Functional and Phenotypic Plasticity of CD4+ T Cell Subsets

The remarkable plasticity of CD4+ T cells allows individuals to respond to environmental stimuli in a context-dependent manner. A balance of CD4+ T cell subsets is critical to mount responses against pathogen challenges to prevent inappropriate activation, to maintain tolerance, and to participate in antitumor immune responses. Specification of subsets is a process beginning in intrathymic development and continuing within the circulation. It is highly flexible to adapt to differences in nutrient availability and the tissue microenvironment. CD4+ T cell subsets have significant cross talk, with the ability to “dedifferentiate” given appropriate environmental signals. This ability is dependent on the metabolic status of the cell, with mTOR acting as the rheostat. Autoimmune and antitumor immune responses are regulated by the balance between regulatory T cells and Th17 cells. When a homeostatic balance of subsets is not maintained, immunopathology can result. CD4+ T cells carry complex roles within tumor microenvironments, with context-dependent immune responses influenced by oncogenic drivers and the presence of inflammation. Here, we examine the signals involved in CD4+ T cell specification towards each subset, interconnectedness of cytokine networks, impact of mTOR signaling, and cellular metabolism in lineage specification and provide a supplement describing techniques to study these processes

Gastrointestinal stromal tumor of the appendix: case report and review of the literature

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumor of the gastrointestinal tract, but are rare in the appendix with only 14 cases reported. Here we report an additional case in the oldest patient to date and review the histologic, immunohistochemical, molecular and clinical findings

Anatomy of the upper lateral cartilage along the lateral pyriform aperture

BACKGROUND: The upper lateral cartilages underlie the nasal bones cephalically, and articulate with the nasal septum medially. The authors studied the histologic and anatomical relationships between the lateral aspect of the upper lateral cartilages and the frontal process of the maxilla. METHODS: Six cadaver noses were dissected by open rhinoplasty to expose the upper lateral cartilages bilaterally. Subperiosteal dissection was performed over the medial maxillae and nasal bones to expose the perimeter of the pyriform aperture. Twelve sides were analyzed anatomically. Three cadavers were used to create six tissue specimens for histologic analysis, by resecting the tissue of the upper lateral cartilage-maxillary bone articulation en bloc. RESULTS: Grossly in all specimens, the upper lateral cartilage articulated with the frontal process of the maxilla laterally, lying deep to the coronal plane of the maxillary bone. In four histologic specimens, the upper lateral cartilage was found to underlie the frontal process of the maxilla laterally, displaying an overlapping relationship. In the other two histologic specimens, the upper lateral cartilage ended medial to the maxilla. In all specimens, the ends of the upper lateral cartilage and maxilla articulated by way of a pyriform ligament. CONCLUSIONS: The upper lateral cartilage articulates laterally with the frontal process of the maxilla by means of the pyriform ligament, with a variable amount of overlap between the upper lateral cartilage and maxilla. Relationships among the upper lateral cartilage, maxilla, and pyriform ligament affect the configuration of the lateral internal nasal valve area, and should be considered when planning internal nasal valve reconstruction

Targeting Hsp90 in urothelial carcinoma.

Urothelial carcinoma, or transitional cell carcinoma, is the most common urologic malignancy that carries significant morbidity, mortality, recurrence risk and associated health care costs. Despite use of current chemotherapies and immunotherapies, long-term remission in patients with muscle-invasive or metastatic disease remains low, and disease recurrence is common. The molecular chaperone Heat Shock Protein-90 (Hsp90) may offer an ideal treatment target, as it is a critical signaling hub in urothelial carcinoma pathogenesis and potentiates chemoradiation. Preclinical testing with Hsp90 inhibitors has demonstrated reduced proliferation, enhanced apoptosis and synergism with chemotherapies and radiation. Despite promising preclinical data, clinical trials utilizing Hsp90 inhibitors for other malignancies had modest efficacy. Therefore, we propose that Hsp90 inhibition would best serve as an adjuvant treatment in advanced muscle-invasive or metastatic bladder cancers to potentiate other therapies. An overview of bladder cancer biology, current treatments, molecular targeted therapies, and the role for Hsp90 inhibitors in the treatment of urothelial carcinoma is the focus of this review

Is MMTV associated with human breast cancer? Maybe, but probably not

Abstract Background Conflicting results regarding the association of MMTV with human breast cancer have been reported. Published sequence data have indicated unique MMTV strains in some human samples. However, concerns regarding contamination as a cause of false positive results have persisted. Methods We performed PCR assays for MMTV on human breast cancer cell lines and fresh frozen and formalin fixed normal and malignant human breast epithelial samples. Assays were also performed on peripheral blood mononuclear cells from volunteer blood donors and subjects at risk for human retroviral infections. In addition, assays were performed on DNA samples from wild and laboratory mice. Sequencing of MMTV positive samples from both humans and mice were performed and phylogenetically compared. Results Using PCR under rigorous conditions to prevent and detect “carryover” contamination, we did detect MMTV DNA in human samples, including breast cancer. However, the results were not consistent and seemed to be an artifact. Further, experiments indicated that the probable source of false positives was murine DNA, containing endogenous MMTV, present in our building. However, comparison of published and, herein, newly described MMTV sequences with published data, indicates that there are some very unique human MMTV sequences in the literature. Conclusion While we could not confirm the true presence of MMTV in our human breast cancer subjects, the data indicate that further, perhaps more traditional, retroviral studies are warranted to ascertain whether MMTV might rarely be the cause of human breast cancer