Phoenix Rising: Inside the Owner\u27s Box with Counsel to Jerry Colangelo

In late spring of 1987, I received a telephone call that changed my law practice. Jerry Colangelo, General Manager of the Suns since its arrival in Phoenix as an expansion NBA franchise in 1969, called me to discuss representing a group of investors he was putting together for the purchase of the franchise. At the time, the Suns franchise was the only major professional sports team in Arizona and had been very successful. Unfortunately, the reputation of the team, carefully nurtured from its arrival, recently had been tarnished by allegations and investigations concerning drugs. Jerry explained that the Tucson and California owners of the Suns were considering selling the franchise or moving it from Phoenix. True to an unwritten understanding with the owners, Jerry was being given an opportunity to buy the franchise if he could meet the price the owners had set. Jerry recounted that he had begun contacting investors by meeting with John W. Teets, Chairman of the Board and CEO of The Greyhound Corporation, and Greyhound\u27s General Counsel, L. Gene Lemon. He proposed that Greyhound consider becoming a lead investor. During the discussions with Greyhound, I had been recommended to assist in putting together the investment group. Having just received the call from John Teets that he was waiting for--confirming that the Board of Directors of Greyhound had voted to put up $6 million for a 25 percent interest in the team--Jerry thought it was time for me to get involved. I had moved my family to Phoenix in 1972 after obtaining an L.L.M. from the Graduate Tax Program at New York University. By 1987, I was primarily a transactional lawyer and it was as a result of several large projects for Greyhound that I became involved with the Suns. Except for a few areas (such as the organization and structure of the professional leagues and associations, player contracting and certain aspects of arena and stadium development matters), sports law differs very little from any other business practice. Needless to say, with its increasing popularity, the markets for related merchandise and business interest in seeking sponsorship and promotion opportunities, professional sports has become big business. This article covers my involvement in Phoenix during what has been a period of unprecedented growth

Effects of 3^3He Impurity on Solid 4^4He Studied by Compound Torsional Oscillator

Frequency shifts and dissipations of a compound torsional oscillator induced by solid $^4$He samples containing $^3$He impurity concentrations ($x_3$ = 0.3, 3, 6, 12 and 25 in units of 10$^{-6}$) have been measured at two resonant mode frequencies ($f_1$ = 493 and $f_2$ = 1164 Hz) at temperatures ($T$) between 0.02 and 1.1 K. The fractional frequency shifts of the $f_1$ mode were much smaller than those of the $f_2$ mode. The observed frequency shifts continued to decrease as $T$ was increased above 0.3 K, and the conventional non-classical rotation inertia fraction was not well defined in all samples with $x_3 \geq$ 3 ppm. Temperatures where peaks in dissipation of the $f_2$ mode occurred were higher than those of the $f_1$ mode in all samples. The peak dissipation magnitudes of the $f_1$ mode was greater than those of the $f_2$ mode in all samples. The activation energy and the characteristic time ($\tau_0$) were extracted for each sample from an Arrhenius plot between mode frequencies and inverse peak temperatures. The average activation energy among all samples was 430 mK, and $\tau_0$ ranged from 2$\times 10^{-7}$ s to 5$\times 10^{-5}$ s in samples with $x_3$ = 0.3 to 25 ppm. The characteristic time increased in proportion to $x_3^{2/3}$. Observed temperature dependence of dissipation were consistent with those expected from a simple Debye relaxation model \emph{if} the dissipation peak magnitude was separately adjusted for each mode. Observed frequency shifts were greater than those expected from the model. The discrepancies between the observed and the model frequency shifts increased at the higher frequency mode.Comment: 10 pages, 10 figure

Laser optical separation of chiral molecules

The optical trapping of molecules with an off-resonant laser beam involves a forward-Rayleigh scattering mechanism. It is shown that discriminatory effects arise on irradiating chiral molecules with circularly polarized light; the complete representation requires ensemble-weighted averaging to account for the influence of the trapping beam on the distribution of molecular orientations. Results of general application enable comparisons to be drawn between the results for two limits of the input laser intensity. It emerges that, in a racemic mixture, there is a differential driving force whose effect, at high laser intensities, is to produce differing local concentrations of the two enantiomers

The Icelandic founder mutation BRCA2 999del5: analysis of expression

INTRODUCTION: A founder mutation in the BRCA2 gene (BRCA2 999del5) accounts for 7–8% of female breast cancers and for 40% of male breast cancers in Iceland. If expressed, the mutant gene would encode a protein consisting of the first 256 amino acids of the BRCA2 protein. The purpose of this study was to determine whether this mutant protein is produced in heterozygous individuals and, if so, what might be the functional consequences of mutant protein production. METHODS: The presence of BRCA2 999del5 transcripts in fibroblasts from heterozygous individuals was assayed by cDNA synthesis and sequencing. The potential protein-coding portion of BRCA2 999del5 was cloned into the pIND(SP1)/V5-His vector and expressed in COS7 cells. The presence of the mutant protein in cell lysates from heterozygous fibroblasts and from COS7 cells was tested by a number of methods including immunoprecipitation, affinity purification with nickel-coated agarose beads, Western blotting and ELISA, using antibodies to the N-terminal end of BRCA2, antiserum specific for the 16 nonrelevant amino acids at the carboxyl end and antibodies to fusion partners of recombinant proteins. RESULTS: The frequency of the BRCA2 999del5 transcript in heterozygous fibroblasts was about one-fifth of the wild-type transcript; however, no mutant protein could be detected. Overexpression of BRCA2 999del5 mRNA in COS7 cells failed to produce a mutant protein unless degradation by proteasomes was blocked. CONCLUSION: Our results show that the protein product of BRCA2 999del5 is extremely unstable. Therefore, an increase in breast cancer risk in BRCA2 999del5 carriers is due to haploinsufficiency at the BRCA2 locus

