallography and other ...approaches, we show how the EGFR ligands epiregulin (EREG) and epigen (EPGN) stabilize different dimeric conformations of the EGFR extracellular region. As a consequence, EREG or EPGN induce less stable EGFR dimers than EGF—making them partial agonists of EGFR dimerization. Unexpectedly, this weakened dimerization elicits more sustained EGFR signaling than seen with EGF, provoking responses in breast cancer cells associated with differentiation rather than proliferation. Our results reveal how responses to different EGFR ligands are defined by receptor dimerization strength and signaling dynamics. These findings have broad implications for understanding receptor tyrosine kinase (RTK) signaling specificity. Our results also suggest parallels between partial and/or biased agonism in RTKs and G-protein-coupled receptors, as well as new therapeutic opportunities for correcting RTK signaling output.
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•Different EGFR ligands stabilize receptor dimers with distinct structures•Epiregulin and epigen induce weaker and more short-lived EGFR dimers than EGF•Weakened dimerization causes sustained EGFR signaling•Epiregulin and epigen can induce cell differentiation through EGFR
Receptor tyrosine kinases operate under principles of biased agonism to shape signaling outputs.
Women were underrepresented in cardiac resynchronization therapy (CRT) trials for heart failure (making up about 20% of enrollees). Combining individual patient data from multiple clinical trials ...would enable assessment of CRT benefit in women.
To evaluate whether women with left bundle branch block (LBBB) benefit from CRT-defibrillators (CRT-D) at a shorter QRS duration than men with LBBB do.
Individual patient data were pooled from 3 CRT-D vs implantable cardioverter defibrillator (ICD) trials (4076 patients) enrolling predominantly patients with New York Heart Association (NYHA) class II heart failure and follow-up to 3 years. The effect of CRT-D compared with ICD on outcomes was assessed using random effects Cox proportional hazards.
Time to heart failure event or death (primary) and death alone (secondary).
Women benefited from CRT-D more than men. The main difference occurred in patients with LBBB and a QRS of 130 to 149 milliseconds. In this group, women had a 76% reduction in heart failure or death (absolute CRT-D to ICD difference, 23%; hazard ratio HR, 0.24, 95% CI, 0.11-0.53; P < .001) and a 76% reduction in death alone (absolute difference 9%; HR, 0.24, 95% CI, 0.06-0.89; P = .03), while there was no significant benefit in men for heart failure or death (absolute difference 4%; HR, 0.85 95% CI, 0.60-1.21; P = .38) or death alone (absolute difference 2%; HR, 0.86 95% CI, 0.49-1.52; P = .60). Neither women nor men with LBBB benefited from CRT-D at QRS shorter than 130 milliseconds, while both sexes with LBBB benefited at QRS of 150 milliseconds or longer.
In this population of patients with primarily mild heart failure, women with LBBB benefited from CRT-D at a shorter QRS duration than men with LBBB. This is important because recent guidelines limit the class I indication for CRT-D to patients with LBBB and QRS of 150 milliseconds or longer. While guidelines do give a class IIa indication to patients with LBBB and a QRS of 120 to 149 milliseconds, the present findings are important to communicate because women are less likely to receive CRT-D than men are. This study exemplifies the potential public health and regulatory science value of combining data from multiple clinical trials submitted to the FDA.
Background
This study presents oncologic outcomes after transoral robotic surgery (TORS) ± adjuvant therapy for oropharyngeal squamous cell carcinoma (SCC).
Methods
Three hundred fourteen patients ...undergoing TORS ± adjuvant therapy for oropharyngeal SCC from May 1, 2007, to May 31, 2015, are analyzed.
