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Non‐small cell lung cancer (NSCLC) has a poor prognosis, and effective therapeutic strategies are lacking. The diabetes drug canagliflozin inhibits NSCLC cell proliferation and the mammalian target of rapamycin (mTOR) pathway, which mediates cell growth and survival, but it is unclear whether this drug can enhance response rates when combined with cytotoxic therapy. Here, we evaluated the effects of canagliflozin on human NSCLC response to cytotoxic therapy in tissue cultures and xenografts. Ribonucleic acid sequencing (RNA‐seq), real‐time quantitative PCR (RT‐qPCR), metabolic function, small interfering ribonucleic acid (siRNA) knockdown, and protein expression assays were used in mechanistic analyses. We found that canagliflozin inhibited proliferation and clonogenic survival of NSCLC cells and augmented the efficacy of radiotherapy to mediate these effects and inhibit NSCLC xenograft growth. Canagliflozin treatment alone moderately inhibited mitochondrial oxidative phosphorylation and exhibited greater antiproliferative capacity than specific mitochondrial complex‐I inhibitors. The treatment downregulated genes mediating hypoxia‐inducible factor (HIF)‐1α stability, metabolism and survival, activated adenosine monophosphate‐activated protein kinase (AMPK) and inhibited mTOR, a critical activator of hypoxia‐inducible factor‐1α (HIF‐1α) signaling. HIF‐1α knockdown and stabilization experiments suggested that canagliflozin mediates antiproliferative effects, in part, through suppression of HIF‐1α. Transcriptional regulatory network analysis pinpointed histone deacetylase 2 (HDAC2), a gene suppressed by canagliflozin, as a key mediator of canagliflozin's transcriptional reprogramming. HDAC2 knockdown eliminated HIF‐1α levels and enhanced the antiproliferative effects of canagliflozin. HDAC2‐regulated genes suppressed by canagliflozin are associated with poor prognosis in several clinical NSCLC datasets. In addition, we include evidence that canagliflozin also improves NSCLC response to chemotherapy. In summary, canagliflozin may be a promising therapy to develop in combination with cytotoxic therapy in NSCLC.

Abstract Radiotherapy is a non-invasive standard treatment for prostate cancer (PC). However, PC develops radio-resistance, highlighting a need for agents to improve radiotherapy response. Canagliflozin, an inhibitor of sodium-glucose co-transporter-2, is approved for use in diabetes and heart failure, but is also shown to inhibit PC growth. However, whether canagliflozin can improve radiotherapy response in PC remains unknown. Here, we show that well-tolerated doses of canagliflozin suppress proliferation and survival of androgen-sensitive and insensitive human PC cells and tumors and sensitize them to radiotherapy. Canagliflozin blocks mitochondrial respiration, promotes AMPK activity, inhibits the MAPK and mTOR-p70S6k/4EBP1 pathways, activates cell cycle checkpoints, and inhibits proliferation in part through HIF-1α suppression. Canagliflozin mediates transcriptional reprogramming of several metabolic and survival pathways known to be regulated by ETS and E2F family transcription factors. Genes downregulated by canagliflozin are associated with poor PC prognosis. This study lays the groundwork for clinical investigation of canagliflozin in PC prevention and treatment in combination with radiotherapy.

