Sydeaka Watson

Mosaic vaccines elicit CD8 + T lymphocyte responses that confer enhanced immune coverage of diverse HIV strains in monkeys

An effective HIV vaccine must elicit immune responses that recognize genetically diverse viruses. It must generate CD8+ T lymphocytes that control HIV replication and CD4+ T lymphocytes that provide help for the generation and maintenance of both cellular and humoral immune responses against the virus. Creating immunogens that can elicit cellular immune responses against the genetically varied circulating isolates of HIV presents a key challenge for creating an HIV vaccine. Polyvalent mosaic immunogens derived by in silico recombination of natural strains of HIV are designed to induce cellular immune responses that recognize genetically diverse circulating virus isolates. Here we immunized rhesus monkeys by plasmid DNA prime and recombinant vaccinia virus boost with vaccine constructs expressing either consensus or polyvalent mosaic proteins. As compared to consensus immunogens, the mosaic immunogens elicited CD8+ T lymphocyte responses to more epitopes of each viral protein than did the consensus immunogens and to more variant sequences of CD8+ T lymphocyte epitopes. This increased breadth and depth of epitope recognition may contribute both to protection against infection by genetically diverse viruses and to the control of variant viruses that emerge as they mutate away from recognition by cytotoxic T lymphocytes.

MR Imaging–guided Focal Laser Ablation for Prostate Cancer: Phase I Trial

PURPOSE To evaluate the feasibility and safety of magnetic resonance (MR) imaging-guided laser-based thermotherapy in men with clinically low-risk prostate cancer and a concordant lesion at biopsy and MR imaging. MATERIALS AND METHODS This HIPAA-compliant phase I prospective study was approved by the institutional review board. Informed consent was obtained from all patients. Transperineal MR imaging-guided focal laser ablation for clinically low-risk prostate cancer was performed in patients with a Gleason score of 7 or less in three or fewer cores limited to one sextant obtained with transrectal ultrasonography (US)-guided biopsy and a concordant lesion at MR imaging. Lesions were targeted with a laser ablation system. Periprocedural complications were recorded. The International Prostate Symptom Score (IPSS) and the Sexual Health Inventory for Men (SHIM) score were collected before and after the procedure. MR imaging-guided biopsy of the ablation zone was performed 6 months after treatment. The prostate-specific antigen level, IPSS, and SHIM score before and after ablation were compared by using the Wilcoxon signed rank test. RESULTS Treatment was successfully completed in nine patients (procedure duration, 2.5-4 hours; mean laser ablation duration, 4.3 minutes). Immediate contrast-enhanced posttreatment MR imaging showed a hypovascular defect in eight patients. Self-resolving perineal abrasion and focal paresthesia of the glans penis each occurred in one patient. The mean (± standard deviation) IPSS and SHIM score at baseline were 5.8 ± 5.3 and 19.0 ± 8.0, respectively. Average score changes were not significantly different from zero during follow-up (P = .18-.99). MR imaging-guided biopsy of the ablation zone showed no cancer in seven patients (78%) and Gleason grade 6 cancer in two (22%). CONCLUSION Transperineal MR imaging-guided focal laser ablation appears to be a feasible and safe focal therapy option for clinically low-risk prostate cancer.

Relationship between Functional Profile of HIV-1 Specific CD8 T Cells and Epitope Variability with the Selection of Escape Mutants in Acute HIV-1 Infection

In the present study, we analyzed the functional profile of CD8+ T-cell responses directed against autologous transmitted/founder HIV-1 isolates during acute and early infection, and examined whether multifunctionality is required for selection of virus escape mutations. Seven anti-retroviral therapy-naïve subjects were studied in detail between 1 and 87 weeks following onset of symptoms of acute HIV-1 infection. Synthetic peptides representing the autologous transmitted/founder HIV-1 sequences were used in multiparameter flow cytometry assays to determine the functionality of HIV-1-specific CD8+ T memory cells. In all seven patients, the earliest T cell responses were predominantly oligofunctional, although the relative contribution of multifunctional cell responses increased significantly with time from infection. Interestingly, only the magnitude of the total and not of the poly-functional T-cell responses was significantly associated with the selection of escape mutants. However, the high contribution of MIP-1β-producing CD8+ T-cells to the total response suggests that mechanisms not limited to cytotoxicity could be exerting immune pressure during acute infection. Lastly, we show that epitope entropy, reflecting the capacity of the epitope to tolerate mutational change and defined as the diversity of epitope sequences at the population level, was also correlated with rate of emergence of escape mutants.