Results
Median follow‐up was 3.3 years (interquartile range IQR 1.8‐5.3 years; range 1 day to 9.3 years). Estimated locoregional recurrence‐free survival, distant metastasis‐free survival (DMFS), overall survival (OS), and cancer‐specific survival (CSS) rates (95% confidence interval CI number still at risk) at 5 years after surgery were 92% (88‐95; 92), 90% (86‐94; 92), 86% (82‐92; 98), and 94% (91‐97; 98), respectively. Negative margins were achieved in 98% of cases. The adult comorbidity evaluation (ACE)‐27 comorbidity index, human papillomavirus (HPV) status, pathologic N classification, and number of attempts to clear margins were associated with death due to cancer (P = .003, P = .002, P = .030, and P = .002, respectively).
Conclusion
The need to take ≥2 margins to achieve resection portends an increased risk of locoregional recurrence and death due to disease in oropharyngeal SCC.
Lateral ankle sprains (LASs) are the most prevalent musculoskeletal injury in physically active populations. They also have a high prevalence in the general population and pose a substantial ...healthcare burden. The recurrence rates of LASs are high, leading to a large percentage of patients with LAS developing chronic ankle instability. This chronicity is associated with decreased physical activity levels and quality of life and associates with increasing rates of post-traumatic ankle osteoarthritis, all of which generate financial costs that are larger than many have realised. The literature review that follows expands this paradigm and introduces emerging areas that should be prioritised for continued research, supporting a companion position statement paper that proposes recommendations for using this summary of information, and needs for specific future research.
Disrupted sleep-wake and molecular circadian rhythms are a feature of aging associated with metabolic disease and reduced levels of NAD+, yet whether changes in nucleotide metabolism control ...circadian behavioral and genomic rhythms remains unknown. Here, we reveal that supplementation with the NAD+ precursor nicotinamide riboside (NR) markedly reprograms metabolic and stress-response pathways that decline with aging through inhibition of the clock repressor PER2. NR enhances BMAL1 chromatin binding genome-wide through PER2K680 deacetylation, which in turn primes PER2 phosphorylation within a domain that controls nuclear transport and stability and that is mutated in human advanced sleep phase syndrome. In old mice, dampened BMAL1 chromatin binding, transcriptional oscillations, mitochondrial respiration rhythms, and late evening activity are restored by NAD+ repletion to youthful levels with NR. These results reveal effects of NAD+ on metabolism and the circadian system with aging through the spatiotemporal control of the molecular clock.
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•NAD+ induces transcription of stress and metabolic genes through the circadian clock•BMAL1 is required for chromatin remodeling and HSF1 recruitment in response to NAD+•NAD+ regulates PER2 acetylation and localization to control feedback repression•NAD+ counters age-related decline in circadian function
Aging is associated with disrupted circadian rhythms through signals that remain unidentified. Levine et al. show that NAD+ controls global circadian transcription through post-translational modification of PER2 and feedback repression. Raising NAD+ restores youthful transcription and mitochondrial rhythms in old age, revealing that NAD+ governs both behavior and metabolic health.
AbstractBackgroundTreatment approaches for patients with psychosis need major improvement. Our approach to improvement is twofold: target putative causal mechanisms for psychotic experiences that are ...treatable and also that patients wish treated. This leads to greater treatment engagement and clinical benefit. To inform mental health service provision we assessed the presence of treatable causal mechanisms and patient treatment preferences. MethodsPatients with non-affective psychosis attending NHS mental health services completed assessments of paranoia, hallucinations, anxious avoidance, worry, self-esteem, insomnia, analytic reasoning, psychological well-being, and treatment preferences. Results1809 patients participated. Severe paranoia was present in 53.4% and frequent voices in 48.2%. Of the causal mechanisms, severe worry was present in 67.7%, avoidance at agoraphobic levels in 64.5%, analytic reasoning difficulties in 55.9%, insomnia in 50.1%, poor psychological well-being in 44.3%, strongly negative self-beliefs in 36.6%, and weak positive self-beliefs in 19.2%. Treatment target preferences were: feeling happier (63.2%), worrying less (63.1%), increasing self-confidence (62.1%), increasing activities (59.6%), improving decision-making (56.5%), feeling safer (53.0%), sleeping better (52.3%), and coping with voices (45.3%). Patients with current paranoia and/or hallucinations had higher levels of the causal factors and of wanting these difficulties treated. ConclusionsPatients with non-affective psychosis have high levels of treatable problems such as agoraphobic avoidance, worry, low self-esteem, and insomnia and they would like these difficulties treated. Successful treatment of these difficulties is also likely to decrease psychotic experiences such as paranoia.
