Neoadjuvant pazopanib and molecular analysis of tissue response in renal cell carcinoma

BACKGROUND. Surgery remains the frontline therapy for patients with localized clear cell renal cell carcinoma (ccRCC); however, 20%–40% recur. Angiogenesis inhibitors have improved survival in metastatic patients and may result in responses in the neoadjuvant setting. The impact of these agents on the tumor genetic heterogeneity or the immune milieu is largely unknown. This phase II study was designed to evaluate safety, response, and effect on tumor tissue of neoadjuvant pazopanib. METHODS. ccRCC patients with localized disease received pazopanib (800 mg daily; median 8 weeks), followed by nephrectomy. Five tumors were examined for mutations by whole exome sequencing from samples collected before therapy and at nephrectomy. These samples underwent RNA sequencing; 17 samples were available for posttreatment assessment. RESULTS. Twenty-one patients were enrolled. The overall response rate was 8 of 21 (38%). No patients with progressive disease. At 1-year, response-free survival and overall survival was 83% and 89%, respectively. The most frequent grade 3 toxicity was hypertension (33%, 7 of 21). Sequencing revealed strong concordance between pre- and posttreatment samples within individual tumors, suggesting tumors harbor stable core profiles. However, a reduction in private mutations followed treatment, suggesting a selective process favoring enrichment of driver mutations. CONCLUSION. Neoadjuvant pazopanib is safe and active in ccRCC. Future genomic analyses may enable the segregation of driver and passenger mutations. Furthermore, tumor infiltrating immune cells persist during therapy, suggesting that pazopanib can be combined with immune checkpoint inhibitors without dampening the immune response. FUNDING. Support was provided by Novartis and GlaxoSmithKline as part of an investigator-initiated study

Declining Lung Function and Cardiovascular Risk: The ARIC Study

Background: Pulmonary dysfunction predicts incident cardiovascular disease (CVD). Objectives: The purpose of this study was to evaluate whether longitudinal decline in lung function is associated with incident heart failure (HF), coronary heart disease (CHD), and stroke. Methods: Among 10,351 participants in the ARIC (Atherosclerosis Risk In Communities) study free of CVD, rapid lung function decline was defined as the greatest quartile (n = 2,585) of decline in either forced expiratory volume in 1 s (FEV1) (>1.9% decline/year) or forced vital capacity (FVC) (>2.1% decline/year) over 2.9 ± 0.2 years. The relationship between rapid decline in FEV1 or FVC and subsequent incident HF, CHD, stroke, or a composite of these was assessed using multivariable Cox regression adjusting for the baseline spirometry value, demographics, height, body mass index, heart rate, diabetes, hypertension, low-density lipoprotein, use of lipid-lowering medication, N-terminal fragment of prohormone for B-type natriuretic peptide, and smoking. Results: The mean age was 54 ± 6 years, 56% were women, and 81% were white. At 17 ± 6 years of follow-up, HF occurred in 14%, CHD 11%, stroke 6%, and the composite in 24%. Rapid decline in FEV1 and in FVC were both associated with a heightened risk of incident HF (hazard ratio [HR]: 1.17; 95% confidence interval [CI]: 1.04 to 1.33; p = 0.010; and HR: 1.27; 95% CI: 1.12 to 1.44; p < 0.001; respectively), with rapid decline in FEV1 most prognostic in the first year of follow-up (HR: 4.22; 95% CI: 1.34 to 13.26; p = 0.01). Rapid decline in FEV1 was also associated with incident stroke (HR: 1.25; 95% CI: 1.04 to 1.50; p = 0.015). Conclusions: A rapid decline in lung function, assessed by serial spirometry, is associated with a higher incidence of subsequent CVD, particularly incident HF

Identifying potential causal effects of age at menarche: A Mendelian randomization phenome-wide association study

Background: Age at menarche has been associated with various health outcomes. We aimed to identify potential causal effects of age at menarche on health-related traits in a hypothesis-free manner. Methods: We conducted a Mendelian randomization phenome-wide association study (MR-pheWAS) of age at menarche with 17,893 health-related traits in UK Biobank (n = 181,318) using PHESANT. The exposure of interest was the genetic risk score for age at menarche. We conducted a second MR-pheWAS after excluding SNPs associated with BMI from the genetic risk score, to examine whether results might be due to the genetic overlap between age at menarche and BMI. We followed up a subset of health-related traits to investigate MR assumptions and seek replication in independent study populations. Results: Of the 17,893 tests performed in our MR-pheWAS, we identified 619 associations with the genetic risk score for age at menarche at a 5% false discovery rate threshold, of which 295 were below a Bonferroni-corrected P value threshold. These included potential effects of younger age at menarche on lower lung function, higher heel bone-mineral density, greater burden of psychosocial/mental health problems, younger age at first birth, higher risk of childhood sexual abuse, poorer cardiometabolic health, and lower physical activity. After exclusion of variants associated with BMI, the genetic risk score for age at menarche was related to 37 traits at a 5% false discovery rate, of which 29 were below a Bonferroni-corrected P value threshold. We attempted to replicate findings for bone-mineral density, lung function, neuroticism, and childhood sexual abuse using 5 independent cohorts/consortia. While estimates for lung function, higher bone-mineral density, neuroticism, and childhood sexual abuse in replication cohorts were consistent with UK Biobank estimates, confidence intervals were wide and often included the null. Conclusions: The genetic risk score for age at menarche was related to a broad range of health-related traits. Follow-up analyses indicated imprecise evidence of an effect of younger age at menarche on greater bone-mineral density, lower lung function, higher neuroticism score, and greater risk of childhood sexual abuse in the smaller replication samples available; hence, these findings need further exploration when larger independent samples become available

