The Renin Angiotensin System (RAS) mediates bifunctional growth regulation in melanoma and is a novel target for therapeutic intervention

Despite emergence of new systemic therapies, metastatic melanoma remains a challenging and often fatal form of skin cancer. The renin–angiotensin system (RAS) is a major physiological regulatory pathway controlling salt–water equilibrium, intravascular volume and blood pressure. Biological effects of the RAS are mediated by the vasoactive hormone angiotensin II (AngII) via two receptor subtypes, AT1R (encoded by AGTR1) and AT2R (encoded by AGTR2). We report decreasing expression and increasing CpG island methylation of AGTR1 in metastatic versus primary melanoma and detection in serum of methylated genomic DNA from the AGTR1 CpG island in metastatic melanoma implying that AGTR1 encodes a tumour suppressor function in melanoma. Consistent with this hypothesis, antagonism of AT1R using losartan or shRNA-mediated knockdown in melanoma cell lines expressing AGTR1 resulted in acquisition of the ability to proliferate in serum-free conditions. Conversely, ectopic expression of AGTR1 in cell lines lacking endogenous expression inhibits proliferation irrespective of the presence of AngII implying a ligand-independent suppressor function for AT1R. Treatment of melanoma cell lines expressing endogenous AT2R with either AngII or the AT2R-selective agonist Y6AII induces proliferation in serum-free conditions whereas the AT2R-specific antagonists PD123319 and EMA401 inhibit melanoma growth and angiogenesis and potentiate inhibitors of BRAF and MEK in cells with BRAF V600 mutations. Our results demonstrate that the RAS has both oncogenic and tumour suppressor functions in melanoma. Pharmacological inhibition of AT2R may provide therapeutic opportunities in melanomas expressing this receptor and AGTR1 CpG island methylation in serum may serve as a novel biomarker of metastatic melanoma

Dynamics and scaling of noise-induced domain growth

The domain growth processes originating from noise-induced nonequilibrium phase transitions are analyzed, both for non-conserved and conserved dynamics. The existence of a dynamical scaling regime is established in the two cases, and the corresponding growth laws are determined. The resulting universal dynamica scaling scenarios are those of Allen-Cahn and Lifshitz-Slyozov, respectively. Additionally, the effect of noise sources on the behaviour of the pair correlation function at short distances is studied.Projects PB94–1167, PB96–0241, PB97–0141-C02-01, and PB98-0935Peer Reviewe

A preliminary investigation on face recognition as a biometric identifier of sheep

The suitability of face recognition was investigated as a biometric-based identifier for sheep using a holistic analysis of face images by the independent components technique. Algorithm training was performed independently on several normalized face images from 50 sheep (sets of two, three, and four training images per sheep). The performance of this technique was assessed on a separate set of images (three normalized face images per sheep) using the cosine distance classifier. When 180 to 200 components were extracted, the recognition rate was as high as 95.3% to 96%. As expected, fewer independent components reduced the recognition rate, while a higher number of training images per sheep improved it. Although our results have demonstrated the potential of face recognition as a non-invasive, inexpensive, and accurate novel biometric identifier of sheep, further work should aim at improving recognition rates on a larger set of sheep faces.Author has checked copyrigh

Risk Adjustment for Lumbar Dysfunction: Comparison of Linear Mixed Models With and Without Inclusion of Between-Clinic Variation as a Random Effect

Background Valid comparison of patient outcomes of physical therapy care requires risk adjustment for patient characteristics using statistical models. Because patients are clustered within clinics, results of risk adjustment models are likely to be biased by random, unobserved between-clinic differences. Such bias could lead to inaccurate prediction and interpretation of outcomes. Purpose The purpose of this study was to determine if including between-clinic variation as a random effect would improve the performance of a risk adjustment model for patient outcomes following physical therapy for low back dysfunction. Design This was a secondary analysis of data from a longitudinal cohort of 147,623 patients with lumbar dysfunction receiving physical therapy in 1,470 clinics in 48 states of the United States. Methods Three linear mixed models predicting patients\u27 functional status (FS) at discharge, controlling for FS at intake, age, sex, number of comorbidities, surgical history, and health care payer, were developed. Models were: (1) a fixed-effect model, (2) a random-intercept model that allowed clinics to have different intercepts, and (3) a random-slope model that allowed different intercepts and slopes for each clinic. Goodness of fit, residual error, and coefficient estimates were compared across the models. Results The random-effect model fit the data better and explained an additional 11% to 12% of the between-patient differences compared with the fixed-effect model. Effects of payer, acuity, and number of comorbidities were confounded by random clinic effects. Limitations Models may not have included some variables associated with FS at discharge. The clinics studied may not be representative of all US physical therapy clinics. Conclusions Risk adjustment models for functional outcome of patients with lumbar dysfunction that control for between-clinic variation performed better than a model that does not

