Combined targeting of CDK4/6 and ER is now the standard of care for patients with advanced ER+/HER2- breast cancer. However, acquired resistance to these therapies frequently leads to disease ...progression. As such, it is critical to identify the mechanisms by which resistance to CDK4/6-based therapies is acquired and also identify therapeutic strategies to overcome resistance.
In this study, we developed and characterized multiple in vitro and in vivo models of acquired resistance to CDK4/6-based therapies. Resistant models were screened by reverse phase protein array (RPPA) for cell signaling changes that are activated in resistance.
We show that either a direct loss of Rb or loss of dependence on Rb signaling confers cross-resistance to inhibitors of CDK4/6, while PI3K/mTOR signaling remains activated. Treatment with the p110α-selective PI3K inhibitor, alpelisib (BYL719), completely blocked the progression of acquired CDK4/6 inhibitor-resistant xenografts in the absence of continued CDK4/6 inhibitor treatment in models of both PIK3CA mutant and wild-type ER+/HER2- breast cancer. Triple combination therapy against PI3K:CDK4/6:ER prevented and/or delayed the onset of resistance in treatment-naive ER+/HER2- breast cancer models.
These data support the clinical investigation of p110α-selective inhibitors of PI3K, such as alpelisib, in patients with ER+/HER2- breast cancer who have progressed on CDK4/6:ER-based therapies. Our data also support the investigation of PI3K:CDK4/6:ER triple combination therapy to prevent the onset of resistance to the combination of endocrine therapy plus CDK4/6 inhibition.
The combination of economic and social costs associated with non-communicable diseases provide a compelling argument for developing strategies that can influence modifiable risk factors, such as ...discrete food choices. Models of behaviour, such as the Theory of Planned Behaviour (TPB) provide conceptual order that allows program designers and policy makers to identify the substantive elements that drive behaviour and design effective interventions. The primary aim of the current review was to examine the association between TPB variables and discrete food choice behaviours. A systematic literature search was conducted to identify relevant studies. Calculation of the pooled mean effect size (r(+)) was conducted using inverse-variance weighted, random effects meta-analysis. Heterogeneity across studies was assessed using the Q- and I(2)-statistics. Meta-regression was used to test the impact of moderator variables: type of food choice behaviour; participants' age and gender. A total of 42 journal articles and four unpublished dissertations met the inclusion criteria. TPB variables were found to have medium to large associations with both intention and behaviour. Attitudes had the strongest association with intention (r(+) = 0.54) followed by perceived behavioural control (PBC, r(+) = 0.42) and subjective norm (SN, r(+) = 0.37). The association between intention and behaviour was r(+) = 0.45 and between PBC and behaviour was r(+) = 0.27. Moderator analyses revealed the complex nature of dietary behaviour and the factors that underpin individual food choices. Significantly higher PBC-behaviour associations were found for choosing health compromising compared to health promoting foods. Significantly higher intention-behaviour and PBC-behaviour associations were found for choosing health promoting foods compared to avoiding health compromising foods. Participant characteristics were also found to moderate associations within the model. Higher intention-behaviour associations were found for older, compared to younger age groups. The variability in the association of the TPB with different food choice behaviours uncovered by the moderator analyses strongly suggest that researchers should carefully consider the nature of the behaviour being exhibited prior to selecting a theory.
The bis-tetrahydroisoquinoline (bis-THIQ) natural products have been studied intensively over the past four decades for their exceptionally potent anticancer activity, in addition to strong ...Gram-positive and Gram-negative antibiotic character. Synthetic strategies toward these complex polycyclic compounds have relied heavily on electrophilic aromatic chemistry, such as the Pictet-Spengler reaction, that mimics their biosynthetic pathways. Herein, we report an approach to two bis-THIQ natural products, jorunnamycin A and jorumycin, that instead harnesses the power of modern transition-metal catalysis for the three major bond-forming events and proceeds with high efficiency (15 and 16 steps, respectively). By breaking from biomimicry, this strategy allows for the preparation of a more diverse set of nonnatural analogs.
Objective: Too much sitting is associated with an increased risk of chronic disease and premature death. This investigation aimed to systematically review the evidence for personality as a correlate ...of time spent in sedentary pursuits. Method: Electronic databases (PubMed; Science Direct; PsycINFO, PsycARTICLES, and SPORTDiscus via EBSCO; Web of Science; MEDLINE via Ovid; Scopus; ProQuest) were searched in December 2015 for studies reporting an association between at least 1 personality trait and time spent in at least 1 sedentary behavior. Pooled mean effect sizes were computed using inverse-variance weighted random effects meta-analysis. Results: Twenty-six studies (28 samples, 110 effect sizes) met inclusion criteria. Higher levels of sedentary behavior were associated with higher levels of neuroticism (r+ = .08, 95% confidence interval CI: .05, .10) and lower levels of conscientiousness (r+ = −.08, 95% CI −.11, −.06). Nonsignificant associations were observed for extraversion (r+ = .00, 95% CI −.07, .06), openness (r+ = −.02, 95% CI −.05, .02), and agreeableness (r+ = −.04, 95% CI −.09, .00). Effects for neuroticism and extraversion were moderated by measurement of sedentary behavior, and effects for openness and agreeableness were moderated by participant age and gender. Conclusions: Findings appear consistent with personality trait associations with other health-related behaviors. More objective measures of sedentary behavior are required to make more definitive conclusions about the contribution of personality to a sedentary lifestyle.
