Despite the development of second-generation antiandrogens, acquired resistance to hormone therapy remains a major challenge in treating advanced prostate cancer. We find that cancer-associated ...fibroblasts (CAFs) can promote antiandrogen resistance in mouse models and in prostate organoid cultures. We identify neuregulin 1 (NRG1) in CAF supernatant, which promotes resistance in tumor cells through activation of HER3. Pharmacological blockade of the NRG1/HER3 axis using clinical-grade blocking antibodies re-sensitizes tumors to hormone deprivation in vitro and in vivo. Furthermore, patients with castration-resistant prostate cancer with increased tumor NRG1 activity have an inferior response to second-generation antiandrogen therapy. This work reveals a paracrine mechanism of antiandrogen resistance in prostate cancer amenable to clinical testing using available targeted therapies.
Display omitted
•CAF-derived NRG1 confers antiandrogen resistance in prostate cancer•Pharmacological blockade of the NRG1-HER3 axis induces tumor regression•NRG1 is upregulated in prostate stroma in patients after androgen deprivation therapy•High NRG1 activity and reduced sensitivity to second-generation antiandrogen therapy
Zhang et al. find that cancer-associated fibroblasts promote antiandrogen resistance in prostate cancer by secreting NRG1 to activate HER3 signaling in prostate cancer cells. Blockade of the NRG1/HER3 axis can re-sensitize prostate cancer models to antiandrogen therapy.
Summary
Sedentary behaviour has emerged as a unique determinant of health in adults. Studies in children and adolescents have been less consistent. We reviewed the evidence to determine if the total ...volume and patterns (i.e. breaks and bouts) of objectively measured sedentary behaviour were associated with adverse health outcomes in young people, independent of moderate‐intensity to vigorous‐intensity physical activity. Four electronic databases (EMBASE MEDLINE, Ovid EMBASE, PubMed and Scopus) were searched (up to 12 November 2015) to retrieve studies among 2‐ to 18‐year‐olds, which used cross‐sectional, longitudinal or experimental designs, and examined associations with health outcomes (adiposity, cardio‐metabolic, fitness, respiratory, bone/musculoskeletal, psychosocial, cognition/academic achievement, gross motor development and other outcomes). Based on 88 eligible observational studies, level of evidence grading and quantitative meta‐analyses indicated that there is limited available evidence that the total volume or patterns of sedentary behaviour are associated with health in children and adolescents when accounting for moderate‐intensity to vigorous‐intensity physical activity or focusing on studies with low risk of bias. Quality evidence from studies with robust designs and methods, objective measures of sitting, examining associations for various health outcomes, is needed to better understand if the overall volume or patterns of sedentary behaviour are independent determinants of health in children and adolescents.
A physiologic pharmacokinetic model describing percutaneous absorption of topically applied compounds in the isolated perfused porcine skin flap (IPPSF) is presented. As an extension of a previously ...reported hybrid physiologically relevant compartmental model of uptake of intra-arterially administered drug in the IPPSF, this percutaneous model should allow experimental results obtained from an in vitro preparation to serve as quantitative input to an in vivo pharmacokinetic system. Model parameters estimated from 8-10-h IPPSF experiments were able to predict 6-day in vivo radiolabel absorptions in pigs for topically applied benzoic acid, caffeine, malathion, parathion, DFP, testosterone, and progesterone. These results compare favorably with those obtained previously using a classical compartmental modeling approach.
Study Objectives. To test the hypothesis that gastric pH would be elevated above pH 3.0 for at least 2 hours after administration of chewable, dispersible, buffered didanosine tablets. Doses tested ...were 200 mg (two 100‐mg tablets) and 400 mg (two 200‐mg tablets). We also sought to compare these doses with regard to maximum gastric pH (pHmax), time to pHmax (TpH‐max), time that gastric pH exceeds 3.0 (TpH>3), and area under the gastric pH versus time curve for pH greater than 3.0 (AUCT>pH 3).
Design. Prospective, parallel‐group, dose‐comparison, gastric pH study.
Setting. General Clinical Research Center, University of Michigan Hospitals, Ann Arbor, Michigan.
Patients. Nineteen patients infected with human immunodeficiency virus, aged 30–62 years, and receiving long‐term didanosine therapy.
Intervention. Patients underwent continuous gastric pH monitoring, using the Heidelberg capsule radiotelemetric pH monitoring device. After documentation of a fasting baseline gastric pH below 3.0, patients were given 180 ml of water (control phase), and gastric pH was allowed to return to baseline. After administration of a single, oral dose of didanosine 200 mg or 400 mg with 180 ml of water, gastric pH was recorded until pH remained below 3.0 for 10 minutes.
