Dilated cardiomyopathy (DCM) is a final common manifestation of heterogenous etiologies. Adverse outcomes highlight the need for disease stratification beyond ejection fraction.
The purpose of this ...study was to identify novel, reproducible subphenotypes of DCM using multiparametric data for improved patient stratification.
Longitudinal, observational UK-derivation (n = 426; median age 54 years; 67% men) and Dutch-validation (n = 239; median age 56 years; 64% men) cohorts of DCM patients (enrolled 2009-2016) with clinical, genetic, cardiovascular magnetic resonance, and proteomic assessments. Machine learning with profile regression identified novel disease subtypes. Penalized multinomial logistic regression was used for validation. Nested Cox models compared novel groupings to conventional risk measures. Primary composite outcome was cardiovascular death, heart failure, or arrhythmia events (median follow-up 4 years).
In total, 3 novel DCM subtypes were identified: profibrotic metabolic, mild nonfibrotic, and biventricular impairment. Prognosis differed between subtypes in both the derivation (P < 0.0001) and validation cohorts. The novel profibrotic metabolic subtype had more diabetes, universal myocardial fibrosis, preserved right ventricular function, and elevated creatinine. For clinical application, 5 variables were sufficient for classification (left and right ventricular end-systolic volumes, left atrial volume, myocardial fibrosis, and creatinine). Adding the novel DCM subtype improved the C-statistic from 0.60 to 0.76. Interleukin-4 receptor-alpha was identified as a novel prognostic biomarker in derivation (HR: 3.6; 95% CI: 1.9-6.5; P = 0.00002) and validation cohorts (HR: 1.94; 95% CI: 1.3-2.8; P = 0.00005).
Three reproducible, mechanistically distinct DCM subtypes were identified using widely available clinical and biological data, adding prognostic value to traditional risk models. They may improve patient selection for novel interventions, thereby enabling precision medicine.
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Ectopic expression of mutant forms of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) lacking lipid (G129E) or lipid and protein (C124S) phosphatase activity decreased sensitivity of ...MCF-7 breast cancer cells, which have wild-type PTEN, to doxorubicin and increased sensitivity to the mammalian target of rapamycin (mTOR) inhibitor rapamycin. Cells transfected with a mutant PTEN gene lacking both lipid and protein phosphatase activities were more resistant to doxorubicin than cells transfected with the PTEN mutant lacking lipid phosphatase activity indicating that the protein phosphatase activity of PTEN was also important in controlling the sensitivity to doxorubicin, while no difference was observed between the lipid (G129E) and lipid and protein (C124S) phosphatase PTEN mutants in terms of sensitivity to rapamycin. A synergistic inhibitory interaction was observed when doxorubicin was combined with rapamycin in the phosphatase-deficient PTEN-transfected cells. Interference with the lipid phosphatase activity of PTEN was sufficient to activate Akt/mTOR/p70S6K signaling. These studies indicate that disruption of the normal activity of the PTEN phosphatase can have dramatic effects on the therapeutic sensitivity of breast cancer cells. Mutations in the key residues which control PTEN lipid and protein phosphatase may act as dominant-negative mutants to suppress endogenous PTEN and alter the sensitivity of breast cancer patients to chemo- and targeted therapies.
Purpose:
The development of computer-aided diagnostic (CAD) methods for lung nodule detection, classification, and quantitative assessment can be facilitated through a well-characterized repository ...of computed tomography (CT) scans. The Lung Image Database Consortium (LIDC) and Image Database Resource Initiative (IDRI) completed such a database, establishing a publicly available reference for the medical imaging research community. Initiated by the National Cancer Institute (NCI), further advanced by the Foundation for the National Institutes of Health (FNIH), and accompanied by the Food and Drug Administration (FDA) through active participation, this public-private partnership demonstrates the success of a consortium founded on a consensus-based process.
Methods:
Seven academic centers and eight medical imaging companies collaborated to identify, address, and resolve challenging organizational, technical, and clinical issues to provide a solid foundation for a robust database. The LIDC/IDRI Database contains 1018 cases, each of which includes images from a clinical thoracic CT scan and an associated XML file that records the results of a two-phase image annotation process performed by four experienced thoracic radiologists. In the initial blinded-read phase, each radiologist independently reviewed each CT scan and marked lesions belonging to one of three categories (“
nodule
≥
3
mm
,” “
nodule
<
3
mm
,” and “non-
nodule
≥
3
mm
”). In the subsequent unblinded-read phase, each radiologist independently reviewed their own marks along with the anonymized marks of the three other radiologists to render a final opinion. The goal of this process was to identify as completely as possible all lung nodules in each CT scan without requiring forced consensus.