Charmless B→PPB \to PP decays using flavor SU(3) symmetry

The decays of $B$ mesons to a pair of charmless pseudoscalar ($P$) mesons are analyzed within a framework of flavor SU(3). Symmetry breaking is taken into account in tree ($T$) amplitudes through ratios of decay constants; exact SU(3) is assumed elsewhere. Acceptable fits to $B \to \pi \pi$ and $B \to K \pi$ branching ratios and CP asymmetries are obtained with tree, color-suppressed ($C$), penguin ($P$), and electroweak penguin ($P_{EW}$) amplitudes. Crucial additional terms for describing processes involving $\eta$ and $\eta'$ include a large flavor-singlet penguin amplitude ($S$) as proposed earlier and a penguin amplitude $P_{tu}$ associated with intermediate $t$ and $u$ quarks. For the $B^+ \to \pi^+ \eta'$ mode a term $S_{tu}$ associated with intermediate $t$ and $u$ quarks also may be needed. Values of the weak phase $\gamma$ are obtained consistent with an earlier analysis of $B \to VP$ decays, where $V$ denotes a vector meson, and with other analyses of CKM parameters.Comment: 26 pages, 1 figure. To be submitted to Phys. Rev. D. Reference update

Local and Global Casimir Energies: Divergences, Renormalization, and the Coupling to Gravity

From the beginning of the subject, calculations of quantum vacuum energies or Casimir energies have been plagued with two types of divergences: The total energy, which may be thought of as some sort of regularization of the zero-point energy, $\sum\frac12\hbar\omega$, seems manifestly divergent. And local energy densities, obtained from the vacuum expectation value of the energy-momentum tensor, $\langle T_{00}\rangle$, typically diverge near boundaries. The energy of interaction between distinct rigid bodies of whatever type is finite, corresponding to observable forces and torques between the bodies, which can be unambiguously calculated. The self-energy of a body is less well-defined, and suffers divergences which may or may not be removable. Some examples where a unique total self-stress may be evaluated include the perfectly conducting spherical shell first considered by Boyer, a perfectly conducting cylindrical shell, and dilute dielectric balls and cylinders. In these cases the finite part is unique, yet there are divergent contributions which may be subsumed in some sort of renormalization of physical parameters. The divergences that occur in the local energy-momentum tensor near surfaces are distinct from the divergences in the total energy, which are often associated with energy located exactly on the surfaces. However, the local energy-momentum tensor couples to gravity, so what is the significance of infinite quantities here? For the classic situation of parallel plates there are indications that the divergences in the local energy density are consistent with divergences in Einstein's equations; correspondingly, it has been shown that divergences in the total Casimir energy serve to precisely renormalize the masses of the plates, in accordance with the equivalence principle.Comment: 53 pages, 1 figure, invited review paper to Lecture Notes in Physics volume in Casimir physics edited by Diego Dalvit, Peter Milonni, David Roberts, and Felipe da Ros

The use of sewage treatment works as foraging sites by insectivorous bats

Sewage treatment works with percolating filter beds are known to provide profitable foraging areas for insectivorous birds due to their association with high macroinvertebrate densities. Fly larvae developing on filter beds at sewage treatment works may similarly provide a valuable resource for foraging bats. Over the last two decades, however, there has been a decline in filter beds towards a system of “activated sludge”. Insects and bat activity were surveyed at 30 sites in Scotland employing these two different types of sewage treatment in order to assess the possible implications of these changes for foraging bats. Bat activity (number of passes) recorded from broad-band bat detectors was quantified at three points within each site. The biomass of aerial insects, sampled over the same period as the detector surveys, was measured using a suction trap. The biomass of insects and activity of Pipistrellus spp. was significantly higher at filter beds than at activated sludge sites. In addition, whilst foraging activity of Pipistrellus spp. at filter beds was comparable to that of adjacent “good” foraging habitat, foraging at activated sludge sites was considerably lower. This study indicates the high potential value of an anthropogenic process to foraging bats, particularly in a landscape where their insect prey has undergone a marked decline, and suggests that the current preference for activated sludge systems is likely to reduce the value of treatment works as foraging sites for bats