Lumbar Spine Manual Therapy for Aging and Older Adults

Low back pain (LBP) is among the most common health problems seen in primary care. The prevalence of severe LBP increased as age increased. Using manual therapy to relieve pain and stiffness associated with LBP is commonly seen in physical therapy practice. We reviewed existing studies, which included aging and older adults to elucidate the effectiveness of manual therapy on LBP in these populations. The techniques reviewed were spinal manipulation and soft tissue massage. We found that existing research on manual therapy for LBP has focused on younger adults, and many trials have excluded adults older than 65 years. Current evidence, though limited, generally supports that manual therapy is effective for treating LBP in aging and older adult populations. We were not able to conclude whether manual therapy is safe for these populations because adverse events were not reported in most studies reviewed. Further research is warranted to address limitations in current literature

Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial

BACKGROUND: Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients. METHODS: INHALE was a prospective, double-blind, randomised, placebo-controlled, phase 3 study comprising two trials (INHALE 1 and INHALE 2) done in 153 hospital intensive-care units in 25 countries. Eligible patients were aged 18 years or older; had pneumonia that had been diagnosed by chest radiography and that was documented as being caused by or showing two risk factors for a Gram-negative, multidrug-resistant pathogen; were intubated and mechanically ventilated; had impaired oxygenation within 48 h before screening; and had a modified Clinical Pulmonary Infection Score of at least 6. Patients were stratified by region and disease severity (according to their Acute Physiology and Chronic Health Evaluation [APACHE] II score) and randomly assigned (1:1) via an interactive voice-recognition system to receive 400 mg amikacin (Amikacin Inhale) or saline placebo, both of which were aerosolised, administered every 12 h for 10 days via the same synchronised inhalation system, and given alongside standard-of-care intravenous antibiotics. All patients and all staff involved in administering devices and monitoring outcomes were masked to treatment assignment. The primary endpoint, survival at days 28-32, was analysed in all patients who received at least one dose of study drug, were infected with a Gram-negative pathogen, and had an APACHE II score of at least 10 at diagnosis. Safety analyses were done in all patients who received at least one dose of study drug. This study is registered with ClinicalTrials.gov, numbers NCT01799993 and NCT00805168. FINDINGS: Between April 13, 2013, and April 7, 2017, 807 patients were assessed for eligibility and 725 were randomly assigned to Amikacin Inhale (362 patients) or aerosolised placebo (363 patients). 712 patients received at least one dose of study drug (354 in the Amikacin Inhale group and 358 in the placebo group), although one patient assigned to Amikacin Inhale received placebo in error and was included in the placebo group for safety analyses. 508 patients (255 in the Amikacin Inhale group and 253 in the placebo group) were assessed for the primary endpoint. We found no between-group difference in survival: 191 (75%) patients in the Amikacin Inhale group versus 196 (77%) patients in the placebo group survived until days 28-32 (odds ratio 0·841, 95% CI 0·554-1·277; p=0·43). Similar proportions of patients in the two treatment groups had a treatment-emergent adverse event (295 [84%] of 353 patients in the Amikacin Inhale group vs 303 [84%] of 359 patients in the placebo group) or a serious treatment-emergent adverse event (101 [29%] patients vs 97 [27%] patients). INTERPRETATION: Our findings do not support use of inhaled amikacin adjunctive to standard-of-care intravenous therapy in mechanically ventilated patients with Gram-negative pneumonia. FUNDING: Bayer AG

Inhaled amikacin adjunctive to intravenous standard-of-care antibiotics in mechanically ventilated patients with Gram-negative pneumonia (INHALE): a double-blind, randomised, placebo-controlled, phase 3, superiority trial

Treatment of ventilated pneumonia is often unsuccessful, even when patients are treated according to established guidelines. Therefore, we aimed to investigate the efficacy of the combination drug device Amikacin Inhale as an adjunctive therapy to intravenous standard-of-care antibiotics for pneumonia caused by Gram-negative pathogens in intubated and mechanically ventilated patients