Lateral ankle sprain injury is the most common musculoskeletal injury incurred by individuals who participate in sports and recreational physical activities. Following initial injury, a high ...proportion of individuals develop long-term injury-associated symptoms and chronic ankle instability. The development of chronic ankle instability is consequent on the interaction of mechanical and sensorimotor insufficiencies/impairments that manifest following acute lateral ankle sprain injury. To reduce the propensity for developing chronic ankle instability, clinical assessments should evaluate whether patients in the acute phase following lateral ankle sprain injury exhibit any mechanical and/or sensorimotor impairments. This modified Delphi study was undertaken under the auspices of the executive committee of the International Ankle Consortium. The primary aim was to develop recommendations, based on expert (n=14) consensus, for structured clinical assessment of acute lateral ankle sprain injuries. After two modified Delphi rounds, consensus was achieved on the clinical assessment of acute lateral ankle sprain injuries. Consensus was reached on a minimum standard clinical diagnostic assessment. Key components of this clinical diagnostic assessment include: establishing the mechanism of injury, as well as the assessment of ankle joint bones and ligaments. Through consensus, the expert panel also developed the International Ankle Consortium Rehabilitation-Oriented ASsessmenT (ROAST). The International Ankle Consortium ROAST will help clinicians identify mechanical and/or sensorimotor impairments that are associated with chronic ankle instability. This consensus statement from the International Ankle Consortium aims to be a key resource for clinicians who regularly assess individuals with acute lateral ankle sprain injuries.
We sought to determine whether maternal vaccination during pregnancy was associated with a reduced risk of laboratory-confirmed influenza hospitalizations in infants <6 months old. Active ...population-based, laboratory-confirmed influenza surveillance was conducted in children hospitalized with fever and/or respiratory symptoms in 3 US counties from November through April during the 2002 through 2009 influenza seasons. The exposure, influenza vaccination during pregnancy, and the outcome, positive/negative influenza testing among their hospitalized infants, were compared using logistic regression analyses. Among 1510 hospitalized infants <6 months old, 151 (10%) had laboratory-confirmed influenza and 294 (19%) mothers reported receiving influenza vaccine during pregnancy. Eighteen (12%) mothers of influenza-positive infants and 276 (20%) mothers of influenza-negative infants were vaccinated (unadjusted odds ratio, 0.53; 95% confidence interval, 0.32–0.88 and adjusted odds ratio, 0.52; 95% confidence interval, 0.30–0.91). Infants of vaccinated mothers were 45-48% less likely to have influenza hospitalizations than infants of unvaccinated mothers. Our results support the current influenza vaccination recommendation for pregnant women.
The Executive Committee of the International Ankle Consortium presents this 2016 position paper with recommendations for information implementation and continued research based on the paradigm that ...lateral ankle sprain (LAS), and the development of chronic ankle instability (CAI), serve as a conduit to a significant global healthcare burden. We intend our recommendations to serve as a mechanism to promote efforts to improve prevention and early management of LAS. We believe this will reduce the prevalence of CAI and associated sequelae that have led to the broader public health burdens of decreased physical activity and early onset ankle joint post-traumatic osteoarthritis. Ultimately, this can contribute to healthier lifestyles and promotion of physical activity.
Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important ...unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation.
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•Cutaneous TRPV1+ neuron activation is sufficient to initiate type 17 inflammation•Cutaneous TRPV1+ neuron activation augments local host defense•Type 17 innate immunity via nerve reflex provides regional anticipatory immunity
Cutaneous sensory neurons can trigger an inflammatory reflex arc that activates anticipatory immunity in the neighboring skin.
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