Human immunodeficiency virus (HIV) protease inhibitors (PIs) act as reversible noncompetitive inhibitors of GLUT4 with binding affinities in the low micromolar range and are known to contribute to alterations in glucose homeostasis during treatment of HIV infection. As aspartyl protease inhibitors, these compounds all possess a core peptidomimetic structure together with flanking hydrophobic moieties. To determine the molecular basis for GLUT4 inhibition, a family of related oligopeptides containing structural elements found in PIs was screened for their ability to inhibit 2-deoxyglucose transport in primary rat adipocytes. The peptide oxybenzylcarbonyl-His-Phe-Phe-O-ethyl ester (zHFFe) was identified as a potent inhibitor of zero-trans glucose flux with a K i of 26 M. Similar to PIs, transport inhibition by this peptide was acute, noncompetitive, and reversible. Within a Xenopus oocyte expression system, zHFFe acutely and reversibly inhibited GLUT4-mediated glucose uptake, whereas GLUT1 activity was unaffected at concentrations as high as 1 mM. The related photoactivatable peptide zHFF-p-benzoylphenylalanine-[125 I]Tyr-O-ethyl ester selectively labeled GLUT4 in rat adipocytes and indinavir effectively protected against photolabeling. Furthermore, GLUT4 bound to a peptide affinity column containing the zHFF sequence and was eluted by indinavir. These data establish a structural basis for PI effects on GLUT4 activity and support the direct binding of PIs to the transport protein as the mechanism for acute inhibition of insulin-stimulated glucose uptake.

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The microcystic elongated and fragmented (MELF) pattern of myoinvasion is a feature of some well-differentiated endometrial endometrioid adenocarcinomas that has been associated with poor prognosis. The myoinvasion in MELF-pattern tumors can be subtle and lead to underestimation of the depth of myometrial invasion resulting in tumor understaging; the presence of lymphvascular space invasion (LVSI) and lymph node metastasis in MELF-pattern tumors can also be subtle and lead to tumor understaging. To investigate the association of MELF-pattern invasion and lymph node metastasis, we reviewed a series of well-differentiated endometrioid adenocarcinomas and correlated the presence of MELF-pattern myoinvasion and LVSI with lymph node metastasis. Cases of T1 stage well-differentiated endometrioid adenocarcinomas with LVSI and a concurrent lymph node dissection were identified from departmental files. Hematoxylin and eosin-stained slides from the hysterectomy specimen and lymph nodes were reviewed for the presence of MELF-pattern myoinvasion, LVSI, and nodal metastasis. MELF-pattern myoinvasion was identified at least focally in 36% of cases. The pattern of LVSI differed between cases with MELF-pattern invasion and conventional-type invasion, as did the pattern of nodal metastasis. A statistically significantly higher rate of lymph node metastasis was present in cases with MELF-pattern invasion than in cases with conventional invasion, and the rate stratified with the proportion of MELF-pattern adenocarcinomas. MELF-pattern cases carry an increased rate of lymph node metastasis even within the subset of endometrioid tumors with LVSI, which has implications in routine clinical practice as it signals the importance of recognizing MELF-pattern myoinvasion.

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Objective: Breast MRI is used to screen high-risk patients and determine extent of disease in breast cancer (BC) patients. The goal of this study was to determine the pathologic correlates of breast MRI abnormalities biopsied under MRI guidance. Methods:We retrospectively identified 101 MRI-guided core needle biopsies (CNB) of the breast from 79 women over a 4-year period. MRI-detected lesions biopsied with ultrasound or stereotactic guidance were excluded. MRI studies and pathology were reviewed by breast radiologists and pathologists.Results: Of the 79 patients, 72 (91%) had a history of prior (n=13) or concurrent (n=59) BC. There were 101 MRI abnormalities: 60 (59%) with non-mass enhancement (NME) and 41 (41%) with mass enhancement. Pathology was benign in 83/101 (82%), including in the majority of NME lesions (43/60, 72%). The most common benign findings were: fibrocystic changes (FCC) (49%), sclerosing lesions (13%), and fibroadenoma (FA) (9%). There were 18 (18%) malignant diagnoses: 8 (44%) invasive lobular carcinoma (ILC), 7 (39%) ductal carcinoma in situ (DCIS), and 3 (17%) invasive ductal carcinoma (IDC). Of the 18 malignant diagnoses, 16 (89%) occurred in 14 unique patients with concurrent BC. Based on the malignant MRI-guided CNB, 6 (46%) of