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National Cancer Institute State of the Science Conference on thyroid fine-needle aspiration (FNA) summarized diagnostic terminology. Six diagnostic categories were proposed including "follicular lesion of undetermined significance" (FLUS). FLUS was defined as findings neither convincingly benign nor sufficiently atypical for a diagnosis of "follicular neoplasm" or "suspicious for malignancy." It was proposed that this category represent less than 7% of thyroid FNAs. A search of the cytology records at three University Hospitals was performed for the term FLUS or older equivalent terms. Usage of FLUS was compared between institutions and among pathologists. Surgical pathology outcome for FLUS cases was determined. Twenty-eight pathologists evaluated 6,872 cases at the three institutions. Use of FLUS varied among pathologists (2.5 to 28.6%). Frequency of use of FLUS among institutions varied from 3.3 to 14.9%. FLUS cases [127 of 673 (18.9%)] underwent surgical exploration with malignancy identified in 36 cases (28.3%) undergoing resection. Use of FLUS varied substantially among pathologists and institutions. FLUS category requires more rigorously defined morphologic criteria for it to become a useful guide in clinical management.

Two-pore domain K(+) (K2P) channels have been cloned from a variety of species and tissues. They have been characterised biophysically as a 'background' K(+)-selective conductance and are gated by pH, stretch, heat, coupling to G-proteins and anaesthetics. Whilst their precise physiological function is unknown, they are likely to represent an increasingly important family of membrane proteins.

TASK-1 and -2 are members of the two-pore domain potassium (K(+)) channel family and are sensitive to changes in extracellular pH. The effects of mutating charged, extracellular-facing residues in TASK-1 and -2 were studied in Xenopusoocytes by two-electrode voltage clamp. Hydrogen ion block was independent of voltage with K(d) values of 149+/-17.9 nM [H(+)] ( n=6) and 5.76+/-1.23 nM [H(+)] ( n=7) for TASK-1 and -2, respectively. Compared to wild-type TASK-1, H72N, H98N, H98D and K210N displayed significant shifts in their K(d) values for hydrogen ion block ([H(+)]; 110+/-9.80 nM, 737+/-170 nM, 321+/-85.9 nM and 267+/-9.92 nM, respectively, n=6 each, P<0.05). Although significantly reducing its pH sensitivity, mutation of H98 in TASK-1 did not abolish pH sensitivity; this implies that H98 is not the only residue or domain involved in pH sensing of TASK-1. TASK-2 does not possess a histidine residue at the homologous position. However, the inclusion of such a residue failed to produce the expected increase in pH sensitivity; instead, a slight decrease was observed. Despite their structural homology and common sensitivity to pH, the TASK family of K(+) channels apparently has diverse pH-sensing mechanisms.

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BACKGROUND: Dysgerminoma, the ovarian counterpart of seminoma, is the most common type of malignant ovarian germ cell tumor. The role of KIT mutation and amplification in the development of dysgerminoma is not currently established. The purpose of this study was to analyze alterations of the KIT gene in a large series of dysgerminomas and correlate the findings with clinicopathological parameters. METHODS: Dysgerminoma cells from 22 patients were analyzed for KIT mutations at exon 17 codon 816. KIT amplification and chromosome 12p anomalies were investigated by way of dual color fluorescence in situ hybridization. KIT protein expression was also examined by way of immunohistochemistry. RESULTS: KIT exon 17 codon 816 mutations and KIT amplification were each detected in 6 cases of dysgerminoma (27%); however, there was no correlation between these 2 factors. KIT expression was detected in 87% of dysgerminomas. The KIT mutation was associated with advanced pathological stage (P < .05), and KIT amplification was associated with elevated KIT protein expression (P < .05). Chromosome 12p anomalies were found in 82% of the dysgerminomas and did not correlate with KIT abnormalities. CONCLUSIONS: KIT mutations occur in approximately one-third of cases of dysgerminomas and are associated with advanced stage at presentation. KIT is a potential therapeutic target for those dysgerminomas that have the mutation.

TASK2 is a member of the two-pore domain K ؉ channel family that plays a role in acid-base homeostasis; TASK2 knockout animals have plasma electrolyte patterns typical of the human clinical condition of renal tubular acidosis. It is expressed preferentially in epithelia, including the proximal tubules of the kidney. In common with the other TASK channels, TASK2 is sensitive to changes in extracellular pH, although the molecular mechanism of such pH sensing is not understood. We have examined the role of charged residues in the extracellular domains in pH sensing using a mutational approach. Mutant channels were expressed in CHO cells and studied by whole-cell and single-channel patch clamp. Neutralization of no single amino acid in isolation gave complete loss of pH sensitivity. However, the combined removal of five charged amino acids in the large extracellular loop linking the first transmembrane and pore domains, the M1-P1 loop, resulted in an essentially pH-insensitive channel, stabilized in the open state. Wild-type channels contain two such loops, but a concatemeric construct, comprised of one wild-type subunit and one containing the five mutations, was fully pH-sensitive, indicating that only one M1-P1 loop is required to yield a fully pH-sensitive channel, demonstrating a regulatory role of this distinctive structure in two-pore domain K ؉ channels. Thus, pH sensing in TASK2 channels is conferred by the combined action of several charged residues in the large extracellular M1-P1 loop.potassium channel ͉ regulation ͉ acid ͉ proton ͉ gating