Fibroblasts drive an immunosuppressive and growth-promoting microenvironment in breast cancer via secretion of Chitinase 3-like 1.

Cancer-Associated Fibroblasts (CAFs) are the most prominent stromal cell type in breast tumors. CAFs promote tumor growth and metastasis by multiple mechanisms, including by mediating tumor-promoting inflammation. Immune modulation in the tumor microenvironment plays a central role in determining disease outcome. However, the functional interactions of CAFs with immune cells are largely unknown. Here we report a novel signaling axis between fibroblasts, cancer cells and immune cells in breast tumors that drives an immunosuppressive microenvironment, mediated by CAF-derived Chi3L1. We demonstrate that Chi3L1 is highly upregulated in CAFs isolated from mammary tumors and pulmonary metastases of transgenic mice, and in the stroma of human breast carcinomas. Genetic ablation of Chi3L1 in fibroblasts in vivo attenuated tumor growth, macrophage recruitment and reprogramming to an M2-like phenotype, enhanced tumor infiltration by CD8+ and CD4+ T cells and promoted a Th1 phenotype. These results indicate that CAF-derived Chi3L1 promotes tumor growth and shifts the balance of the immune milieu towards type 2 immunity. Taken together, our findings implicate fibroblast-derived Chi3L1 as a novel key player in the complex reciprocal interactions of stromal cells that facilitate tumor progression and metastasis, and suggest that targeting Chi3L1 may be clinically beneficial in breast cancer.

Safety of the live, attenuated varicella vaccine in pediatric recipients of hematopoietic SCTs.

VZV is an important cause of morbidity and mortality among patients after hematopoietic SCT (HSCT). There is controversy surrounding the use of the live attenuated varicella vaccine (LAVV) in this population due to concerns that the immunization may cause VZ-related disease. The Blood and Marrow Transplant (BMT) group at the University of California, San Francisco (UCSF) Children's Hospital has been recommending the LAVV for immunocompetent HSCT patients since 1995. We retrospectively examined the incidence of post-immunization complications attributable to the LAVV in pediatric patients after HSCT. We also reported seroconversion rates when possible. Among 68 recipients of the LAVV after HSCT, 3 (4.4%; 95% confidence interval (CI)=1.0-12.7%) experienced mild-to-moderate symptoms potentially attributable to vaccination, and there were no severe reactions. Among 28 patients analyzed for seroconversion, 18 (64.3%; 95% CI=45.8-79.4%) seroconverted, 3 (10.7%; 95% CI 2.9-28.0%) possibly seroconverted and 7 (25.0%; 95% CI=12.4-43.6%) failed to seroconvert. It appears safe to administer the LAVV to immunocompetent patients after HSCT. Prospective studies are needed to more accurately determine rates of vaccine complications, efficacy and immunologic responses to vaccination.

Functional variant of KLOTHO: a breast cancer risk modifier among BRCA1 mutation carriers of Ashkenazi origin.

Klotho is a transmembrane protein that can be shed and act as a circulating hormone and is a putative tumor suppressor in breast cancer. A functional variant of KLOTHO (KL-VS) contains two amino acid substitutions F352V and C370S and shows reduced activity. Germ-line mutations in BRCA1 and BRCA2 substantially increase lifetime risk of breast and ovarian cancers. Yet, penetrance of deleterious BRCA1 and BRCA2 mutations is incomplete even among carriers of identical mutations. We examined the association between KL-VS and cancer risk among 1115 Ashkenazi Jewish women: 236 non-carriers, 631 BRCA1 (185delAG, 5382insC) carriers and 248 BRCA2 (6174delT) carriers. Among BRCA1 carriers, heterozygosity for the KL-VS allele was associated with increased breast and ovarian cancer risk (hazard ratio 1.40, 95% confidence intervals 1.08-1.83, P=0.01) and younger age at breast cancer diagnosis (median age 48 vs 43 P=0.04). KLOTHO and BRCA2 are located on 13q12, and we identified linkage disequilibrium between KL-VS and BRCA2 6174delT mutation. Studies in breast cancer cells showed reduced growth inhibitory activity and reduced secretion of klotho F352V compared with wild-type klotho. These data suggest KL-VS as a breast and ovarian cancer risk modifier among BRCA1 mutation carriers. If validated in additional cohorts, the presence of KL-VS may serve as a predictor of cancer risk among BRCA1 mutation carriers.