Antigenicity and immunogenicity of transmitted/founder, consensus, and chronic envelope glycoproteins of human immunodeficiency virus type 1

ABSTRACT Human immunodeficiency virus type 1 (HIV-1) vaccine development requires selection of appropriate envelope (Env) immunogens. Twenty HIV-1 Env glycoproteins were examined for their ability to bind human anti-HIV-1 monoclonal antibodies (MAbs) and then used as immunogens in guinea pigs to identify promising immunogens. These included five Envs derived from chronically infected individuals, each representing one of five common clades and eight consensus Envs based on these five clades, as well as the consensus of the entire HIV-1 M group, and seven transmitted/founder (T/F) Envs from clades B and C. Sera from immunized guinea pigs were tested for neutralizing activity using 36 HIV-1 Env-pseudotyped viruses. All Envs bound to CD4 binding site, membrane-proximal, and V1/V2 MAbs with similar apparent affinities, although the T/F Envs bound with higher affinity to the MAb 17b, a CCR5 coreceptor binding site antibody. However, the various Envs differed in their ability to induce neutralizing antibodies. Consensus Envs elicited the most potent responses, but neutralized only a subset of viruses, including mostly easy-to-neutralize tier 1 and some more-difficult-to-neutralize tier 2 viruses. T/F Envs elicited fewer potent neutralizing antibodies but exhibited greater breadth than chronic or consensus Envs. Finally, chronic Envs elicited the lowest level and most limited breadth of neutralizing antibodies overall. Thus, each group of Env immunogens elicited a different antibody response profile. The complementary benefits of consensus and T/F Env immunogens raise the possibility that vaccines utilizing a combination of consensus and T/F Envs may be able to induce neutralizing responses with greater breadth and potency than single Env immunogens.

Breadth of cellular and humoral immune responses elicited in rhesus monkeys by multi-valent mosaic and consensus immunogens

To create an HIV-1 vaccine that generates sufficient breadth of immune recognition to protect against the genetically diverse forms of the circulating virus, we have been exploring vaccines based on consensus and mosaic protein designs. Increasing the valency of a mosaic immunogen cocktail increases epitope coverage but with diminishing returns, as increasingly rare epitopes are incorporated into the mosaic proteins. In this study we compared the immunogenicity of 2-valent and 3-valent HIV-1 envelope mosaic immunogens in rhesus monkeys. Immunizations with the 3-valent mosaic immunogens resulted in a modest increase in the breadth of vaccine-elicited T lymphocyte responses compared to the 2-valent mosaic immunogens. However, the 3-valent mosaic immunogens elicited significantly higher neutralizing responses to Tier 1 viruses than the 2-valent mosaic immunogens. These findings underscore the potential utility of polyvalent mosaic immunogens for eliciting both cellular and humoral immune responses to HIV-1.

Survival in pulmonary arterial hypertension patients awaiting lung transplantation

BACKGROUND Pulmonary arterial hypertension (PAH) is a progressive disease with lung transplantation as the only option for those patients refractory to medical therapy. Although several equations have been developed to predict PAH patient survival, it is unclear whether they can predict survival for patients awaiting transplantation. METHODS Data were analyzed on 827 patients listed since 1991 on the Scientific Registry of Transplant Recipients. Overall survival and survival for patients listed prior to and after January 1, 2006 was estimated using the Kaplan-Meier (K-M) method and compared with predicted survival from the pulmonary hypertension connection (PHC) and lung allocation system (LAS) equations. A new equation using a novel model selection algorithm for correlated covariates and missing data was developed using clinical factors and variables in the LAS score. Model validation statistics were calculated and averaged across 500 bootstrap resamples within each of 5 imputation data sets. K-M with 95% confidence intervals and receiver-operator characteristic (ROC) curves assessed model performance. RESULTS PHC predicted overall survival but underestimated and overestimated survival for those listed pre- and post-2006, respectively. The best model included baseline 6-minute walk distance (6MWD), invasive cardiac output and resting oxygen requirement (O2). Factors associated with 1-year waitlist survival included: resting O2 amount; invasive hemodynamics; 6MWD; and functional class. The new equation by ROC analysis outperformed the LAS and PHC equations. CONCLUSIONS Current prediction models overestimate survival for PAH patients listed for transplant in the LAS era. This new survival equation can help guide clinicians caring for PAH patients with progression of disease requiring transplant.

Clinical and molecular markers of long-term survival after oligometastasis-directed stereotactic body radiotherapy (SBRT)

The selection of patients for oligometastasis‐directed ablative therapy remains a challenge. The authors report on clinical and molecular predictors of survival from a stereotactic body radiotherapy (SBRT) dose‐escalation trial for oligometastases.