Metabolic dysregulation is an early event in carcinogenesis. Here, we examined the expression of enzymes involved in de novo lipogenesis (ATP-citrate lyase: ACLY), glucose uptake (Glucose Transporter 1: GLUT1), and folate–glutamate metabolism (Prostate-Specific Membrane Antigen: PSMA) as potential biomarkers of risk for early prostate cancer progression. Patients who were managed initially on active surveillance with a Gleason score of 6 or a low-volume Gleason score of 7 (3 + 4) were accrued from a prostate cancer diagnostic assessment program. Patients were asked to donate their baseline diagnostic biopsy tissues and permit access to their clinical data. PSMA, GLUT1, and ACLY expression were examined with immunohistochemistry (IHC) in baseline biopsies, quantitated by Histologic Score for expression in benign and malignant glands, and compared with patient time remaining on active surveillance (time-on-AS). All three markers showed trends for elevated expression in malignant compared to benign glands, which was statistically significant for ACLY. On univariate analysis, increased PSMA and GLUT1 expression in malignant glands was associated with shorter time-on-AS (HR: 5.06, [CI 95%: 1.83–13.94] and HR: 2.44, [CI 95%: 1.10–5.44], respectively). Malignant ACLY and benign gland PSMA and GLUT1 expression showed non-significant trends for such association. On multivariate analysis, overexpression of PSMA in malignant glands was an independent predictor of early PC progression (p = 0.006). This work suggests that the expression of metabolic enzymes determined by IHC on baseline diagnostic prostate biopsies may have value as biomarkers of risk for rapid PC progression. PSMA may be an independent predictor of risk for progression and should be investigated further in systematic studies.

Abstract Improving sleep quality in patients with obstructive sleep apnea (OSA) by positive airway pressure therapy is associated with a decrease of blood pressure (BP). It remains elusive, whether treatment of sleep disturbances due to restless legs syndrome with symptomatic periodic limb movements in sleep (PLMS) affects BP as well. The present study provides first data on this issue. Retrospective study on patients undergoing polysomnography in a German University Hospital. Inclusion criteria were first diagnosis of restless legs syndrome with PLMS (PLM index ≥ 15/h and PLM arousal index ≥ 5/h) with subsequent initiation of levodopa/benserazide or dopamine agonists. Exclusion criterion was an initiation or change of preexisting positive airway pressure therapy between baseline and follow-up. BP and Epworth sleepiness scale were assessed at two consecutive polysomnographies. After screening of 953 PLMS data sets, 114 patients (mean age 62.1 ± 12.1 years) were included. 100 patients (87.7%) were started on levodopa/benserazide, 14 patients (12.2%) on dopamine agonists. Treatment was associated with significant reductions of PLM index (81.2 ± 65.0 vs. 39.8 ± 51.2, p

Abstract Background While pain is often the focus of clinical interventions, other clinical outcomes (e.g., discomfort, stiffness) might also contribute to patients’ functionality and well-being. Although researchers and clinicians may view discomfort, pain and stiffness as different constructs, it remains unclear how patients perceive and differentiate between these constructs. Therefore, the purpose of this study was to explore patients’ perceptions of pain, discomfort, and stiffness. Methods Chiropractic patients were invited to complete an online cross-sectional survey and describe what ‘discomfort’, ‘pain’ and ‘stiffness’ meant to them using their own words. Lexical and inductive qualitative content analyses were conducted independently and then triangulated. Results Fifty-three chiropractic patients (47.2% female, mean age: 39.1 ± 15.1 years) responded. The most common combinations of words to describe discomfort were “can be ignored” and “less severe than”. “Cannot be ignored” and “sharp shooting” were used to describe pain. “Limited range of motion” was used to describe stiffness. Qualitatively, five themes were developed: impact, character, feeling, intensity and temporality. Stiffness was described as limited movement/mobility. Although discomfort and stiffness impacted patients’ activities, patients remained functional; pain was described as stopping/limiting activities. Discomfort was described as dull and tingling, pain as sharp and shooting, and stiffness as tight and restricted. Patients felt displeased and annoyed when experiencing discomfort and stiffness but hurt and in danger of harm when experiencing pain. Discomfort and stiffness were described as less intense than pain, with shorter/intermittent duration; however, all constructs could be experienced constantly. Conclusion Patients perceived discomfort, pain and stiffness as different, yet overlapping constructs. This preliminary work advances our knowledge of how patients conceptualize these constructs, contributing to better understanding of what patients mean when reporting these experiences, potentially improving the clinician-patient communication.