Results:
The Database contains 7371 lesions marked “nodule” by at least one radiologist. 2669 of these lesions were marked “
nodule
≥
3
mm
” by at least one radiologist, of which 928 (34.7%) received such marks from all four radiologists. These 2669 lesions include nodule outlines and subjective nodule characteristic ratings.
Conclusions:
The LIDC/IDRI Database is expected to provide an essential medical imaging research resource to spur CAD development, validation, and dissemination in clinical practice.
CD8+ T cells contribute to the control of HIV, but it is not clear whether initial immune responses modulate the viral set point. We screened high-risk uninfected women twice a week for plasma HIV ...RNA and identified 12 hyperacute infections. Onset of viremia elicited a massive HIV-specific CD8+ T cell response, with limited bystander activation of non-HIV memory CD8+ T cells. HIV-specific CD8+ T cells secreted little interferon-γ, underwent rapid apoptosis, and failed to upregulate the interleukin-7 receptor, known to be important for T cell survival. The rapidity to peak CD8+ T cell activation and the absolute magnitude of activation induced by the exponential rise in viremia were inversely correlated with set point viremia. These data indicate that rapid, high magnitude HIV-induced CD8+ T cell responses are crucial for subsequent immune control of acute infection, which has important implications for HIV vaccine design.
•Onset of HIV viremia induces a massive HIV-specific CD8+ T cell response•Timing and strength of initial HIV-specific CD8+ T cell response impact viral load•IFN-γ secretion is an inadequate measure of CD8+ T cell responses in acute infection•The initial CD8+ T cell response fails to upregulate molecules for long-term memory
The relationship between onset of HIV viremia and CD8+ T cell responses is not well defined. Walker and colleagues screened high-risk uninfected women to identify cases of hyperacute infection, and show that the magnitude and kinetics of initial HIV-specific CD8+ T cell responses are associated with subsequent control of viremia.
Drawing the analogy to BaBiO3, we investigate via ab initio electronic structure calculations potential new superconductors of the type ATlX3 with A = Rb and Cs and X = F, Cl, and Br, with a ...particular emphasis on RbTlCl3. On the basis of chemical reasoning, supported by the calculations, we show that Tl-based perovskites have structural and charge instabilities driven by the lone pair effect, similar to the case of BaBiO3, effectively becoming A2Tl+Tl3+X6. We find that upon hole doping of RbTlCl3, structures without Tl+ and Tl3+ charge disproportionation become more stable, although the ideal cubic perovskite, often viewed as the best host for superconductivity, should not be the most stable phase in the system. The known superconductor (Sr,K)BiO3 and hole doped RbTlCl3, predicted to be most stable in the same tetragonal structure, display highly analogous calculated electronic band structures.
The extreme polymorphism in the human leukocyte antigen (HLA) class I region of the human genome is suggested to provide an advantage in pathogen defence mediated by CD8+ T cells. HLA class I ...molecules present pathogen-derived peptides on the surface of infected cells for recognition by CD8+ T cells. However, the relative contributions of HLA-A and -B alleles have not been evaluated. We performed a comprehensive analysis of the class I restricted CD8+ T-cell responses against human immunodeficiency virus (HIV-1), immune control of which is dependent upon virus-specific CD8+ T-cell activity. In 375 HIV-1-infected study subjects from southern Africa, a significantly greater number of CD8+ T-cell responses are HLA-B-restricted, compared to HLA-A (2.5-fold; P = 0.0033). Here we show that variation in viral set-point, in absolute CD4 count and, by inference, in rate of disease progression in the cohort, is strongly associated with particular HLA-B but not HLA-A allele expression (P < 0.0001 and P = 0.91, respectively). Moreover, substantially greater selection pressure is imposed on HIV-1 by HLA-B alleles than by HLA-A (4.4-fold, P = 0.0003). These data indicate that the principal focus of HIV-specific activity is at the HLA-B locus. Furthermore, HLA-B gene frequencies in the population are those likely to be most influenced by HIV disease, consistent with the observation that B alleles evolve more rapidly than A alleles. The dominant involvement of HLA-B in influencing HIV disease outcome is of specific relevance to the direction of HIV research and to vaccine design.
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