Targeted PI3K/AKT/mTOR therapy for metastatic carcinomas of the cervix: A phase I clinical experience.

BackgroundActivated PI3K/AKT/mTOR pathway frequently occurs in metastatic or recurrent cervical carcinomas. However, the clinical benefits of matched therapy, a therapeutic approach targeting a specific mutational abnormality, have not yet been established.MethodsWe analyzed the outcomes of patients with metastatic or recurrent cervical carcinomas who had a test for PIK3CA mutation and/or PTEN loss/mutation, and received ≥1 phase I therapeutic regimen between January 2006 and June 2013.ResultsPatients with adenocarcinoma had fewer PIK3CA mutations (14%), and survived longer (median, 14.2 months) than those with squamous cell carcinoma (48% and 7.2 months; p = 0.016, and 0.001, respectively). Matched therapy targeting the activated PI3K/AKT/mTOR pathway led to a favorable rate of SD ≥ 6 months/CR/PR (53%) and significantly longer progression-free survival (median, 6.0 months) than non-matched therapy (11% and 1.5 months; p = 0.08 and 0.026; respectively). In patients with squamous cell carcinoma of the cervix, the presence of PIK3CA mutations was associated with a significantly longer overall survival (median, 9.4 months) than the absence of PIK3CA mutations (median, 4.2 months; p = 0.019).ConclusionsMatched therapy targeting the activated PI3K/AKT/mTOR pathway provided meaningful clinical benefits. Thus, further evaluation of PI3K/AKT/mTOR pathway targeted therapy is warranted, especially in metastatic or recurrent squamous cell carcinoma

Abnormal cognitive aging in people with HIV: evidence from data integration between two countries’ cohort studies

Objectives: Previous research has shown inconsistent results on whether cognitive aging is abnormal in people with HIV (PWH) because of low sample size, cross-sectional design, and nonstandard neuropsychological methods. To address these issues, we integrated data from two longitudinal studies: Australian HIV and Brain Ageing Research Program (N = 102) and CNS HIV Antiretroviral Therapy Effects Research (CHARTER) study (N = 924) and determined the effect of abnormal aging on neurocognitive impairment (NCI) among PWH. Methods: Both studies used the same neuropsychological test battery. NCI was defined based on demographically corrected global deficit score (≥0.5 = impaired). Both studies also assessed comorbidities, neuropsychiatric conditions and functional status using similar tools. To determine the cross-sectional and longitudinal effects of age on the risk of NCI, a generalized linear mixed-effect model tested main and interaction effects of age group (young, <50 vs. old, ≥50) and time on NCI adjusting the effects of covariates. Results: Older PWH had 83% higher chance of NCI compared with younger PWH [odds ratio (OR) = 1.83 (1.15 – 2.90), P < 0.05]. Older participants also had a greater risk of increases in NCI over the follow-up [OR = 1.66 (1.05 – 2.64), P < 0.05] than younger participants. Nonwhite ethnicity (P < 0.05), having a contributing (P < 0.05) or confounding (P < 0.001) comorbidity, greater cognitive symptoms (P < 0.001), and abnormal creatinine level (P < 0.05), plasma viral load greater than 200 copies/ml (P < 0.05), being from the Australian cohort (P < 0.05) were also associated with a higher risk of NCI. Conclusion: Data integration may serve as a strategy to increase sample size and study power to better assess abnormal cognitive aging effect in PWH, which was significant in the current study

Non-equilibrium thermodynamics. IV: Generalization of Maxwell, Claussius-Clapeyron and Response Functions Relations, and the Prigogine-Defay Ratio for Systems in Internal Equilibrium

We follow the consequences of internal equilibrium in non-equilibrium systems that has been introduced recently [Phys. Rev. E 81, 051130 (2010)] to obtain the generalization of Maxwell's relation and the Clausius-Clapeyron relation that are normally given for equilibrium systems. The use of Jacobians allow for a more compact way to address the generalized Maxwell relations; the latter are available for any number of internal variables. The Clausius-Clapeyron relation in the subspace of observables show not only the non-equilibrium modification but also the modification due to internal variables that play a dominant role in glasses. Real systems do not directly turn into glasses (GL) that are frozen structures from the supercooled liquid state L; there is an intermediate state (gL) where the internal variables are not frozen. Thus, there is no single glass transition. A system possess several kinds of glass transitions, some conventional (L \rightarrow gL; gL\rightarrow GL) in which the state change continuously and the transition mimics a continuous or second order transition, and some apparent (L\rightarrow gL; L\rightarrow GL) in which the free energies are discontinuous so that the transition appears as a zeroth order transition, as discussed in the text. We evaluate the Prigogine-Defay ratio {\Pi} in the subspace of the observables at these transitions. We find that it is normally different from 1, except at the conventional transition L\rightarrow gL, where {\Pi}=1 regardless of the number of internal variables.Comment: 42 pages, 3 figures, citations correcte

