Type III TGF-β receptor downregulation generates an immunotolerant tumor microenvironment

Cancers subvert the host immune system to facilitate disease progression. These evolved immunosuppressive mechanisms are also implicated in circumventing immunotherapeutic strategies. Emerging data indicate that local tumor-associated DC populations exhibit tolerogenic features by promoting Treg development; however, the mechanisms by which tumors manipulate DC and Treg function in the tumor microenvironment remain unclear. Type III TGF-β receptor (TGFBR3) and its shed extracellular domain (sTGFBR3) regulate TGF-β signaling and maintain epithelial homeostasis, with loss of TGFBR3 expression promoting progression early in breast cancer development. Using murine models of breast cancer and melanoma, we elucidated a tumor immunoevasion mechanism whereby loss of tumor-expressed TGFBR3/sTGFBR3 enhanced TGF-β signaling within locoregional DC populations and upregulated both the immunoregulatory enzyme indoleamine 2,3-dioxygenase (IDO) in plasmacytoid DCs and the CCL22 chemokine in myeloid DCs. Alterations in these DC populations mediated Treg infiltration and the suppression of antitumor immunity. Our findings provide mechanistic support for using TGF-β inhibitors to enhance the efficacy of tumor immunotherapy, indicate that sTGFBR3 levels could serve as a predictive immunotherapy biomarker, and expand the mechanisms by which TGFBR3 suppresses cancer progression to include effects on the tumor immune microenvironment.     

Peer Reviewed: Anthropometric Measures,Presence of Metabolic Syndrome,and Adherence to Physical Activity Guidelines Among African American Church Members,Dallas, Texas, 2008

Introduction

The low prevalence of physical activity among African Americans and high risk of cardiovascular disease lends urgency to assessing the association between metabolic syndrome, abdominal obesity, and adherence to current physical activity guidelines. Few studies have examined this association among African American adults.

Methods

We examined the association between demographic characteristics, anthropometric measures, and metabolic syndrome and adherence to the 2008 Department of Health and Human Services guidelines for moderate and vigorous physical activity. Participants were 392 African American church members from congregations in Dallas, Texas. Physical activity levels were assessed via a validated questionnaire (7-Day Physical Activity Recall), and metabolic syndrome was determined on the basis of the American Heart Association/National Heart, Lung, and Blood Institute diagnostic criteria. We used bivariate and multinomial logistic regression to examine the associations.

Results

Meeting guidelines for vigorous physical activity was significantly and independently associated with the absence of metabolic syndrome among women (odds ratio, 4.71; 95% confidence interval, 1.63-13.14; P = .003), after adjusting for covariates. No association was found between meeting moderate or vigorous physical activity guidelines and metabolic syndrome among men. Meeting physical activity guidelines was not associated with body mass index or waist circumference among this sample of predominantly overweight and obese African American church members.

Conclusion

Results indicate that meeting the 2008 guidelines for vigorous physical activity is associated with the absence of metabolic syndrome among African American women. This finding might suggest the need to integrate vigorous physical activity into interventions for African American women as a preventive therapy for cardiovascular risk.      

Complications and long-term outcome of primary obstructive megaureter in childhood

We assessed the clinical outcome of 49 children with 56 primary obstructive megaureters (POM) treated with the primarily conservative approach recommended by the 2001 German consensus guidelines. POM occurred more often in boys (71%) and on the left side (67%). Forty-three POM (77%) were treated conservatively. Four kidneys underwent immediate surgery and nine of 52 kidneys managed primarily conservatively worsened subsequently, requiring surgery. Urinary tract infections (UTI) were the most common complication (mean 1.3 per patient), with frequent hospital admission (45%). During the first year of life, the incidence of UTIs was 55% less during prophylactic antibiotic treatment (0.94 vs.0.42 UTIs per year, p < 0.05). Spontaneous regression occurred in 80% of POMs with dilated non-obstructive renogram, but in <20% with intermediate or relevant obstruction. All megaureters with <8.5 mm sonographic diameter regressed, but none over 15 mm. Eight patients had a poor outcome (partial kidney function <40% (n = 6), renal atrophy (n = 3)), but in seven of the patients, these findings were already present postnatally. In summary, the long-term outcome of POM appears favorable with mainly conservative treatment. UTI as the most common complication was 55% lower with antibiotic prophylaxis in infants. Adverse outcome was more closely related to congenital kidney hypoplasia than to degree of obstruction.     

