Longitudinal Intra- and Inter-individual variation in T-cell subsets of HIV-infected and uninfected men participating in the LA Multi-Center AIDS Cohort Study.

To assess the intra-individual and inter-individuals biological variation and the effect of aging on lymphocyte T-cells subsets.We assessed lymphocyte phenotypes (CD3, CD4, and CD8 T-cells) in 89 HIV-1-infected and 88 uninfected white non-Hispanic men every 6 months, to examine the biological variation for those measurements, and the average change in lymphocyte phenotype over 34 years.The markers showed significant intra-individuality in HIV-infected and uninfected individuals with index of individuality of <1.4. No mean changes were seen over the 34 years, with the exception of percentage CD4T-cells in HIV-uninfected individuals.In the pre-HAART era, HIV-infected individuals experienced an increase in mean absolute CD3 T-cell numbers (11.21 cells/μL, P = 0.02) and absolute CD8 T-cell numbers (34.57 cell/μl, P < .001), and in the percentage of CD8 T-cells (1.45%, P < .001) per year and a significant decrease in mean absolute CD4 T-cell numbers (23.68 cells/μl, P < .001) and in the percentage of CD4 T-cells (1.49%, P < .001) per year.In the post-HAART era, no changes in mean levels were observed in absolute CD3 T-cell count (P = .15) or percentage (P = .99). Significant decreases were seen in mean count (8.56 cells/μl, P < .001) and percentage (0.59%, P < .001) of CD8 T-cells, and increases in mean absolute count (10.72 cells/μl, P < .001) and percentage (0.47%, P < .001) of CD4 T-cells.With the exception of CD4 (%), no average changes per year were seen in lymphocyte phenotype of HIV-uninfected men. The results of coefficients of variation of intra and inter-individuals of this study can be useful for HIV-1 infection monitoring and in addition the observation could be a useful guide for intra- and inter-individual coefficient variations, and establishing quality goal studies of different blood biomarkers in healthy and other diseases

Circulating markers of microbial translocation and host response to bacteria with risk of colorectal cancer: A prospective, nested case-control study in men

BACKGROUND: Gut microbial dysbiosis contributes to colorectal cancer (CRC) pathogenesis, possibly mediated in part by increased intestinal permeability to endotoxin lipopolysaccharide (LPS), microbial translocation, and subsequent endotoxemia and inflammation. However, epidemiologic evidence linking circulating markers of microbial translocation with CRC risk is limited. METHODS: We conducted a prospective, nested case-control study of 261 incident CRC cases and 261 controls (matched on age and time of blood draw) among 18,159 men with pre-diagnostic blood specimens in the Health Professionals Follow-Up Study (1993-2009). We examined three complementary markers of microbial translocation and host response to bacteria, including LPS-binding protein (LBP), soluble CD14 (sCD14), and endotoxincore antibody (EndoCAb) immunoglobulin M (IgM), with subsequent risk of CRC. Unconditional logistic regressions were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). FINDINGS: Pre-diagnostic circulating levels of sCD14 were associated with a higher risk of incident CRC. Compared to men in the lowest quartile, the multivariable OR was 1.90 (95% CI, 1.13-3.22) for men in the highest quartile (OR INTERPRETATION: Microbial translocation and host response to bacteria, as reflected by sCD14, is associated with risk of incident CRC in men. FUNDING: US National Institutes of Health

P38 MAPK expression and activation predicts failure of response to CHOP in patients with Diffuse Large B-Cell Lymphoma