‘Perceptions of non-accidental child deaths as preventable events: The impact of probability heuristics and biases on child protection work'

Anxiety about the possibility of non-accidental deaths of children has had a major influence on child care policy and practice over the last 40 years. The formal inquiry reports and media coverage of these rare events serve to maintain the perception that these are regular incidents that happen far too often and that they could have been prevented. This focus on individual events tends to distort a clear view of the actual probability of non-accidental deaths and serves to reinforce the notion that potentially all child care cases are risky and that any social work practitioner could be involved in such a case. As a result, work with children has become highly risk averse. However, in statistical terms, the probability of non-accidental child deaths is very low and recently has averaged about 55 deaths a year. Children are at considerably higher risk of being killed on the roads. This paper examines the way in which perceptions of the ‘high’ level of risk of possible child deaths are maintained despite the very low statistical probability of such incidents. It draws on thinking from behavioural psychology and, in particular the work of Kahneman and Tversky, to consider some of the biases in probability reasoning affecting people’s perception of risk and explores how inquiry reports into single past events reconfirm risk perceptions. It is suggested that recognition of the essentially unpredictable nature of future non-accidental child deaths would free up childcare professionals to work in a more positive and less risk-averse manner in the present

‘Perceptions of non-accidental child deaths as preventable events: The impact of probability heuristics and biases on child protection work'

Anxiety about the possibility of non-accidental deaths of children has had a major influence on child care policy and practice over the last 40 years. The formal inquiry reports and media coverage of these rare events serve to maintain the perception that these are regular incidents that happen far too often and that they could have been prevented. This focus on individual events tends to distort a clear view of the actual probability of non-accidental deaths and serves to reinforce the notion that potentially all child care cases are risky and that any social work practitioner could be involved in such a case. As a result, work with children has become highly risk averse. However, in statistical terms, the probability of non-accidental child deaths is very low and recently has averaged about 55 deaths a year. Children are at considerably higher risk of being killed on the roads. This paper examines the way in which perceptions of the ‘high’ level of risk of possible child deaths are maintained despite the very low statistical probability of such incidents. It draws on thinking from behavioural psychology and, in particular the work of Kahneman and Tversky, to consider some of the biases in probability reasoning affecting people’s perception of risk and explores how inquiry reports into single past events reconfirm risk perceptions. It is suggested that recognition of the essentially unpredictable nature of future non-accidental child deaths would free up childcare professionals to work in a more positive and less risk-averse manner in the present

Measurement of the B0-anti-B0-Oscillation Frequency with Inclusive Dilepton Events

The $B^0$-$\bar B^0$ oscillation frequency has been measured with a sample of 23 million \B\bar B pairs collected with the BABAR detector at the PEP-II asymmetric B Factory at SLAC. In this sample, we select events in which both B mesons decay semileptonically and use the charge of the leptons to identify the flavor of each B meson. A simultaneous fit to the decay time difference distributions for opposite- and same-sign dilepton events gives $\Delta m_d = 0.493 \pm 0.012{(stat)}\pm 0.009{(syst)}$ ps$^{-1}$.Comment: 7 pages, 1 figure, submitted to Physical Review Letter

Lung function impairment and risk of incident heart failure: the NHLBI Pooled Cohorts Study

Aims: The aim is to evaluate associations of lung function impairment with risk of incident heart failure (HF). Methods and results: Data were pooled across eight US population-based cohorts that enrolled participants from 1987 to 2004. Participants with self-reported baseline cardiovascular disease were excluded. Spirometry was used to define obstructive [forced expiratory volume in 1 s/forced vital capacity (FEV1/FVC) <0.70] or restrictive (FEV1/FVC ≥0.70, FVC <80%) lung physiology. The incident HF was defined as hospitalization or death caused by HF. In a sub-set, HF events were sub-classified as HF with reduced ejection fraction (HFrEF; EF <50%) or preserved EF (HFpEF; EF ≥50%). The Fine-Gray proportional sub-distribution hazards models were adjusted for sociodemographic factors, smoking, and cardiovascular risk factors. In models of incident HF sub-types, HFrEF, HFpEF, and non-HF mortality were treated as competing risks. Among 31 677 adults, there were 3344 incident HF events over a median follow-up of 21.0 years. Of 2066 classifiable HF events, 1030 were classified as HFrEF and 1036 as HFpEF. Obstructive [adjusted hazard ratio (HR) 1.17, 95% confidence interval (CI) 1.07-1.27] and restrictive physiology (adjusted HR 1.43, 95% CI 1.27-1.62) were associated with incident HF. Obstructive and restrictive ventilatory defects were associated with HFpEF but not HFrEF. The magnitude of the association between restrictive physiology and HFpEF was similar to associations with hypertension, diabetes, and smoking. Conclusion: Lung function impairment was associated with increased risk of incident HF, and particularly incident HFpEF, independent of and to a similar extent as major known cardiovascular risk factors