Low incidence of advanced neurological burden but high incidence of age-related conditions that are dementia risk factors in aging people living with HIV: a data-linkage 10-year follow-up study

Although increasing research is focusing on age-related comorbidities (ARC) among people living with HIV (PLHIV), no studies have concomitantly assessed non-HIV age-related neurological disorders (e.g., Alzheimer’s dementia). A total of 254 PLHIV and 69 HIV-negative controls completed baseline medical history and cognitive testing. ARC data were collected from medical records over the subsequent 9-10 years and included all types of strokes, all types of dementia, mild cognitive impairment, Parkinson's disease, motor neuron disease (grouped into a non-HIV age-related neurological category), cardiovascular disease, chronic kidney disease, chronic liver disease, chronic lung disease, non-AIDS cancers, osteoporosis, and diabetes. Kaplan–Meier curves assessed differences in the incident rates (per 1000 person year) of groups of ARC as defined above and combined ARC (i.e., development of any of the ARC) among younger (baseline age < 50) and older (baseline age ≥ 50) PLHIV and younger and older controls. Cox-proportional hazard models assessed the individual and interaction effects of HIV status and chronological age, in addition to a range of demographic and clinical variables including historical and baseline HIV brain involvement on the risk of developing combined ARC. Older PLHIV had a higher incidence of cardiovascular disease, osteoporosis, and combined ARC compared to other groups (p < 0.05). Incident rate of non-HIV age-related neurological disorders was 2.3 [0.93, 4.79] per 1000 person year. While this incident rate was higher in older PLHIV (5.37 [1.97, 11.92]) than older HIV-negative participants (3.58 [0.18-17.67]), this was not significant. In multivariate analyses, HIV status and chronological age, but not their interaction, and smoking were associated with higher risk of combined ARC (p < 0.05). In analyses focusing on PLHIV, older age and taking abacavir/efavirenz/atazanavir/darunavir containing antiretroviral treatments at the time of diagnosis were associated with greater ARC (p < 0.05). Non-HIV age-related neurological disorders are uncommon in older PLHIV, where the majority were < 70 years of age at the end of follow-up. However, the greater burden of ARC among older PLHIV, most of which are established dementia risk factors, warrants the establishment of commensurate prevention strategies and greater attention to neurocognitive screening

Clusters Have Edges: The Projected Phase SpaceStructure of SDSS redMaPPer Clusters

We study the distribution of line-of-sight velocities of galaxies in the vicinity of SDSS redMaPPer galaxy clusters. Based on their velocities, galaxies can be split into two categories: galaxies that are dynamically associated with the cluster, and random line-of-sight projections. Both the fraction of galaxies associated with the galaxy clusters, and the velocity dispersion of the same, exhibit a sharp feature as a function of radius. The feature occurs at a radial scale $R_{\rm edge} \approx 2.2R_{\rm{\lambda}}$, where $R_{\rm{\lambda}}$ is the cluster radius assigned by redMaPPer. We refer to $R_{\rm edge}$ as the "edge radius." These results are naturally explained by a model that further splits the galaxies dynamically associated with a galaxy cluster into a component of galaxies orbiting the halo and an infalling galaxy component. The edge radius $R_{\rm edge}$ constitutes a true "cluster edge", in the sense that no orbiting structures exist past this radius. A companion paper (Aung et al. 2020) tests whether the "halo edge" hypothesis holds when investigating the full three-dimensional phase space distribution of dark matter substructures in numerical simulations, and demonstrates that this radius coincides with a suitably defined splashback radius.Comment: 10 pages, 5 figures, submitted to MNRAS, companion paper to Aung et al. 202

Meaningful cognitive decline is uncommon in virally suppressed HIV, but sustained impairment, subtle decline and abnormal cognitive aging are not