The p38 MAPK is constitutively activated in B-NHL cell lines and regulates chemoresistance. Accordingly, we hypothesized that activated p38 MAPK may be associated with the in vivo unresponsiveness to chemotherapy in B-NHL patients.Tissue microarrays generated from eighty untreated patients with Diffused Large B Cell Lymphoma (DLBCL) were examined by immunohistochemistry for the expression of p38 and phospho p38 (p-p38) MAPK. In addition, both Bcl-2 and NF-κB expressions were determined. Kaplan Meier analysis was assessed.Tumor tissues expressed p38 MAPK (82 %) and p-p38 MAPK (30 %). Both p38 and p-p38 MAPK expressions correlated with the high score performance status. A significant correlation was found between the expression p-p38 and poor response to CHOP. The five year median follow-up FFS was 81 % for p38(-) and 34 % for p38(+) and for OS was 83 % for p38(-) and 47 % for p38(+). The p-p38(+) tissues expressed Bcl-2 and 90 % of p-p38(-) where Bcl-2(-). The coexpression of p-p38 and Bcl-2 correlated with pool EFS and OS. There was no correlation between the expression of p-p38 and the expression of NF-κB.The findings revealed, for the first time, that a subset of patients with DLBCL and whose tumors expressed high p-p38 MAPK responded poorly to CHOP therapy and had poor EFS and OS. The expression of p38, p-p38, Bcl2 and the ABC subtype are significant risk factors both p38 and p-p38 expressions remain independent prognostic factors

Lymphoma-Associated Biomarkers Are Increased in Current Smokers in Twin Pairs Discordant for Smoking

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of >3.08 ng/mL and ≤3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (Ptrend < 0.05). The strongest association was observed for CCL17/TARC (Ptrend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas

Sustained delivery and molecular targeting of a therapeutic monoclonal antibody to metastases in the central nervous system of mice.

Approximately 15-40% of all cancers develop metastases in the central nervous system (CNS), yet few therapeutic options exist to treat them. Cancer therapies based on monoclonal antibodies are widely successful, yet have limited efficacy against CNS metastases, owing to the low levels of the drug reaching the tumour site. Here, we show that the encapsulation of rituximab within a crosslinked zwitterionic polymer layer leads to the sustained release of rituximab as the crosslinkers are gradually hydrolysed, enhancing the CNS levels of the antibody by approximately tenfold with respect to the administration of naked rituximab. When the nanocapsules were functionalized with CXCL13-the ligand for the chemokine receptor CXCR5, which is frequently found on B-cell lymphoma-a single dose led to improved control of CXCR5-expressing metastases in a murine xenograft model of non-Hodgkin lymphoma, and eliminated lymphoma in a xenografted humanized bone marrow-liver-thymus mouse model. Encapsulation and molecular targeting of therapeutic antibodies could become an option for the treatment of cancers with CNS metastases

Lymphoma-Associated Biomarkers Are Increased in Current Smokers in Twin Pairs Discordant for Smoking

Smoking is associated with a moderate increased risk of Hodgkin and follicular lymphoma. To understand why, we examined lymphoma-related biomarker levels among 134 smoking and non-smoking twins (67 pairs) ascertained from the Finnish Twin Cohort. Previously collected frozen serum samples were tested for cotinine to validate self-reported smoking history. In total, 27 immune biomarkers were assayed using the Luminex Multiplex platform (R & D Systems). Current and non-current smokers were defined by a serum cotinine concentration of >3.08 ng/mL and ≤3.08 ng/mL, respectively. Associations between biomarkers and smoking were assessed using linear mixed models to estimate beta coefficients and standard errors, adjusting for age, sex and twin pair as a random effect. There were 55 never smokers, 43 current smokers and 36 former smokers. CCL17/TARC, sgp130, haptoglobin, B-cell activating factor (BAFF) and monocyte chemoattractant protein-1 (MCP1) were significantly (p < 0.05) associated with current smoking and correlated with increasing cotinine concentrations (Ptrend < 0.05). The strongest association was observed for CCL17/TARC (Ptrend = 0.0001). Immune biomarker levels were similar in former and never smokers. Current smoking is associated with increased levels of lymphoma-associated biomarkers, suggesting a possible mechanism for the link between smoking and risk of these two B-cell lymphomas

Insights into the mechanism of cell death induced by saporin delivered into cancer cells by an antibody fusion protein targeting the transferrin receptor 1