Measurements and Main Results. A mean pHmax of 8.6 (range 6.3–9.5) was achieved with a TpH‐max of 4.1 minutes (range 1–12.0 min). Mean TpH>3 was 24.9 minutes (range 15–55 min), with an AUCT>pH 3 of 2.6 pH•min−1 (range 1.2–6.9 pH•min−1). The two doses of didanosine tested did not differ significantly in mean gastric pH parameters.
Conclusions. After administration of chewable, dispersible, buffered didanosine tablets, 200 or 400 mg, the mean duration of elevated gastric pH (TpH>3) was less than 30 minutes, with a range of 15–55 minutes. Characterization of the magnitude and duration of elevated gastric pH may allow for earlier administration of other pH‐sensitive drugs. The short duration of elevated gastric pH may help explain the wide variability in didanosine bioavailability observed clinically.
The use of stereotactic ablative radiotherapy (SABR) in the UK has expanded over the past decade, in part as the result of several UK clinical trials and a recent NHS England Commissioning through ...Evaluation programme. A UK SABR Consortium consensus for normal tissue constraints for SABR was published in 2017, based on the existing literature at the time. The published literature regarding SABR has increased in volume over the past 5 years and multiple UK centres are currently working to develop new SABR services. A review and update of the previous consensus is therefore appropriate and timely. It is hoped that this document will provide a useful resource to facilitate safe and consistent SABR practice.
The function of ScHSP26 is thermally controlled: the heat shock that causes the destabilization of target proteins leads to its activation as a molecular chaperone. We investigate the structural and ...dynamical properties of ScHSP26 oligomers through a combination of multiangle light scattering, fluorescence spectroscopy, NMR spectroscopy, and mass spectrometry. We show that ScHSP26 exists as a heterogeneous oligomeric ensemble at room temperature. At heat-shock temperatures, two shifts in equilibria are observed: toward dissociation and to larger oligomers. We examine the quaternary dynamics of these oligomers by investigating the rate of exchange of subunits between them and find that this not only increases with temperature but proceeds via two separate processes. This is consistent with a conformational change of the oligomers at elevated temperatures which regulates the disassembly rates of this thermally activated protein.
Display omitted
► Combining biophysical approaches allows characterization of a molecular chaperone ► ScHSP26 populates a heterogeneous ensemble of oligomers ► Upon thermal activation, ScHSP26 oligomers dissociate and shift to larger species ► Quaternary dynamics of ScHSP26 are underpinned by two separate processes
Correlative data suggest that cardiac mast cells are a component of the inflammatory response that is important to hypertension-induced adverse myocardial remodeling. However, a causal relationship ...has not been established. We hypothesized that adverse myocardial remodeling would be inhibited by preventing the release of mast cell products that may interact with fibroblasts and other inflammatory cells. Eight-week-old male spontaneously hypertensive rats were treated for 12 weeks with the mast cell stabilizing compound nedocromil (30 mg/kg per day). Age-matched Wistar-Kyoto rats served as controls. Nedocromil prevented left ventricular fibrosis in the spontaneously hypertensive rat independent of hypertrophy and blood pressure, despite cardiac mast cell density being elevated. The mast cell protease tryptase was elevated in the spontaneously hypertensive rat myocardium and was normalized by nedocromil. Treatment of isolated adult spontaneously hypertensive rat cardiac fibroblasts with tryptase induced collagen synthesis and proliferation, suggesting this as a possible mechanism of mast cell-mediated fibrosis. In addition, nedocromil prevented macrophage infiltration into the ventricle. The inflammatory cytokines interferon-gamma and interleukin (IL)-4 were increased in the spontaneously hypertensive rat and normalized by nedocromil, whereas IL-6 and IL-10 were decreased in the spontaneously hypertensive rat, with nedocromil treatment normalizing IL-6 and increasing IL-10 above the control. These results demonstrate for the first time a causal relationship between mast cell activation and fibrosis in the hypertensive heart. Furthermore, these results identify several mechanisms, including tryptase, inflammatory cell recruitment, and cytokine regulation, by which mast cells may mediate hypertension-induced left ventricular fibrosis.
Because cancer patients survive longer, the impact of cardiotoxicity associated with the use of cancer treatments escalates. The present study investigates whether early alterations of myocardial ...strain and blood biomarkers predict incident cardiotoxicity in patients with breast cancer during treatment with anthracyclines, taxanes, and trastuzumab.