Background: High antiretroviral therapy (ART) coverage and viral suppression among people with HIV (PWH) in Australia provide a unique context to study individual cognitive trajectories, cognitive aging and factors associated with longitudinal cognitive function during chronic and stable HIV disease. Methods: Participants from the Predictors of Adherence to Antiretroviral Therapy study (n = 457, recruited between September 2013 and November 2015, median age = 52 years, and all with HIV RNA 0.5). Meaningful cognitive change was statistically defined (decline or improvement versus stability, i.e., 90% CI, that is p < 0.05, 2-tailed) using a novel evidence-based change score: the linear mixed-effect regression (LMER)-based GZS change score. A separate LMER model with a top-down variable selection approach identified the independent effects of age and other demographic, HIV disease characteristics, socioeconomic and health-related factors on the demographically corrected GZS. The combined definitions of change and cross-sectional impairment enabled the identification of cognitive trajectories. Findings: At Month-12 and Month-24, 6% and 7% showed meaningful cognitive decline and 4% and 3% improved respectively. Only 1% showed sustained decline. Incident impairment due to subtle cognitive decline (i.e., below the threshold of meaningful cognitive decline) was 31% and 25% at Month-12 and Month-24, while 14% showed sustained impairment (i.e., cognitively impaired at all study visits). Older age (≥50 years) and time interaction was associated with lower demographically corrected GZS (β = −0.31, p < 0.001). Having a regular relationship, excellent English proficiency, and perceived stigma (avoidance) were associated with higher GZS (all p < 0.05). Relying on government subsidy, severe depression, and lower belief in ART necessity and higher concerns were associated with lower GZS (all p < 0.05). No HIV disease characteristics had a significant effect. Interpretations: Meaningful cognitive decline was not different from normal expectation in chronic stable HIV disease. Despite this, subtle cognitive decline, sustained cognitive impairment, and greater than normative-age cognitive aging were evident. Funding: Funding for the PAART study was provided in part by unrestricted educational grants from Gilead Sciences (www.gilead.com) (Grant Number: IN-AU-264- 0131), the Balnaves Foundation (www.balnavesfoundation.com), the Victorian Department of Health and Human Services (Australia) (www.dhs.vic.gov.au/home), Western Australia Health (www.health.wa.gov.au), the ACT Ministry of Health (Australia) (www.health.act.gov.au), and in-kind support from the Queensland Department of Health (Australia) (www.health.qld.gov.au), and NHMRC Partnership grant APP1058474 (PI: Carr, Andrew)

Hydrophobic Coupling of Lipid Bilayer Energetics to Channel Function

The hydrophobic coupling between membrane-spanning proteins and the lipid bilayer core causes the bilayer thickness to vary locally as proteins and other “defects” are embedded in the bilayer. These bilayer deformations incur an energetic cost that, in principle, could couple membrane proteins to each other, causing them to associate in the plane of the membrane and thereby coupling them functionally. We demonstrate the existence of such bilayer-mediated coupling at the single-molecule level using single-barreled as well as double-barreled gramicidin channels in which two gramicidin subunits are covalently linked by a water-soluble, flexible linker. When a covalently attached pair of gramicidin subunits associates with a second attached pair to form a double-barreled channel, the lifetime of both channels in the assembly increases from hundreds of milliseconds to a hundred seconds—and the conductance of each channel in the side-by-side pair is almost 10% higher than the conductance of the corresponding single-barreled channels. The double-barreled channels are stabilized some 100,000-fold relative to their single-barreled counterparts. This stabilization arises from: first, the local increase in monomer concentration around a single-barreled channel formed by two covalently linked gramicidins, which increases the rate of double-barreled channel formation; and second, from the increased lifetime of the double-barreled channels. The latter result suggests that the two barrels of the construct associate laterally. The underlying cause for this lateral association most likely is the bilayer deformation energy associated with channel formation. More generally, the results suggest that the mechanical properties of the host bilayer may cause the kinetics of membrane protein conformational transitions to depend on the conformational states of the neighboring proteins

PIK3CA mutations in advanced cancers: characteristics and outcomes.

PIK3CA mutations are frequently diagnosed in diverse cancers and may predict response to PI3K/AKT/mTOR inhibitors. It remains unclear whether they are associated with other characteristics. We analyzed characteristics and outcome of 90 consecutive patients with diverse advanced tumors and PIK3CA mutations and 180 wild-type PIK3CA controls matched by tumor type, gender, and age referred to the Clinical Center for Targeted Therapy. PIK3CA and MAPK mutations (KRAS, NRAS, and BRAF) were analyzed using polymerase chain reaction-based DNA sequencing. The most frequent PIK3CA mutations were E545K (31/90, 34%), E542K (16/90, 18%) in exon 9, and H1047R (20/90, 22%) in exon 20. PIK3CA mutations compared to wild-type PIK3CA were associated with simultaneous KRAS (p=0.047) and MAPK mutations (p=0.03), but only MAPK mutations were confirmed as having an independent association in multivariate analysis. Rates of lung, bone, liver and brain metastases were similar in PIK3CA-mutant and wild-type patients. Patients with PIK3CA mutations treated on trials with PI3K/AKT/mTOR inhibitors had a higher partial/complete response (PR/CR) rate than wild-type PIK3CA patients treated with their best phase I therapy (10/56, 18% vs. 12/152, 8%; p=0.045), but not a prolonged progression-free survival. Patients with H1047R PIK3CA mutations had higher PR/CR rate with PI3K/AKT/mTOR inhibitors compared to wild-type PIK3CA patients treated with their best phase I therapy (6/16, 38% vs. 12/152, 8%; p=0.003). In conclusion, PIK3CA mutations in diverse cancers were not associated with clinical characteristics, but were correlated with MAPK mutations. PIK3CA mutations, especially, H1047R, were associated with attaining a PR/CR to PI3K/AKT/mTOR pathway inhibitors