After endocytosis, transmembrane cargo is differentially sorted into degradative or recycling pathways. This process is facilitated by recruitment into physically distinct degradative or recycling microdomains on the limiting membrane of individual endosomes. Endosomal sorting complexes required for transport (ESCRT) mark the degradative microdomain, while the recycling domain is marked by the retromer complex and associated proteins RME-8 and SNX-1. The separation of endosomal microdomains is also controlled by RME-8 and SNX-1, at least in part via removal of degradative component HRS/HGRS-1 from the recycling microdomain. This activity is likely due to recruitment and activation of chaperone Hsc70 on the endosome by the RME-8 DNAJ domain. To better understand the mechanism of RME-8 function we performed a new phylogenetic analysis of RME-8 and identified new conserved sequence features. In a complementary approach, we performed structure-function analysis that identified the C-terminus as important for microdomain localization and likely substrate binding, while N-terminal sequences beyond the known single N-terminal PH-like domain are important for endosome recruitment. Random mutagenesis identified IWN4, and by analogy IWN3, to be important for the autoinhibitory DNAJ domain binding, with IWN3 playing a critical role in HRS uncoating activity. Combining AlphaFold structural predictions with in vivo mutation analysis of RME-8, we propose a model whereby SNX-1 and the IWN domains control the conformation of RME-8 and hence the productive exposure of the DNAJ domain. Furthermore, we propose that the activation of RME-8 is cyclical, with SNX-1 acting as an activator and a target of RME-8 uncoating activity.

Abstract Background Developing therapeutic strategies for a SARS-CoV-2 infection is challenging, but first the correct diagnosis has to be made. Unspecific upper and lower respiratory tract symptoms can be misleading; hence, a nasopharyngeal swab test with a real-time reverse-transcription-polymerase chain reaction is of great importance. However, early viral clearing jeopardizes a sound diagnosis of COVID-19. Case presentation We report on two Caucasian patients who had negative pharyngeal swab tests at the onset of SARS-CoV-2 pneumonia. In one patient, the virus was not even detectable in bronchoalveolar lavage despite typical radiomorphologic changes. Conclusions Negative PCR findings in both the pharynx and bronchoalveolar lavage do not exclude COVID-19 pneumonia. Computed tomography is a crucial diagnostic prerequisite in this context.

Stop-loss reinsurance is a risk management tool that allows an insurance company to transfer part of their risk to a reinsurance company. Ruin probabilities allow us to measure the effect of stop-loss reinsurance on the solvency of the primary insurer. They further permit the calculation of the economic capital, or the required initial capital to hold, corresponding to the 99.5% value-at-risk of its surplus. Specifically, we show that under a stop-loss contract, the ruin probability for the primary insurer, for both a finite- and infinite-time horizon, can be obtained from the finite-time ruin probability when no reinsurance is bought. We develop a finite-difference method for solving the (partial integro-differential) equation satisfied by the finite-time ruin probability with no reinsurance, leading to numerical approximations of the ruin probabilities under a stop-loss reinsurance contract. Using the method developed here, we discuss the interplay between ruin probability, reinsurance retention level and initial capital.

The use of social media, such as Twitter, has changed the information landscape for citizens’ participation in crisis response and recovery activities. Given that drought progression is slow and also spatially extensive, an interesting set of questions arise, such as how the usage of Twitter by a large population may change during the development of a major drought alongside how the changing usage facilitates drought detection. For this reason, contemporary analysis of how social media data, in conjunction with meteorological records, was conducted towards improvement in the detection of drought and its progression. The research utilized machine learning techniques applied over satellite-derived drought conditions in Colorado. Three different machine learning techniques were examined: the generalized linear model, support vector machines and deep learning, each applied to test the integration of Twitter data with meteorological records as a predictor of drought development. It is found that the integration of data resources is viable given that the Twitter-based model outperformed the control run which did not include social media input. Eight of the ten models tested showed quantifiable improvements in the performance over the control run model, suggesting that the Twitter-based model was superior in predicting drought severity. Future work lies in expanding this method to depict drought in the western U.S.

