CD8+ T‐cell immunosurveillance constrains lymphoid premetastatic myeloid cell accumulation

Increasing evidence suggests that premetastatic niches, consisting mainly of myeloid cells, provide microenvironment critical for cancer cell recruitment and survival to facilitate metastasis. While CD8⁺ T cells exert immunosurveillance in primary human tumors, whether they can exert similar effects on myeloid cells in the premetastatic environment is unknown. Here, we show that CD8⁺ T cells are capable of constraining premetastatic myeloid cell accumulation by inducing myeloid cell apoptosis in C57BL/6 mice. Ag‐specific CD8⁺ T‐cell cytotoxicity against myeloid cells in premetastatic lymph nodes is compromised by Stat3. We demonstrate here that Stat3 ablation in myeloid cells leads to CD8⁺ T‐cell activation and increased levels of IFN‐γ and granzyme B in the premetastatic environment. Furthermore, Stat3 negatively regulates soluble Ag cross‐presentation by myeloid cells to CD8⁺ T cells in the premetastatic niche. Importantly, in tumor‐free lymph nodes of melanoma patients, infiltration of activated CD8⁺ T cells inversely correlates with STAT3 activity, which is associated with a decrease in number of myeloid cells. Our study suggested a novel role for CD8⁺ T cells in constraining myeloid cell activity through direct killing in the premetastatic environment, and the therapeutic potential by targeting Stat3 in myeloid cells to improve CD8⁺ T‐cell immunosurveillance against metastasis.     

Development of remineralizing, antibacterial dental materials

Light curable methacrylate dental monomers containing reactive calcium phosphate filler (monocalcium phosphate monohydrate (MCPM) with particle diameter of 29 or 90 μm) and β-tricalcium phosphate (β-TCP) at 1:1 weight ratio in a powder:liquid ratio (PLR) of 1:1 or 3:1 and chlorhexidine diacetate (0 or 5 wt.%), were investigated. Upon light exposure, approximately 90% monomer conversion was gained irrespective of the formulation. Increasing the PLR promoted water sorption by the set material, induced expansion and enhanced calcium, phosphate and chlorhexidine release. Concomitantly, a decline in compressive and biaxial flexural strengths occurred. With a reduction in MCPM particle diameter, however, calcium and phosphate release was reduced and less deterioration in strength observed. After 24 h, the remaining MCPM had reacted with water and β-TCP, forming, within the set materials, brushite of lower solubility. This provided a novel means to control water sorption, component release and strength properties. Measurable chlorhexidine release was observed for 6 weeks. Both diffusion rate and total percentage of chlorhexidine release decreased with lowering PLR or by adding buffer to the storage solutions. Higher chlorhexidine release was associated with reduced bacterial growth on agar plates and in a biofilm fermenter. In cell growth media, brushite and hydroxyapatite crystals precipitated on the composite material surfaces. Cells spread on both these crystals and the exposed polymer composite surfaces, indicating their cell compatibility. These formulations could be suitable antibacterial, biocompatible and remineralizing dental adhesives/liners.     

Differentially modulated dendritic cells induce regulatory T cells with different characteristics

Dexamethason (DEX) treated DC display several features that establish them as candidates for specific allogeneic tolerance induction. We report the results of in vitro studies of polarization of the alloimmune T cell response with two types of differentially modulated human DC. Both DEX treated DC triggered by LPS for 6 h (DEX6-DC) and DEX treated DC triggered by LPS for 48 h (DEX48-DC) acquired low levels of costimulatory, adhesion, and MHC class II molecules compared with mature DC (mDC). In contrast to mDC, both DEX6-DC and DEX48-DC did not produce any IL-12. DEX6-DC were able to produce significant amounts of IL-10 whereas DEX48-DC did not actively produce IL-10. Conversely, the induction of IL-10 producing cells was significantly increased when PBL were stimulated with DEX48-DC compared with DEX6-DC. Both stimulation of PBL with DEX6-DC and DEX48-DC led to the induction of cell populations able to suppress the proliferative alloimmune response of primed T cells in a cell-cell contact independent and antigen-nonspecific manner. Tregs obtained after stimulation with DEX48-DC were also able to inhibit the IFN-gamma production of the effector cells and this effect could be blocked by anti-IL-10. Tregs induced by DEX6-DC produced similar amounts of IL-10, yet were not able to inhibit IFN-gamma production of the effector T cells, indicating a different mechanism. In summary, we show that differential modulation of DC results in the induction of different populations of regulatory T cells.     