Eighty-one women with newly diagnosed human epidermal growth factor receptor 2-positive breast cancer, treated with anthracyclines followed by taxanes and trastuzumab were enrolled to be evaluated every 3 months during their cancer therapy (total of 15 months) using echocardiograms and blood samples. Left ventricular ejection fraction, peak systolic longitudinal, radial, and circumferential myocardial strain were calculated. Ultrasensitive troponin I, N-terminal pro-B-type natriuretic peptide, and the interleukin family member (ST2) were also measured. Left ventricular ejection fraction decreased (64 ± 5% to 59 ± 6%; P<0.0001) over 15 months. Twenty-six patients (32%, 22%-43%) developed cardiotoxicity as defined by the Cardiac Review and Evaluation Committee Reviewing Trastuzumab; of these patients, 5 (6%, 2%-14%) had symptoms of heart failure. Peak systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines treatment predicted the subsequent development of cardiotoxicity; no significant associations were observed for left ventricular ejection fraction, N-terminal pro-B-type natriuretic peptide, and ST2. Longitudinal strain was <19% in all patients who later developed heart failure.
In patients with breast cancer treated with anthracyclines, taxanes, and trastuzumab, systolic longitudinal myocardial strain and ultrasensitive troponin I measured at the completion of anthracyclines therapy are useful in the prediction of subsequent cardiotoxicity and may help guide treatment to avoid cardiac side-effects.
Antibiotic-resistant bacteria are associated with increased patient morbidity and mortality. It is unknown whether wearing gloves and gowns for all patient contact in the intensive care unit (ICU) ...decreases acquisition of antibiotic-resistant bacteria.
To assess whether wearing gloves and gowns for all patient contact in the ICU decreases acquisition of methicillin-resistant Staphylococcus aureus (MRSA) or vancomycin-resistant Enterococcus (VRE) compared with usual care.
Cluster-randomized trial in 20 medical and surgical ICUs in 20 US hospitals from January 4, 2012, to October 4, 2012.
In the intervention ICUs, all health care workers were required to wear gloves and gowns for all patient contact and when entering any patient room.
The primary outcome was acquisition of MRSA or VRE based on surveillance cultures collected on admission and discharge from the ICU. Secondary outcomes included individual VRE acquisition, MRSA acquisition, frequency of health care worker visits, hand hygiene compliance, health care–associated infections, and adverse events.
From the 26,180 patients included, 92,241 swabs were collected for the primary outcome. Intervention ICUs had a decrease in the primary outcome of MRSA or VRE from 21.35 acquisitions per 1000 patient-days (95% CI, 17.57 to 25.94) in the baseline period to 16.91 acquisitions per 1000 patient-days (95% CI, 14.09 to 20.28) in the study period, whereas control ICUs had a decrease in MRSA or VRE from 19.02 acquisitions per 1000 patient-days (95% CI, 14.20 to 25.49) in the baseline period to 16.29 acquisitions per 1000 patient-days (95% CI, 13.48 to 19.68) in the study period, a difference in changes that was not statistically significant (difference, −1.71 acquisitions per 1000 person-days, 95% CI, −6.15 to 2.73; P = .57). For key secondary outcomes, there was no difference in VRE acquisition with the intervention (difference, 0.89 acquisitions per 1000 person-days; 95% CI, −4.27 to 6.04, P = .70), whereas for MRSA, there were fewer acquisitions with the intervention (difference, −2.98 acquisitions per 1000 person-days; 95% CI, −5.58 to −0.38; P = .046). Universal glove and gown use also decreased health care worker room entry (4.28 vs 5.24 entries per hour, difference, −0.96; 95% CI, −1.71 to −0.21, P = .02), increased room-exit hand hygiene compliance (78.3% vs 62.9%, difference, 15.4%; 95% CI, 8.99% to 21.8%; P = .02) and had no statistically significant effect on rates of adverse events (58.7 events per 1000 patient days vs 74.4 events per 1000 patient days; difference, −15.7; 95% CI, −40.7 to 9.2, P = .24).
The use of gloves and gowns for all patient contact compared with usual care among patients in medical and surgical ICUs did not result in a difference in the primary outcome of acquisition of MRSA or VRE. Although there was a lower risk of MRSA acquisition alone and no difference in adverse events, these secondary outcomes require replication before reaching definitive conclusions.
clinicaltrials.gov Identifier: NCT0131821.
PDF