The dynamic mode-II energy release rate (ERR) of the end-loaded split (ELS) test with applied time-dependent displacement is derived for the first time with the effect of vibration included. Dynamic Euler-Bernoulli beams are used together with a deflection condition to simulate contact. To understand the dynamic effect and the relative dynamic contribution from each vibration mode, a ‘dynamic factor’ and a ‘spatial factor’ are defined. It is found that the contribution of the ith vibration mode is dependent on the spatial factor, which is a function of the delamination length and the total length of the ELS specimen. Certain vibration modes are dominant dependent on the spatial factor. In addition, for a given spatial factor, there may be a certain vibration mode, which makes approximately zero contribution to the ERR. The developed theory is verified against results from finite-element method (FEM) simulations and it is in excellent agreement. This work now allows the loading rate-dependent mode-II delamination toughness of materials to be determined by using ELS tests. In addition, it provides understanding of the structural dynamic response in the presence of mode-II delamination and can guide the design of structures to mitigate against vibration-driven delamination.

ABSTRACT: Laboratory experiments were conducted to study the spallation behaviour of thermal barrier coatings (TBCs) on aero-engine turbine blades manufactured by the electron-beam physical vapour deposition technique (EB-PVD). Intact blades were heated at temperature 1135°C in a furnace for certain time and then cooled to the room temperature in the laboratory condition. It was found that no spallation occurred during cooling, but spallation happened at constant room temperature after cooling. The spallation mechanism is studied by using the mechanical model developed (Harvey 2017 and Wang 2017), which are based on the hypothesis of pockets of energy concentration (PECs). Some observations of the spallation behaviour are well predicted by the model. Keywords: Thermal barrier coating, Interface fracture, Spallation, Pockets of energy concentration, Buckling

The reason why the surface adhesion of a graphene monolayer is much greater than that of graphene multilayers remains unclear. Here, the authors build a model to show interlayer sliding and fracture mode mixity cause the decrease in adhesion toughness of multilayer graphene.

Abstract In the minimal U(1) extension of the Standard Model (SM), a new gauge boson referred to as “dark photon” is predicted. The dark-photon mass can be generated from an additional Higgs mechanism associated with a dark scalar boson. At B-factories such as Belle II, large numbers of B-mesons are produced and can decay to a kaon plus the dark scalar via the latter’s mixing with the SM Higgs boson. We evaluate the sensitivity of Belle II for the case in which the dark scalar decays exclusively into a pair of dark photons via the new U(1) gauge coupling, and the dark photons are long lived owing to a small kinetic mixing ϵ. We study the experimental signature in which each dark photon decays into a pair of charged leptons, pions, or kaons, resulting in a pair of displaced vertices, and argue that the search is essentially background-free. We perform detailed Monte-Carlo simulations to determine the expected number of signal events at Belle II with an integrated luminosity of 50 ab −1, taking into account the efficiencies for both final-state-particle identification and displaced tracking. We find that for experimentally allowed values of the scalar mixing angle and kinematically allowed dark-photon and dark-scalar masses, the proposed search is uniquely sensitive to the medium-ϵ regime, which is currently mostly unexcluded by experiments.

Three days of extreme rainfall in late December 2015 in the middle of the Mississippi River led to severe flooding in Missouri. The meteorological context of this event was analyzed through synoptic diagnosis into the atmospheric circulation that contributed to the precipitation event’s severity. The midlatitude synoptic waves that induced the extreme precipitation and ensuing flooding were traced to the Madden Julian Oscillation (MJO), which amplified the trans-Pacific Rossby wave train likely associated with the strong El Niño of December 2015. Though the near-historical El Niño contributed to a quasi-stationary trough over the western U.S. that induced the high precipitation event, an interference between the MJO and El Niño teleconnections resulted in a relatively weak atmospheric signature of the El Niño in comparison to that of the MJO. The influence of anthropogenic climate change on the relationship between ENSO and precipitation across several central U.S. states was also investigated using 17 CMIP5 models from the historical single-forcing experiments. A regime change in ENSO-related precipitation anomalies appears to have occurred, from being negatively correlated before 1950 to positive and significantly correlated after 1970, suggesting a likely effect of anthropogenic warming on the December 2015 extreme precipitation event.