The unpredictability of seal after post space preparation: a fluid transport study.

A root canal filling remaining after post space preparation is commonly expected to provide adequate seal. Coronal leakage of 30 endodontically treated teeth was measured before post space preparation using a fluid transport assay. In 10 of these teeth post space was prepared, using a two-step procedure, first to a remaining filling of 6 mm and then to 3 mm, with the leakage studied after each step. In 10 teeth the removal was done in one step to a remaining length of 3 mm. The other 10 teeth, with intact root canal fillings, served as controls and were tested twice for leakage. A significant difference was found between the sealing ability of intact fillings and that of partially removed ones (p < 0.05). The difference between the sealing ability of 3 and 6 mm remaining length group was not statistically significant. The lack of statistical differences between the 6 mm and 3 mm fillings was due to a great variability which existed among the 3 mm remaining fillings. These results suggest that 3 to 6 mm fillings provided a seal inferior to that of intact root canal fillings. Reduction of the fillings to 3 mm resulted in an unpredictable seal.

Correlation between remaining length of root canal fillings after immediate post space preparation and coronal leakage.

The seal provided by root canal fillings after post space preparation was studied using a pressure-driven radioactive tracer assay. The coronal part of root canal fillings was immediately removed, using a hot plugger, to a remaining length of either 3, 5, 7, or 9 mm. Intact root canal fillings of 14 mm served as control. Application of air pressure of 130 mm Hg to the tracer solution drove it through the fillings and into phosphate-buffered saline surrounding the apex. Leakage gradually increased for 28 days, and differences in the leakage through 3 to 9 mm fillings were demonstrated. In a passive system by which an additional group of teeth were tested none of these differences could be detected. It was concluded that: (a) root canal fillings of 3, 5, and 7 mm have an inferior seal, compared with that of an intact filling; (b) the sealing is proportional to the length of the remaining filling; and (c) a passive system is unable to detect these differences, even when conducted for as long as 28 days.

Starved Saccharomyces cerevisiae cells have the capacity to support internal initiation of translation.

Internal initiation of translation, whereby ribosomes are directed to internal AUG codon independently of the 5' end of the mRNA, has been observed rarely in higher eucaryotes and has not been demonstrated in living yeast. We report here that starved yeast cells are capable of initiating translation of a dicistronic message internally. The studied element that functions as an internal ribosome entry site (IRES) is hardly functional or not functional at all in logarithmically growing cells. Moreover, during the logarithmic growth phase, this element seems to inhibit translation reinitiation when placed as an intercistronic spacer or to inhibit translation when placed in the 5'-untranslated region of a monocistronic message. Inhibition of translation is likely due to the putative strong secondary structure of the IRES that interferes with the cap-dependent scanning process. When cells exit the logarithmic growth phase, or when artificially starved for carbon source, translation of the IRES-containing messages is substantially induced. Our findings imply that the capacity to translate internally is a characteristic of starved rather than vegetatively growing yeast cells.

Pediatric bone marrow transplantation update.

PURPOSE/OBJECTIVES: To review the diseases of childhood for which bone marrow transplantation (BMT) is an accepted treatment modality. DATA SOURCES: Book chapters, journal articles. DATA SYNTHESIS: BMT is used to treat a wide variety of nonmalignant and malignant childhood conditions. Despite treatment successes, BMT and its complications present a serious threat to children and a challenge for care providers. Identification of suitable donors is an ongoing concern. CONCLUSIONS: Acute and chronic/long-term effects of BMT are many and varied. Care of children and their families is ongoing and critical to achieving quality of life following successful transplantation. IMPLICATIONS FOR NURSING PRACTICE: In addition to the intensive care required by BMT, nurses must be knowledgeable about normal growth and development and encourage each child to achieve his or her full potential.

What teachers want to know about students with cancer.

This article reports the results of a survey of classroom teachers in elementary and high schools in the San Francisco Bay Area. The teachers were asked to respond to questions about their informational needs and concerns related to students in their classroom who were diagnosed with cancer or receiving cancer treatment. Findings indicated that classroom teachers perceive themselves to be ill prepared to address the needs of the student with cancer. Specific concerns clustered around information deficits regarding the students' physiological and physical vulnerability, physical limitations/alterations following treatment, psychological responses to cancer treatment, and peer interactions. Utilizing data from the survey, a conceptual approach and collaborative intervention scheme were developed.