cDNA and genomic cloning of lacritin, a novel secretion enhancing factor from the human lacrimal gland.

Multiple extracellular factors are hypothesized to promote the differentiation of unstimulated and/or stimulated secretory pathways in exocrine secretory cells, but the identity of differentiation factors, particularly those organ-specific, remain largely unknown. Here, we report on the identification of a novel secreted glycoprotein, lacritin, that enhances exocrine secretion in overnight cultures of lacrimal acinar cells which otherwise display loss of secretory function. Lacritin mRNA and protein are highly expressed in human lacrimal gland, moderately in major and minor salivary glands and slightly in thyroid. No lacritin message or protein is detected elsewhere among more than 50 human tissues examined. Lacritin displays partial similarity to the glycosaminoglycan-binding region of brain-specific neuroglycan C (32 % identity over 102 amino acid residues) and to the possibly mucin-like amino globular region of fibulin-2 (30 % identity over 81 amino acid residues), and localizes primarily to secretory granules and secretory fluid. The lacritin gene consists of five exons, displays no alternative splicing and maps to 12q13. Recombinant lacritin augments unstimulated but not stimulated acinar cell secretion, promotes ductal cell proliferation, and stimulates signaling through tyrosine phosphorylation and release of calcium. It binds collagen IV, laminin-1, entactin/nidogen-1, fibronectin and vitronectin, but not collagen I, heparin or EGF. As an autocrine/paracrine enhancer of the lacrimal constitutive secretory pathway, ductal cell mitogen and stimulator of corneal epithelial cells, lacritin may play a key role in the function of the lacrimal gland-corneal axis.

Histologic grade of locally advanced infiltrating ductal carcinoma after treatment with induction chemotherapy.

Multiagent chemotherapy is often used to treat patients with locally advanced infiltrating breast carcinoma before mastectomy. One of the most important prognostic factors, histologic grade, may be altered by induction chemotherapy. Because locally advanced infiltrating breast carcinomas are frequently diagnosed by fine-needle aspiration, histologic grade can be determined in the mastectomy specimens only after chemotherapy. Histologic grade, with its three components, was examined in 30 mastectomy specimens after induction chemotherapy for infiltrating ductal carcinoma and compared with findings in available pretreatment incisional biopsy specimens. Histologic grade for the 24 axillary lymph node-positive carcinomas treated with induction chemotherapy was compared with the grade for 24 axillary lymph node-positive ductal cancers that had been treated by surgery only. Complete, partial, or no clinical response was seen in 4 (13%), 21 (70%), and 5 (17%) patients after chemotherapy. In six of seven tumors, there was complete agreement between biopsy and postchemotherapy mastectomy specimens in grade and in scores for the three components. Half of the 24 node-positive tumors from patients treated with chemotherapy and 21% of node-positive neoplasms from patients treated initially with surgery had a mitotic count score of 1. In these two node-positive groups, 71% of tumors from patients treated with surgery and 92% of cancers from patients treated with induction chemotherapy showed a nuclear pleomorphism score of 3. For these two groups, however, there were no statistically significant differences in histologic grade or in any of its three components.