Disruption of STAT3 signaling promotes KRAS induced lung tumorigenesis

STAT3 is considered to play an oncogenic role in several malignancies including lung cancer; consequently, targeting STAT3 is currently proposed as therapeutic intervention. Here we demonstrate that STAT3 plays an unexpected tumour-suppressive role in KRAS mutant lung adenocarcinoma (AC). Indeed, lung tissue-specific inactivation of Stat3 in mice results in increased KrasG12D-driven AC initiation and malignant progression leading to markedly reduced survival. Knockdown of STAT3 in xenografted human AC cells increases tumour growth. Clinically, low STAT3 expression levels correlate with poor survival and advanced malignancy in human lung AC patients with smoking history, which are prone to KRAS mutations. Consistently, KRAS mutant lung tumours exhibit reduced STAT3 levels. Mechanistically, we demonstrate that STAT3 controls NF-B-induced IL-8 expression by sequestering NF-B within the cytoplasm, thereby inhibiting IL-8-mediated myeloid tumour infiltration and tumour vascularization and hence tumour progression. These results elucidate a novel STAT3NF-BIL-8 axis in KRAS mutant AC with therapeutic and prognostic relevance.P 25599(VLID)183891

Effect of angiotensin-converting enzyme inhibitor and angiotensin receptor blocker initiation on organ support-free days in patients hospitalized with COVID-19

IMPORTANCE Overactivation of the renin-angiotensin system (RAS) may contribute to poor clinical outcomes in patients with COVID-19. Objective To determine whether angiotensin-converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) initiation improves outcomes in patients hospitalized for COVID-19. DESIGN, SETTING, AND PARTICIPANTS In an ongoing, adaptive platform randomized clinical trial, 721 critically ill and 58 non–critically ill hospitalized adults were randomized to receive an RAS inhibitor or control between March 16, 2021, and February 25, 2022, at 69 sites in 7 countries (final follow-up on June 1, 2022). INTERVENTIONS Patients were randomized to receive open-label initiation of an ACE inhibitor (n = 257), ARB (n = 248), ARB in combination with DMX-200 (a chemokine receptor-2 inhibitor; n = 10), or no RAS inhibitor (control; n = 264) for up to 10 days. MAIN OUTCOMES AND MEASURES The primary outcome was organ support–free days, a composite of hospital survival and days alive without cardiovascular or respiratory organ support through 21 days. The primary analysis was a bayesian cumulative logistic model. Odds ratios (ORs) greater than 1 represent improved outcomes. RESULTS On February 25, 2022, enrollment was discontinued due to safety concerns. Among 679 critically ill patients with available primary outcome data, the median age was 56 years and 239 participants (35.2%) were women. Median (IQR) organ support–free days among critically ill patients was 10 (–1 to 16) in the ACE inhibitor group (n = 231), 8 (–1 to 17) in the ARB group (n = 217), and 12 (0 to 17) in the control group (n = 231) (median adjusted odds ratios of 0.77 [95% bayesian credible interval, 0.58-1.06] for improvement for ACE inhibitor and 0.76 [95% credible interval, 0.56-1.05] for ARB compared with control). The posterior probabilities that ACE inhibitors and ARBs worsened organ support–free days compared with control were 94.9% and 95.4%, respectively. Hospital survival occurred in 166 of 231 critically ill participants (71.9%) in the ACE inhibitor group, 152 of 217 (70.0%) in the ARB group, and 182 of 231 (78.8%) in the control group (posterior probabilities that ACE inhibitor and ARB worsened hospital survival compared with control were 95.3% and 98.1%, respectively). CONCLUSIONS AND RELEVANCE In this trial, among critically ill adults with COVID-19, initiation of an ACE inhibitor or ARB did not improve, and likely worsened, clinical outcomes. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT0273570

The effect of shear crack geometry on aggregate interlock action in reinforced concrete