The Great Salt Lake entered the zeitgeist of environmental concern in 2022 when a coalition of scientists and activists warned in a highly publicized report that the lake might be just five years away from complete desiccation, a possibility one state official warned was tantamount to an “environmental nuclear bomb”. Shortly thereafter, an unpredicted and unprecedented pluvial winter resulted in an increase in inflow, temporarily halting the lake’s decline and prompting Utah’s governor to mock the dire prediction as “a joke”, an outcome that speaks to the tension between agenda-setting and trust-building that researchers face when sharing worst-case warnings, particularly those based on short-term variability. Here, we describe a robust relationship between the lake and groundwater in the surrounding region and demonstrate how coupled models can thus be used to improve lake elevation predictions, suggesting that while the situation may not be as dire as some have warned, the lake remains at long-term risk as a result of climate warming. We further suggest that efforts to communicate the risk of future desiccation should be informed by stochastic variability and guided by long-term fluctuations in the total water storage of the endorheic lake’s watershed.

Precisely regulated signal transduction pathways are crucial for the regulation of developmental events and prevention of tumorigenesis. Both the Transforming Growth Factor beta (TGFbeta)/Bone morphogenetic protein (BMP) and Wnt/Wingless (Wg) pathways play essential roles in organismal patterning and growth, and their deregulation can lead to cancers. We describe a mechanism of interaction between Drosophila Wg and BMP signaling in which Wg target gene expression is antagonized by BMP signaling. In vivo, high levels of both an activated BMP receptor and the BMP effector Mad can inhibit the expression of Wg target genes. Conversely, loss of mad can induce Wg target gene expression. In addition, we find that ectopic expression in vivo of the Wg transcription factor dTcf is able to suppress the inhibitory effect caused by ectopic Mad. In vitro binding studies revealed competition for dTcf binding between Mad and the Wnt effector beta-catenin/Armadillo (Arm). Our in vivo genetic analyses and target gene studies support a mechanism consistent with the in vitro binding and competition studies, namely that BMP pathway components can repress Wg target gene expression by influencing the binding of Arm and dTcf.

Abstract Assuming ALPs couple to gluons only, they can be produced via the pp → aj process and decay into two jets at the LHC. When the coupling parameter, C G ~ $$ {C}_{\overset{\sim }{G}} $$ /f a , is small, the lifetime of ALPs can be long enough leading to displaced final state jets. In this paper, we consider the signal including both the prompt and long-lived cases of ALPs by employing a specialized Delphes module to handle displaced jets. Relevant background processes are generated and simulated at the detector level, and multivariate analyses based on machine-learning are performed to discriminate signal and background events and achieve the best sensitivities. Based on the data accumulated for this study, we forecast the expected upper limits on C G ~ $$ {C}_{\overset{\sim }{G}} $$ /f a for ALP mass m a in the range 5–2300 GeV at 2-, 3- and 5-σ significances at the High Luminosity-LHC with 14 TeV center-of-mass energy and 3 ab−1 integrated luminosity. Vast previously unprobed regions in the parameter space spanned by C G ~ $$ {C}_{\overset{\sim }{G}} $$ /f a and m a are probed and the best upper limits on C G ~ $$ {C}_{\overset{\sim }{G}} $$ /f a at 2-σ significance are found to be around 1.0 × 10−2 TeV−1 for m a ∼ 500 GeV. The ALP mass is reconstructed from the kinematics of final state jets and we find that it is measurable with this method when m a is below about 1 TeV at the HL-LHC. The effects of systematic uncertainties and validation of the EFT framework are also checked and discussed.