User-guided 3D active contour segmentation of anatomical structures: significantly improved efficiency and reliability

Active contour segmentation and its robust implementation using level set methods are well-established theoretical approaches that have been studied thoroughly in the image analysis literature. Despite the existence of these powerful segmentation methods, the needs of clinical research continue to be fulfilled, to a large extent, using slice-by-slice manual tracing. To bridge the gap between methodological advances and clinical routine, we developed an open source application called ITK-SNAP, which is intended to make level set segmentation easily accessible to a wide range of users, including those with little or no mathematical expertise. This paper describes the methods and software engineering philosophy behind this new tool and provides the results of validation experiments performed in the context of an ongoing child autism neuroimaging study. The validation establishes SNAP intrarater and interrater reliability and overlap error statistics for the caudate nucleus and finds that SNAP is a highly reliable and efficient alternative to manual tracing. Analogous results for lateral ventricle segmentation are provided.     

Evaluating the clinical skills of osteopathic medical students

Because clinical skills play an important role in health services, many medical credentialing organizations are making performance-based assessments part of the board-certification and licensure processes. While clinical skills are taught and evaluated at colleges of osteopathic medicine, the development and validation of standardized assessment methodologies is far from complete. The purpose of this study was to gather data to support the use of a performance-based assessment of osteopathic clinical skills. A sample of 121 fourth-year osteopathic medical students was tested using the Comprehensive Osteopathic Medical Licensing Examination-USA performance-based clinical skills examination (COMLEX-USA-PE) prototype, a standardized patient performance evaluation that involves a series of 12 simulated encounters. Students were evaluated in a number of domains that included history taking, physical examination, osteopathic manipulative treatment techniques, written communication and clinical problem solving, and physician-patient communication. The analysis of data from 1452 standardized patient encounters suggests that reliable and valid scores can be obtained using the current prototype. The use of COMLEX-USA-PE to assess the readiness of osteopathic medical students to provide patient care in supervised graduate medical education training programs is supported.     

Using National Medical Care Survey data to validate examination content on a performance-based clinical skills assessment for osteopathic physicians

Patient characteristics, chief complaints, and diagnoses can be used to specify the examination content for performance-based assessments of clinical skills. The purpose of this investigation was to explore osteopathic and allopathic medical practice patterns and to provide summary statistics that can be used to delimit potential assessment content areas for a clinical skills assessment targeted at osteopathic physicians. Analyses of the National Ambulatory Medical Care Survey indicated that the types of patients seen by osteopathic and allopathic physicians in office-based settings are somewhat different. Furthermore, the reasons that patients seek care, and accompanying diagnostic outcomes, can vary by physician type. These differences suggest that from a content perspective, a performance-based clinical skills evaluation targeted at osteopathic physicians should be characteristically different from one designed for allopathic physicians.     

Maternal serum free beta-hCG levels in uncomplicated pregnancies at the 10th-15th week of gestation and the development of obstetric complications

OBJECTIVE: To determine if free beta-human chorionic gonadotropin (hCG) serum levels at the 10th-14th week of gestation were different in groups of women who had experienced pregnancy complications. STUDY DESIGN: The obstetric records of women who had uncomplicated pregnancies when they consented to donate blood for biochemical research purposes early in pregnancy were reviewed. Two hundred thirteen of these women had donated blood at the 10th-14th week of gestation. Of these, 135 had uneventful pregnancies and delivered at term, 19 delivered before 37 weeks'gestation, 10 had fetuses small for gestational age, 4 developed pregnancy-induced hypertension, 7 developed gestational diabetes, 10 aborted spontaneously, 4 had an intrauterine fetal death after 20 weeks' gestation, and 24 were lost to follow-up. After the clinical groups had been identified, the 213 maternal serum stored samples were thawed and free beta-hCG measured by enzyme-linked immunosorbent assay. After normalization of the data, ANOVA was used to compare mean gestational age and mean free beta-hCG levels within groups. RESULTS: The overall mean gestational age at maternal blood sampling was 12.5 weeks. All groups had similar gestational ages at blood sampling (P = .18). The overall mean free beta-hCG serum level was 18.05 mIU/mL. Only the group of women who went on to experience spontaneous abortions had significantly lower free beta-hCG lev- els (mean, 10.45 mIU/mL; P < .03) CONCLUSION: Our data suggest that of the groups with obstetric complications evaluated, only the group of women who experienced spontaneous abortions had significantly different serum levels of free beta-hCG at the 10th-14th week of gestation.