Despite a lack of empirical evidence, many smokers and health professionals believe that tobacco smoking reduces anxiety, which may deter smoking cessation.
The study aim was to assess whether ...successful smoking cessation or relapse to smoking after a quit attempt are associated with changes in anxiety.
A total of 491 smokers attending National Health Service smoking cessation clinics in England were followed up 6 months after enrolment in a trial of pharmacogenetic tailoring of nicotine replacement therapy (ISRCTN14352545).
There was a points difference of 11.8 (95% CI 7.7-16.0) in anxiety score 6 months after cessation between people who relapsed to smoking and people who attained abstinence. This reflected a three-point increase in anxiety from baseline for participants who relapsed and a nine-point decrease for participants who abstained. The increase in anxiety in those who relapsed was largest for those with a current diagnosis of psychiatric disorder and whose main reason for smoking was to cope with stress. The decrease in anxiety on abstinence was larger for these groups also.
People who achieve abstinence experience a marked reduction in anxiety whereas those who fail to quit experience a modest increase in the long term. These data contradict the assumption that smoking is a stress reliever, but suggest that failure of a quit attempt may generate anxiety.
: To gauge the public health impact of new nicotine products, information is needed on use among different populations. Aims were to assess in adults who smoked, vaped, did both or had recently ...stopped: (1) awareness, ever and current use of heated tobacco products (HTPs) and nicotine pouches (NP), (2) characteristics associated with ever use, (3) reasons for use of and satisfaction with HTPs, (4) characteristics associated with interest in use of HTPs.
: Online survey in the UK in 2019,
= 3883. (1) Proportion aware, ever and current (≥monthly) use; (2) ever use regressed onto socio-demographics and smoking/vaping; (3) frequency of reasons for HTP use and satisfaction; (4) interest in trying HTPs regressed onto socio-demographics and smoking/vaping status.
: Awareness was 34.8% for HTP and 15.9% for NP; current use was 3.2% and 2.7%. Being <45 years, higher education, living in London and currently both smoking and vaping were associated with ever having used the products. Curiosity was the most common reason for HTP use (79.8%) and 72.0% of ever HTP users found them at least as satisfying as smoking. Among those not currently using HTPs, 48.5% expressed any interest-lower among those aged over 65 and higher among those smoking and vaping.
: In this sample of adults with a history of nicotine use, very few currently used heated tobacco products or nicotine pouches. Satisfaction with and interest in HTPs were substantial. The low level of use is unlikely to substantially reduce the public health impact of smoking.
AIMTo assess if radiomic feature analysis could help to differentiate between the lipid-poor adenomas and metastases to the adrenal glands. MATERIALS AND METHODSEighty-six patients (women:men 42:44; ...mean age 66 years) with biopsy-proven adrenal metastases and 55 patients (women:men 39:16; mean age 67 years) with lipid-poor adenomas who underwent contrast-enhanced, portal-venous phase CT of the abdomen. Radiomic features were extracted using the PyRadiomics extension for 3D Slicer. Following elastic net regularisation, seven of 1,132 extracted radiomic features were selected to build a radiomic signature. This was combined with patient demographics to create a predictive nomogram. The calibration curves in both the training and validation cohorts were assessed using a Hosmer-Lemeshow test. RESULTSThe radiomic signature alone yielded an area under the curve of 91.7% in the training cohort (n=93) and 87.1% in the validation cohort (n=48). The predictive nomogram, which combined age, a previous history of malignancy, and the radiomic signature, had an AUC of 97.2% in the training cohort and 90.4% in the validation cohort. CONCLUSIONThe present nomogram has the potential to differentiate between a lipid-poor adrenal adenoma and adrenal metastasis on portal-venous CT.
Background and aims
Evidence on the effectiveness of electronic cigarettes (ECs) to facilitate abstinence from smoking is limited. The current study aimed to estimate the relative effectiveness of ...ECs and smoking cessation medication compared with using no help, accounting for frequency of use of ECs.
Design
Four consecutive wave‐to‐wave transitions (waves 1–2, 2–3, 3–4 or 4–5) of a longitudinal online survey collected between 2012 and 2017 were analysed. Time between waves ranged between 12 and 17 months. Cigarette smokers at the baseline wave who attempted to quit smoking between waves were included.
