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Tumor-associated macrophages (TAM) with an M2-like phenotype have been linked to tumor-elicited inflammation, immunosuppression, and resistance to chemotherapies in cancer, thus representing an attractive target for an effective cancer immunotherapy. Here, we demonstrate that particulate yeast-derived β-glucan, a natural polysaccharide compound, converts polarized M2 macrophages or immunosuppressive TAM into an M1-like phenotype with potent immuno-stimulating activity. This process is associated with macrophage metabolic reprograming with enhanced glycolysis, krebs cycle and glutamine utilization. In addition, particulate β-glucan converts immunosuppressive TAM via the C-type lectin receptor dectin-1-induced Syk-Card9-Erk pathway. Further in vivo studies show that oral particulate β-glucan treatment significantly delays tumor growth, which is associated with in vivo TAM phenotype conversion and enhanced effector T cell activation. Mice injected with particulate β-glucan-treated TAM mixed with tumor cells have significantly reduced tumor burden with less blood vascular vessels compared to those with TAM plus tumor cell injection. In addition, macrophage depletion significantly reduced the therapeutic efficacy of particulate β-glucan in tumor-bearing mice. These findings have established a new paradigm for macrophage polarization and immunosuppressive TAM conversion and shed the light on the action mode of β-glucan treatment in cancer.

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We have previously reported that high aldehyde dehydrogenase (ALDH) enzyme activity in breast cancer cells results in breast cancer stem cell (BCSC) properties by upregualting Notch-1 and epithelial mesenchymal markers. This results in chemoresistance in breast cancer. Here, we examined the functional and clinical significance of ALDH expression by measuring the ALDH levels in breast cancer tissues by immunohistochemistry. There was a significantly higher ALDH expression in higher grade breast cancer tumor tissues (Grade- II and III) versus normal breast tissues. Injection of BCSC (ALDH and CD44 /CD22 ) cells resulted in aggressive tumor growth in athymic mice versus ALDH cells. The ALDH and CD44 /CD22 tumors grow rapidly and are larger than ALDH tumors which were slow growing and smaller. Molecularly, ALDH tumors expressed higher expression of Notch-1 and EMT markers than ALDH tumors. Oral administration of the naturally occurring Psoralidin (Pso, 25 mg/kg of body weight) significantly inhibited the growth in ALDH and ALDH tumors as well. Psoralidin inhibited Notch-1 mediated EMT activation in ALDH and ALDH tumors-this confirms our in vitro findings. Our results suggest that Notch-1 could be an attractive target and inhibition of Notch-1 by Psoralidin may prevent pathogenesis of breast cancer as well as metastasis. © 2016 Wiley Periodicals, Inc.

Currently radiologists have the option of subcategorizing BI-RADS 4 breast lesions into 4A (low suspicion for malignancy), 4B (intermediate suspicion of malignancy), and 4C (moderate concern, but not classic for malignancy). To determine the clinical significance of BI-RADS 4 subcategories and the common pathologic changes associated with these mammographic lesions, a retrospective review of 239 consecutive stereotactic-needle core biopsies (SNCB) for microcalcifications was performed. All 239 SNCBs were BI-RADS 4 lesions, and of these, 191 were subcategorized to 4A, 4B or 4C. Ninety-four of 191 (49%) were 4A, 73 (38%) were 4B, and 24 (13%) were 4C. Fibrocystic change was the most common finding (66/239; 28%) followed by ductal carcinoma in situ (DCIS) accounting for 23% of cases. This was followed by columnar cell alteration with or without atypia (47/239; 19%), and fibroadenoma (45/239; 19%). While 70% (17/24) of BI-RADS 4C category lesions were DCIS, only 21% (15/73) of BI-RADS 4B and 10% (10/94) of BI-RADS 4A were DCIS. Without sub-categorization, carcinoma was diagnosed in 23% (55/239) of all cases with BI-RADS 4. Therefore, subcategorizing BI-RADS 4 lesions is important since it not only benefits the patient and clinician in understanding the level of concern for carcinoma, but will also alert the pathologist.

Differentiated vulvar intraepithelial neoplasia (dVIN), precursor of vulvar squamous cell carcinoma, is human papilloma virus independent and often found in a background of lichen sclerosus (LS) and lichen simplex chronicus (LSC). Subtle histologic findings make the diagnosis of dVIN difficult, and, although the use of p53 and Ki-67 has been of some value, there is a need for a better immunohistochemical marker. Cytokeratin 17 (CK17), a cytoskeletal intermediate filament protein, has previously been used in the diagnosis of anogenital lesions. Here we evaluated CK17 in dVIN in comparison with LS, LSC, and usual VIN (uVIN/HSIL). Twenty-nine cases of dVIN, 9 cases of uVIN, 8 cases of LS, and 7 of LSC were evaluated using CK17, Ki-67, and p53. All 29 dVIN cases displayed immunoreactivity for CK17, with 27 (93%) showing intermediate to strong and diffuse reactivity. No cases of uVIN displayed diffuse CK17 expression, whereas 63% of LS and 29% of LSC displayed intermediate to strong diffuse immunoreactivity, confined to the upper half of the epithelium. P53 and Ki-67 expression was present in varying degrees in all types of lesions, displaying limited discriminatory power for dVIN. Our findings suggest that CK17, although not specific for dVIN, when combined with histologic findings, Ki-67, and p53 immunohistochemistry, can be a marker of vulvar dysplasia and serve as an adjunct in the diagnosis of dVIN. Specifically, in small biopsies, the presence of diffuse suprabasal or full thickness expression strongly favors a diagnosis of dVIN over LSC, whereas focal and/or superficial expression supports a diagnosis of LSC.

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