Malignant Hidradenocarcinoma in the Lower Extremity: A Case Report of a Rare Tumor.

Malignant hidradenocarcinomas are rare soft tissue tumors of sweat gland origin. We present the case of a soft tissue, fungating tumor of 15 years' duration of the medial ankle in an 85-year-old male that exhibited malignant features clinically and radiographically. Subsequent punch biopsy revealed a diagnosis of malignant hidradenocarcinoma. Given the risk of recurrence and the poor radiation and chemotherapy options, the patient initially decided to leave the lesion untreated. However, he soon developed lower extremity cellulitis from the exposed lesion and decided to have the tumor excised, eliminating the source of the infection. In the present case study, we discuss the etiology, clinical and radiographic characteristics, and treatment options for this rare lesion. At the 18-month follow-up visit, he had had no recurrence of the lesion.

Targeted attenuation of elevated histone marks at SNCA alleviates α-synuclein in Parkinson's disease.

Epigenetic deregulation of α-synuclein plays a key role in Parkinson's disease (PD). Analysis of the SNCA promoter using the ENCODE database revealed the presence of important histone post-translational modifications (PTMs) including transcription-promoting marks, H3K4me3 and H3K27ac, and repressive mark, H3K27me3. We investigated these histone marks in post-mortem brains of controls and PD patients and observed that only H3K4me3 was significantly elevated at the SNCA promoter of the substantia nigra (SN) of PD patients both in punch biopsy and in NeuN-positive neuronal nuclei samples. To understand the importance of H3K4me3 in regulation of α-synuclein, we developed CRISPR/dCas9-based locus-specific H3K4me3 demethylating system where the catalytic domain of JARID1A was recruited to the SNCA promoter. This CRISPR/dCas9 SunTag-JARID1A significantly reduced H3K4me3 at SNCA promoter and concomitantly decreased α-synuclein both in the neuronal cell line SH-SY5Y and idiopathic PD-iPSC derived dopaminergic neurons. In sum, this study indicates that α-synuclein expression in PD is controlled by SNCA's histone PTMs and modulation of the histone landscape of SNCA can reduce α-synuclein expression.

Impact of tumor-derived CCL2 on T cell effector function.

To study the effects of tumor-derived monocyte chemoattractant protein-1 (MCP-1, CCL2) on the anti-tumor immune response we used the 4T1 murine mammary carcinoma which constitutively expresses CCL2. We generated 4T1 that do not express detectable levels of CCL2 and found that the T cell response to the tumors were altered. Lymph nodes draining the CCL2- tumor contained CD62Llo cells that produced greater levels of INF-gamma in response to the tumor than CD62Llo cells from lymph nodes draining a tumor that produced CCL2. Moreover, exposure of splenic T cells to recombinant CCL2 in vitro decreased the ability of the T cells to produce IFN-gamma. However, despite the enhanced effector function evident in the absence of CCL2, vaccination/challenge experiments failed to reveal an increase in immunogenicity of the CCL2 null cells relative to the CCL2+ cells. Collectively, these data indicate that tumor-derived CCL2 could decrease T cell effector function, yet not the overall immunogenicity of the tumor.

A dual role for tumor-derived chemokine RANTES (CCL5).

To investigate the role of tumor-derived CCL5 (regulated upon activation, normal T cell expressed and secreted, RANTES) in tumor immunity we compared the T cell response to tumors derived from the 4T1 murine mammary carcinoma cell line that express different levels of CCL5. Tumors that expressed low levels of CCL5 exhibited a decrease in the in vivo, but not the in vitro, growth rate. In conjunction with the decreased growth rate the tumors that produced lower levels of CCL5 contained a greater number of tumor infiltrating lymphocytes compared to tumors that express normal levels of CCL5. One explanation for these findings was that a reduction in tumor-derived CCL5 prevented the tumor-associated alteration in T cell chemotactic activity. Tumors expressing lower levels of CCL5 also elicited a greater tumor-specific T cell response as evident by examination of recently activated T cells from tumor-draining lymph nodes. However, despite the enhanced T cell response, tumors expressing low levels of CCL5 still grew slower than tumors expressing normal levels of CCL5 in SCID mice. These data are consistent with the ability of CCL5 to upregulate transcription of matrix metalloproteinase-9 (MMP9), which can contribute to angiogenesis and thus, foster growth in vivo. Consequently, these data indicate that tumor-derived CCL5 can inhibit the T cell response and enhance the in vivo growth of murine mammary carcinoma.

Altered chemokine receptor sensitivity in FVBN202 rat neu transgenic mice.

We report here that breast cancer cells from spontaneous tumors that arise in rat neu transgenic mice produce several chemokines capable of acting upon cells of the immune system. Moreover, mice bearing these spontaneous tumors possess splenic T cells as well as CD11c+, CD11b+ and CD19+ cells with an altered sensitivity to recombinant chemokines compared to naïve mice. A comparison between T-cell migration and the level of chemokines produced by the tumor cells revealed that the altered chemotactic activity was not a direct consequence of tumor-derived chemokines. These data suggest that a growing tumor may indirectly alter leukocyte chemotactic activity.