Effects of FDA advisories on the pharmacologic treatment of ADHD, 2004-2008

OBJECTIVE This study assessed the effect of public health advisories issued between 2005 and 2007 by the U.S. Food and Drug Administration (FDA) on treatments of attention-deficit hyperactivity disorder (ADHD) and physician prescribing practices. METHODS Data obtained from the IMS Health National Disease and Therapeutic Index, a nationally representative audit of ambulatory physicians, were used to examine trends in office visits by children and adolescents (under age 18) during which ADHD was treated with Adderall, other psychostimulants, or atomoxetine. Segmented time series regressions were conducted to determine changes in use associated with three advisories issued between 2005 and 2007. RESULTS In 2004, before the first FDA advisory, Adderall accounted for 36% of ADHD pharmacotherapy treatment visits. Other stimulants accounted for 46%, and atomoxetine accounted for 19%. Overall pharmacotherapy treatment rates were stable over the study period, but by 2008 the treatment visits accounted for by Adderall (that is, market share) declined to 24%, and the market share for atomoxetine declined to 8%. The market share for substitute therapies-clonidine, guanfacine, and bupropion-was stable over this period, ranging from 5% to 7%. Despite the declines in the use of Adderall and atomoxetine over the study period, results from the regression models suggest that the advisories did not have a statistically significant effect on ADHD medication prescribing. CONCLUSIONS FDA advisories regarding potential cardiovascular and other risks of ADHD medications had little discernible incremental effect on the use of these medicines in this nationally representative ambulatory audit.

Predicted postoperative lung function is associated with all-cause long-term mortality after major lung resection for cancer

OBJECTIVES Preoperative lung function is an independent predictor of long-term survival after lung resection for non-small-cell lung cancer (NSCLC). The extent of resection has an impact on operative mortality, determines postoperative lung function and may influence both overall- and cancer-specific survival. We sought to determine the impact of predicted postoperative (ppo) lung function on long-term survival after lung cancer resection. METHODS We previously reported long-term survival analyses for patients who underwent major lung resection for NSCLC 1980-2006. For this study, we calculated ppo spirometry (forced expiratory volume in the first second, FEV1) and diffusing capacity of the lung for carbon monoxide (DLCO) in the same cohort using the functional segment technique or quantitative perfusion scans when available, and updated survival data; missing data were imputed. We assessed the relationship of ppoFEV1 and ppoDLCO to long-term survival using Cox regression. RESULTS Of 854 patients, 471 (55%) were men, the mean age was 63 years and median survival was 42 months. At the time of analysis, 70% of patients had died. On regression analysis, all-cause mortality was related to age, stage, performance status, renal function and prior myocardial infarction. Preoperative lung function was marginally associated with mortality [DLCO (10-percentage point decrease): HR (hazard ratio) 1.04, 95% confidence interval (95% CI) 1.00-1.08, P = 0.056; FEV1 (10-percentage point decrease): HR 1.04, 95% CI 1.00-1.09, P = 0.067]. In contrast, ppo lung function was strongly associated with mortality (ppoDLCO: HR 1.06, 95% CI 1.01-1.12, P = 0.024; ppoFEV1: HR 1.06, 95% CI 1.01-1.12, P = 0.031). CONCLUSIONS Ppo lung function is strongly associated with long-term survival after major lung resection and is more strongly related to survival than preoperative lung function. Surgeons struggle with challenging decisions about the appropriate extent of resection for early-stage cancer, balancing factors such as operative morbidity/mortality, local recurrence and postoperative quality of life. Ppo lung function and its relation to survival also should be taken into consideration during such deliberations.

Association of body mass index and outcomes after major lung resection

OBJECTIVES Obesity has been thought to predispose patients to excess morbidity after lung resection because of decreased diaphragm excursion, reduced lung volumes and relative immobility. We assessed the relationship of body mass index (BMI) to acute outcomes after major lung resection. METHODS Information from our database of lung resections was evaluated for the period 1980-2011. Univariate analysis for adverse events (pulmonary, cardiovascular, other and overall) was used to select variables for inclusion in multivariate logistic regression analyses. Missing values were imputed. BMI was categorized as underweight (<18.5), normal (18.5-24.9), overweight (25-29.9), obese (30-34.9) and very obese (≥ 35). RESULTS Among 1369 patients, there were 703 males (51%) and the mean age was 62 ± 11 years. Complications included the following: pulmonary 12%, cardiovascular 15%, other 16%, mortality 5% and any 29%. The incidence of complications decreased during each decade of study (40, 30, 26, 20%; P < 0.0001) and the incidence of obese/very obese increased during the same intervals (11, 22, 30, 25%; P = 0.0007). Adjusting for age, performance status, coronary artery disease, smoking status, diffusing capacity of the lung for carbon monoxide, forced expiratory volume in 1 s and operation year, being overweight/obese/very obese did not increase the risk of postoperative complications in any category. In fact, patients in this group showed a lower rate of cardiovascular complications than those with BMI ≤ 25 (odds ratio (OR): 0.72; 95% confidence interval (CI): 0.51-1.00; P = 0.048). However, being underweight was importantly associated with an increased risk of pulmonary complications (OR: 2.5; 95% CI: 1.3-4.9; P = 0.0087) and of operative mortality (OR: 2.96; 95% CI: 1.28-6.86; P = 0.011). CONCLUSION Being overweight or obese does not increase the risk of complications after major lung resection. In contrast, patients who are underweight are at significantly increased risk of pulmonary complications and mortality. Knowledge of the relationship of BMI to perioperative risk for major lung resection is essential in proper risk stratification.