We previously developed an antibody-avidin fusion protein (ch128.1Av) that targets the human transferrin receptor 1 (TfR1) and exhibits direct cytotoxicity against malignant B cells in an iron-dependent manner. ch128.1Av is also a delivery system and its conjugation with biotinylated saporin (b-SO6), a plant ribosome-inactivating toxin, results in a dramatic iron-independent cytotoxicity, both in malignant cells that are sensitive or resistant to ch128.1Av alone, in which the toxin effectively inhibits protein synthesis and triggers caspase activation. We have now found that the ch128.1Av/b-SO6 complex induces a transcriptional response consistent with oxidative stress and DNA damage, a response that is not observed with ch128.1Av alone. Furthermore, we show that the antioxidant N-acetylcysteine partially blocks saporin-induced apoptosis suggesting that oxidative stress contributes to DNA damage and ultimately saporin-induced cell death. Interestingly, the toxin was detected in nuclear extracts by immunoblotting, suggesting the possibility that saporin might induce direct DNA damage. However, confocal microscopy did not show a clear and consistent pattern of intranuclear localization. Finally, using the long-term culture-initiating cell assay we found that ch128.1Av/b-SO6 is not toxic to normal human hematopoietic stem cells suggesting that this critical cell population would be preserved in therapeutic interventions using this immunotoxin.Fil: Daniels Wells, Tracy R.. University of California; Estados Unidos de América;Fil: Helguera, Gustavo Fernando. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Biología y Medicina Experimental (i); Argentina. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica; Argentina. University of California; Estados Unidos de América;Fil: Rodríguez, José A.. University of California; Estados Unidos de América;Fil: Leoh, Lai Sum. University of California; Estados Unidos de América;Fil: Erb, Michael A.. University of California; Estados Unidos de América;Fil: Diamante, Graciel. University of California; Estados Unidos de América;Fil: Casero, David. University Of California; Estados Unidos de América;Fil: Pellegrini, Mateo. University of California; Estados Unidos de América;Fil: Martinez Maza, Otoniel. University of California; Estados Unidos de América;Fil: Penichet, Manuel L.. University of California; Estados Unidos de América

Pre-diagnosis plasma immune markers and risk of non-Hodgkin lymphoma in two prospective cohort studies

Inflammation and B-cell hyperactivation have been associated with non-Hodgkin lymphoma development. This prospective analysis aimed to further elucidate pre-diagnosis plasma immune marker profiles associated with non-Hodgkin lymphoma risk. We identified 598 incident lymphoma cases and 601 matched controls in Nurses\u27 Health Study and Health Professionals Follow-up Study participants with archived pre-diagnosis plasma samples and measured 13 immune marker levels with multiplexed immunoassays. Using multivariable logistic regression we calculated odds ratios and 95% confidence intervals per standard deviation unit increase in biomarker concentration for risk of non-Hodgkin lymphoma and major histologic subtype, stratifying additional models by years ( \u3c 5, 5 to \u3c 10, \u3e /=10) after blood draw. Soluble interleukin-2 receptor-alpha, CXC chemokine ligand 13, soluble CD30, and soluble tumor necrosis factor receptor-2 were individually positively associated, and B-cell activating factor of the tumor necrosis factor family inversely associated, with all non-Hodgkin lymphoma and one or more subtypes. The biomarker combinations associated independently with lymphoma varied somewhat by subtype and years after blood draw. Of note, the unexpected inverse association between B-cell activating factor and chronic lymphocytic leukemia/small lymphocytic lymphoma risk (odds ratio: 95% confidence interval: 0.51, 0.43-0.62) persisted more than 10 years after blood draw (odds ratio: 0.70; 95% confidence interval: 0.52-0.93). In conclusion, immune activation precedes non-Hodgkin lymphoma diagnosis by several years. Decreased B-cell activating factor levels may denote nascent chronic lymphocytic leukemia many years pre-diagnosis