Bronchioalveolar Carcinoma in Jefferson and McCracken Counties, Kentucky: Gender Differences in Survival.

Bronchioalveolar carcinoma (BAC), a rare lung cancer, is more common in women, has a high proportion of non-smokers, and better survival, especially in women, than other lung cancers. Study subjects were 83 BAC patients from two Kentucky counties. Mean survival differences were compared by selected variables. The results showed better survival for females (6.5 years) than males (3.0 years, p-value 0.02); for urban (4.3 years) compared to rural residents (2.6 years, p-value 0.04); and for females with history of hysterectomy (5.1 years) compared to females without such history (3.3 years, p-value 0.02); the last finding supports a hormonal role in survival. Study results support the previous findings of a female survival advantage in BAC. Additional research is needed to determine reasons for this female survival advantage

Chronic HCV Infection Affects the NK Cell Phenotype in the Blood More than in the Liver

Although epidemiological and functional studies have implicated NK cells in protection and early clearance of HCV, the mechanism by which they may contribute to viral control is poorly understood, particularly at the site of infection, the liver. We hypothesized that a unique immunophenotypic/functional NK cell signature exists in the liver that may provide insights into the contribution of NK cells to viral control. Intrahepatic and blood NK cells were profiled from chronically infected HCV-positive and HCV-negative individuals. Baseline expression of activating and inhibitory receptors was assessed, as well as functional responses following stimulation through classic NK cell pathways. Independent of HCV infection, the liver was enriched for the immunoregulatory CD56bright NK cell population, which produced less IFNγ and CD107a but comparable levels of MIP1β, and was immunophenotypically distinct from their blood counterparts. This profile was mostly unaltered in chronic HCV infection, though different expression levels of NKp46 and NKG2D were associated with different grades of fibrosis. In contrast to the liver, chronic HCV infection associated with an enrichment of CD161lowperforinhigh NK cells in the blood correlated with increased AST and 2B4 expression. However, the association of relatively discrete changes in the NK cell phenotype in the liver with the fibrosis stage nevertheless suggests an important role for the NK response. Overall these data suggest that tissue localization has a more pervasive effect on NK cells than the presence of chronic viral infection, during which these cells might be mostly attuned to limiting immunopathology. It will be important to characterize NK cells during early HCV infection, when they should have a critical role in limiting infection

Early Transcriptional Divergence Marks Virus-Specific Primary Human CD8+ T Cells in Chronic versus Acute Infection.

Distinct molecular pathways govern the differentiation of CD8+ effector T cells into memory or exhausted T cells during acute and chronic viral infection, but these are not well studied in humans. Here, we employed an integrative systems immunology approach to identify transcriptional commonalities and differences between virus-specific CD8+ T cells from patients with persistent and spontaneously resolving hepatitis C virus (HCV) infection during the acute phase. We observed dysregulation of metabolic processes during early persistent infection that was linked to changes in expression of genes related to nucleosomal regulation of transcription, T cell differentiation, and the inflammatory response and correlated with subject age, sex, and the presence of HCV-specific CD4+ T cell populations. These early changes in HCV-specific CD8+ T cell transcription preceded the overt establishment of T cell exhaustion, making this signature a prime target in the search for the regulatory origins of T cell dysfunction in chronic viral infection

Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence

Vigorous proliferative CD4+ T cell responses are the hallmark of spontaneous clearance of acute hepatitis C virus (HCV) infection, whereas comparable responses are absent in chronically evolving infection. Here, we comprehensively characterized the breadth, specificity, and quality of the HCV-specific CD4+ T cell response in 31 patients with acute HCV infection and varying clinical outcomes. We analyzed in vitro T cell expansion in the presence of interleukin-2, and ex vivo staining with HCV peptide-loaded MHC class II tetramers. Surprisingly, broadly directed HCV-specific CD4+ T cell responses were universally detectable at early stages of infection, regardless of the clinical outcome. However, persistent viremia was associated with early proliferative defects of the HCV-specific CD4+ T cells, followed by rapid deletion of the HCV-specific response. Only early initiation of antiviral therapy was able to preserve CD4+ T cell responses in acute, chronically evolving infection. Our results challenge the paradigm that HCV persistence is the result of a failure to prime HCV-specific CD4+ T cells. Instead, broadly directed HCV-specific CD4+ T cell responses are usually generated, but rapid exhaustion and deletion of these cells occurs in the majority of patients. The data further suggest a short window of opportunity to prevent the loss of CD4+ T cell responses through antiviral therapy

Maximizing Clinical Research Participation in Vulnerable Older Persons: Identification of Barriers and Motivators

OBJECTIVES: To identify barriers and motivators to participation in long-term clinical research by high-risk elderly people and to develop procedures to maximize recruitment and retention. DESIGN: Quantitative and qualitative survey. SETTING: Academic primary care medicine and pre-anesthesia testing clinics. PARTICIPANTS: Fifty patients aged 70 and older, including 25 medical patients at high risk of hospitalization and 25 patients with planned major surgery. MEASUREMENTS: Fifteen- to 20-minute interviews involved open- and closed-ended questions guided by an in-depth script. Two planned study protocols were presented to each participant. Both involved serial neuropsychological assessments, blood testing, and magnetic resonance brain imaging (MRI); one added lumbar puncture (LP). Participants were asked whether they would be willing to participate in these protocols, rated barriers and incentives to participation, and were probed with open-ended questions. RESULTS: Of 50 participants (average age 78, 44% male, 40% nonwhite), 32 (64%) expressed willingness to participate in the LP-containing protocol, with LP cited as the strongest disincentive. Thirty-eight (76%) expressed willingness to participate in the protocol without LP, with phlebotomy and long interviews cited as the strongest disincentives. Altruism was a strong motivator for participation, whereas transportation was a major barrier. Study visits at home, flexible appointment times, assessments shorter than 75 minutes, and providing transportation and free parking were strategies developed to maximize study participation. CONCLUSION: Vulnerable elderly people expressed a high rate of willingness to participate in an 18-month prospective study. Participants identified incentives and barriers that enabled investigators to develop procedures to maximize recruitment and retention

Immunophenotypic profiles of blood and liver-resident NK cell subsets.

<p>Immunophenotyping of liver and blood NK cell subsets in groups of HCV-infected and –uninfected individuals was performed by flow cytometry, and both tissue-specific differences (A) and disease-specific differences (B) were analyzed. Data is presented as a heatmap, with values displayed as relative within each row. Statistical significance was accepted at p<0.05 and is indicated by * (p<0.05), ** (p<0.01), *** (p<0.001) and **** (p<0.0001).</p

Clinical characteristics of HCV-infected individuals.

<p>*p.i. =  post infection; Risk factor for HCV acquisition; GT =  HCV genotype; ND = not determined. # normal range of ALT = 7–56 IU/ml, AST = 5–40 IU/ml.</p

Tissue- and disease-specific differences in NK cell functionality.

<p>Functional responses of liver-resident and blood NK cells were assessed in groups of HCV-infected and –uninfected individuals. NK cell degranulation (CD107a) and cytokine production (MIP1β and IFNγ) were measured by flow cytometry in the absence (A) or presence (B) of K562 cells (NKG2D ligation), 721.221 cells (NCR ligation) or antibody-coated p815 cells (ADCC-mediated stimulation). Statistical significance was accepted at p<0.05 and is indicated by * (p<0.05), ** (p<0.01), *** (p<0.001) and **** (p<0.0001).</p