A shear crack in an RC beam undergoes a load sharing stage where aggregate interlock is dominant along particular segments of the crack path. However, one of the challenges is that this estimation of the aggregate interlock contribution is highly dependent on the shape of the critical shear crack. Therefore, a thorough study is required to determine the characteristics of crack shapes observed in measured experimental crack patterns and subsequently to develop predictive tools. This paper investigates the sensitivity of aggregate interlock action on simplified and higher-order shear crack geometries to assess the best ways of idealising the critical shear crack such that they could be adapted for analytical tools.In addition, a refinement of an existing crack kinematic model is developed for RC beams with low shear reinforcement. As a comparative study, an RC beam which may exhibit different possibilities in terms of the shape of the critical shear crack is considered to calculate the relative aggregate interlock contributions. A polynomial representation of the shear crack is found to be a good approximation for a critical shear crack. It is found that critical shear cracks with a concave downward segment which are located in the middle of a shear span generate larger aggregate interlock contributions than cracks with a concave upward segment or cracks which are located closest to the support.Cambridge Commonwealth, European and International Trust; the HRH The Prince of Wales Commonwealth Scholarshi

SHEAR BEHAVIOUR IN SLENDER REINFORCED CONCRETE BEAMS WITHOUT STIRRUPS

Many analytical tools for the prediction of the shear capacity of reinforced concrete beams do not explicitly predict the crack kinematics that reflect the actual cracking behaviour. As a result, most models require experimentally measured crack patterns and kinematics as input parameters. Hence the crack analysis is a post-assessment technique for shear failures exhibited in laboratory specimens. A significant challenge in the development of a priori critical shear crack analysis is that the critical shear crack shape is known to be unpredictable. There is thus an important need for approaches that reliably and accurately predict the shape of a critical shear crack in slender reinforced concrete beams. Experiments on shear-critical concrete beams without transverse reinforcement were undertaken to investigate the influence of the span to depth ratio and longitudinal reinforcement ratio on the crack shape at failure. Digital image correlation was used to map the dominant crack which was then modelled mathematically using curve fitting tools. The crack shapes were normalised with respect to the beam depth to compare the results for different span to depth ratios. It was found that the beams with longitudinal reinforcement ratios between 0.84% and 1.50% had similar critical crack shapes but the crack shape in the beam with 2.35% reinforcement differed. In the latter case, the dominant crack intersected with the longitudinal steel closer to the beam support leading to a shorter delamination crack and higher ultimate capacity. The initial findings of the study provide a basis for the development of crack-based predictive tools for the shear behaviour of slender reinforced concrete beams without transverse reinforcement.HRH The Prince of Wales Commonwealth Scholarship under Cambridge Commonwealth, European and International Trus

Influence of moisture out-gassing from encapsulant materials on the lifetime of organic solar cells

The results of a study on the effects of encapsulant pre-conditioning (drying) on the durability of "conventional" and "inverted" bulk-heterojunction organic solar cells based on P3HT:PCBM are presented. The architectures of the conventional and inverted devices were ITO/PEDOT:PSS/P3HT: PCBM/Al and ITO/ZnO/P3HT:PCBM/MoO3/Ag, respectively. Quantitative analysis of the moisture content, moisture out-gassing, and re-absorbing properties of flexible barrier encapsulant films under ambient conditions was conducted. The effect of moisture out-gassing from the encapsulation materials on device performance was studied and the lifetime of conventional and inverted devices was found to decline significantly for the devices encapsulated using materials without pre-conditioning. This study reveals the essential role of pre-conditioning of materials in the encapsulation of organic photovoltaic devices. Current-voltage characteristics exhibit a clear increase in the series resistance of the devices during storage under ambient conditions, and Spectroscopic Impedance analysis indicates that charge-transport resistance within the devices increases significantly during the degradation process. The results are consistent with the primary degradation mechanism being corrosion at the metal-electrode surface

Thigh-length compression stockings and DVT after stroke

Controversy exists as to whether neoadjuvant chemotherapy improves survival in patients with invasive bladder cancer, despite randomised controlled trials of more than 3000 patients. We undertook a systematic review and meta-analysis to assess the effect of such treatment on survival in patients with this disease