Treatment Resistance in Stem Cells and Breast Cancer

Cancer stem cells are resistant to current chemotherapy and radiation regimens available for breast cancer, making it imperative to study the mechanisms of resistance and development of therapeutic strategies that targets the tumor initiating cell population. One of the difficulties in identifying new drug targets has been that our current high throughput drug screens look for tumor shrinkage and do not incorporate the impact of compounds on the cancer stem cell population. In this review we discuss the literature on treatment resistance in breast cancer and the design of new clinical trials for test compounds which will allow us to determine both the reduction in tumor size and decrease in cancer stem cell population. In order to detect the effect of target compounds on cancer stem cells in a clinical setting, we will need to do multiple assays which include high throughput flow sorting analysis to determine the total number of CD44⁺/CD24^−/low/Lin⁻ and ALDH1 positive cells, as well as in-vitro mammosphere formation assay which is a functional assay dependent on the self renewal and anchorage independent growth properties of these cells.     

Benzodiazepine use in older adults enrolled in a health maintenance organization.

OBJECTIVES: The authors examined patterns of benzodiazepine use in older adults. Specifically, they describe prevalence and incidence of benzodiazepine use during the index year, describe persistence and intensity of benzodiazepine use over a 4-year period; and examine factors associated with benzodiazepine use in the upcoming year. METHODS: Authors performed a secondary analysis of data collected as part of a health promotion intervention trial conducted from 1986 to 1992 in older health maintenance organization enrollees (N=1,505). Benzodiazepine use was ascertained from computerized pharmacy records. Demographic characteristics, health status, and health behaviors were ascertained from mailed questionnaires. RESULTS: During the index year, the prevalence and incidence of benzodiazepine use was 12.3% and 6.6%, respectively. Of those using during the index year, 16% of new users and 63% of previous users continued to use for the following 3 years. The factors significantly associated with benzodiazepine use in the following year were female gender, high school education, higher chronic disease score, higher levels of self-reported pain and stress, low-to-normal body mass index (BMI), and self-reported nervous disorder. CONCLUSIONS: New users had low intensity of use and a low probability of continuing use over the following 3 years. A very small percentage of this sample had evidence of daily use for 4 years. Of concern, benzodiazepines were used by the segment of the sample that were at greatest risk for hip fractures (women with normal/low BMI). Clinicians should assess the need for continued benzodiazepine use at regular intervals.     

Predictors of congruency between self-reported hypertension status and measured blood pressure in the stroke belt

BackgroundFew studies have comprehensively investigated the validity of self-reported hypertension (HTN) and assessed predictors of HTN status in the stroke belt. This study evaluates validity self-reporting as a tool to screen large study populations and determine predictors of congruency between self-reported HTN and clinical measures.MethodsCommunity Initiative to Eliminate Stroke project (n = 16,598) was conducted in two counties of North Carolina in 2004 to 2007, which included collection of self-reported data and clinical data of stroke-related risk factors. Congruency between self-reported HTN status and clinical measures was based on epidemiological parameters of sensitivity, specificity, and predictive values. McNemar’s test and Kappa agreement levels assessed differences in congruency, while odds ratios and logistic regression determined significant predictors of congruency.ResultsSensitivity of self-reported HTN was low (33.3%), but specificity was high (89.5%). Prevalence of self-reported HTN was 16.15%. Kappa agreement between self-report and clinical measures for blood pressure was fair (k = 0.25). Females, whites, and young adults were most likely to be positively congruent, whereas individuals in high risk categories for total blood cholesterol, low density lipoproteins, triglycerides, and diabetes were least likely to accurately capture their HTN status.ConclusionSelf-report HTN information should be used with caution as an epidemiological investigation tool.     

Conservative,open or percutaneous repair for acute rupture of the Achilles tendon

Purpose. To review the complications and recovery of patients with Achilles tendon rupture managed by percutaneous repair, open repair, and non-operative means in a tertiary referral centre between 2001 and 2003.

Methods. The operating theatre register and logbooks of the Consultants were used to identify surgically managed patients, while plaster room records were used for conservatively managed patients. We collated demographic and management details.

Results. The number of plaster changes (p < 0.001), median length of time in cast (p < 0.001), and number of outpatient visits (p < 0.05) was greater in conservatively managed patients. We performed no formal statistical analysis given the small numbers. Conservative management was the least expensive and open surgery the most costly modality of management. Percutaneous surgery was approximately a third of the cost of open surgery when performed under local anaesthetic.

Conclusion. In our setting, percutaneous repair and conservative management are viable alternatives to open surgery, which carries higher complications rates and was the most costly of the three. Individual patients will have different needs due to their age, occupation, or level of sporting activity.