Setting
United Kingdom
Participants
A total of 1155 respondents (aged 18–81, 56.1% male, 64.6% in social grade C2DE, 93.8% white) provided 1580 pairs of observations for the primary analysis.
Measurements
Primary outcome: abstinence from smoking for at least 1 month at follow‐up; secondary outcome: at least 1 month's abstinence from smoking between baseline and follow‐up. The main predictor was stop smoking aid used (No help, nicotine replacement therapy only, smoking cessation medication only, disposable/cartridge EC, refill/modular EC, combination), adjusted for demographics.
Findings
Primary Compared with using no help, the odds of abstinence were increased by daily use of disposable/cartridge ECs (OR = 3.31 (1.32, 8.26), P = .010) and daily use of refill/modular ECs (OR = 5.47 (2.70, 11.11), P < .001). Odds were reduced by non‐daily use of disposable/cartridge ECs (OR = 0.23 (0.08–0.63), P = .005), and by use of disposable/cartridge ECs to quit and no longer using at follow‐up (OR = 0.10 (0.16–0.62), P < .013). Secondary Results were similar to the primary outcome; however, odds of abstinence were also increased by use of smoking cessation medication (OR = 4.15 (1.79, 9.62), P = .001).
Conclusions
When used daily, electronic cigarettes appear to facilitate abstinence from smoking when compared with using no help.
Aims
To assess the association between doctors' smoking status and the use of the ‘5As’ of smoking cessation.
Methods
A systematic search of 11 databases covering English and Spanish language ...publications since 1996 was undertaken. Studies were included if they reported doctors' smoking status (current, former or never smoker) and rates of practising any of the 5As of smoking cessation (Ask; Advise; Assess; Assist; and Arrange). Frequencies and proportions were extracted from individual papers and risk ratios (RR) were calculated. A random‐effects meta‐analysis model was used to assess the effect of the doctor's personal smoking history. Covariate effects were explored using meta‐regression for three pre‐specified study characteristics: doctors' role, smoking prevalence of the sample and study quality.
Results
Twenty studies were included in this systematic review. The RR of always asking patients about their smoking was not associated significantly with doctors' smoking status RR = 0.98; 95% confidence interval (CI) = 0.94–1.02; P = 0.378; I2 = 0.00%; 10 studies. Meta‐analysis suggested that doctors who were current smokers had a 17% increased risk of not advising their patients to quit compared with never‐smokers (RR = 0.83; 95% CI = 0.77–0.90; P < 0.000; I2 = 82.14%; 14 studies). However, high levels of heterogeneity were found that were not explained by the meta‐regression. Regarding assisting patients to quit, never smokers were more likely to counsel than current smokers (RR = 0.92; 95% CI = 0.85–0.99; P = 0.036; I2 = 0.00%; three studies) but less likely to make a referral (RR = 1.40; 95% CI = 1.09–1.79; P = 0.009; I2 = 0.00%; five studies). No statistically significant differences were found in arranging future contact by smoking status (RR = 0.80; 95% CI = 0.52–1.23; P = 0.315; I2 = 47.03%; four studies).
Conclusions
Smoking status of doctors may affect their delivery of smoking cessation treatments to patients, with smokers being less likely than non‐smokers or ex‐smokers to advise and counsel their patients to quit but more likely to refer them to smoking cessation programmes.
The English network of stop-smoking services (SSSs) is among the best-value life-preserving clinical intervention in the UK NHS and is internationally renowned. However, success varies considerably ...across services, making it important to examine the factors that influence their effectiveness.
Data from 126,890 treatment episodes in 24 SSSs in 2009-10 were used to assess the association between intervention characteristics and success rates, adjusting for key smoker characteristics. Treatment characteristics examined were setting (eg, primary care, specialist clinics, pharmacy), type of support (eg, group, one-to-one) and medication (eg, varenicline, single nicotine replacement therapy (NRT), combination of two or more forms of NRT). The main outcome measure was abstinence from smoking 4 weeks after the target quit date, verified by carbon monoxide concentration in expired air.
There was substantial variation in success rates across intervention characteristics after adjusting for smoker characteristics. Single NRT was associated with higher success rates than no medication (OR 1.75, 95% CI 1.39 to 2.22); combination NRT and varenicline were more successful than single NRT (OR 1.42, 95% CI 1.06 to 1.91 and OR 1.78, 95% CI 1.57 to 2.02, respectively); group support was linked to higher success rates than one-to-one support (OR 1.43, 95% CI 1.16 to 1.76); primary care settings were less successful than specialist clinics (OR 0.80, 95% CI 0.66 to 0.99).
Routine clinic data support findings from randomised controlled trials that smokers receiving stop-smoking support from specialist clinics, treatment in groups and varenicline or combination NRT are more likely to succeed than those receiving treatment in primary care, one-to-one and single NRT. All smokers should have access to, and be encouraged to use, the most effective intervention options.
PDF