Increasing the source/sink ratio in Vitis vinifera (cv Sangiovese) induces extensive transcriptome reprogramming and modifies berry ripening

<p>Abstract</p> <p>Background</p> <p>Cluster thinning is an agronomic practice in which a proportion of berry clusters are removed from the vine to increase the source/sink ratio and improve the quality of the remaining berries. Until now no transcriptomic data have been reported describing the mechanisms that underlie the agronomic and biochemical effects of thinning.</p> <p>Results</p> <p>We profiled the transcriptome of <it>Vitis vinifera </it>cv. Sangiovese berries before and after thinning at veraison using a genome-wide microarray representing all grapevine genes listed in the latest V1 gene prediction. Thinning increased the source/sink ratio from 0.6 to 1.2 m²leaf area per kg of berries and boosted the sugar and anthocyanin content at harvest. Extensive transcriptome remodeling was observed in thinned vines 2 weeks after thinning and at ripening. This included the enhanced modulation of genes that are normally regulated during berry development and the induction of a large set of genes that are not usually expressed.</p> <p>Conclusion</p> <p>Cluster thinning has a profound effect on several important cellular processes and metabolic pathways including carbohydrate metabolism and the synthesis and transport of secondary products. The integrated agronomic, biochemical and transcriptomic data revealed that the positive impact of cluster thinning on final berry composition reflects a much more complex outcome than simply enhancing the normal ripening process.</p

Spectrum and characterisation of BRCA1 and BRCA2 deleterious mutations in high-risk Czech patients with breast and/or ovarian cancer

<p>Abstract</p> <p>Background</p> <p>The incidence of breast cancer has doubled over the past 20 years in the Czech Republic. Hereditary factors may be a cause of young onset, bilateral breast or ovarian cancer, and familial accumulation of the disease. <it>BRCA1 </it>and <it>BRCA2 </it>mutations account for an important fraction of hereditary breast and ovarian cancer cases. One thousand and ten unrelated high-risk probands with breast and/or ovarian cancer were analysed for the presence of a <it>BRCA1 </it>or <it>BRCA2 </it>gene mutation at the Masaryk Memorial Cancer Institute (Czech Republic) during 1999–2006.</p> <p>Methods</p> <p>The complete coding sequences and splice sites of both genes were screened, and the presence of large intragenic rearrangements in <it>BRCA1 </it>was verified. Putative splice-site variants were analysed at the cDNA level for their potential to alter mRNA splicing.</p> <p>Results</p> <p>In 294 unrelated families (29.1% of the 1,010 probands) pathogenic mutations were identified, with 44 different <it>BRCA1 </it>mutations and 41 different <it>BRCA2 </it>mutations being detected in 204 and 90 unrelated families, respectively. In total, three <it>BRCA1 </it>founder mutations (c.5266dupC; c.3700_3704del5; p.Cys61Gly) and two <it>BRCA2 </it>founder mutations (c.7913_7917del5; c.8537_8538del2) represent 52% of all detected mutations in Czech high-risk probands. Nine putative splice-site variants were evaluated at the cDNA level. Three splice-site variants in <it>BRCA1 </it>(c.302-3C>G; c.4185G>A and c.4675+1G>A) and six splice-site variants in <it>BRCA2 </it>(c.475G>A; c.476-2>G; c.7007G>A; c.8755-1G>A; c.9117+2T>A and c.9118-2A>G) were demonstrated to result in aberrant transcripts and are considered as deleterious mutations.</p> <p>Conclusion</p> <p>This study represents an evaluation of deleterious genetic variants in the <it>BRCA1 </it>and <it>2 </it>genes in the Czech population. The classification of several splice-site variants as true pathogenic mutations may prove useful for genetic counselling of families with high risk of breast and ovarian cancer.</p

The RSPO–LGR4/5–ZNRF3/RNF43 module controls liver zonation and size

LGR4/5 receptors and their cognate RSPO ligands potentiate Wnt/β-catenin signalling and promote proliferation and tissue homeostasis in epithelial stem cell compartments. In the liver, metabolic zonation requires a Wnt/β-catenin signalling gradient, but the instructive mechanism controlling its spatiotemporal regulation is not known. We have now identified the RSPO-LGR4/5-ZNRF3/RNF43 module as a master regulator of Wnt/β-catenin-mediated metabolic liver zonation. Liver-specific LGR4/5 loss of function (LOF) or RSPO blockade disrupted hepatic Wnt/β-catenin signalling and zonation. Conversely, pathway activation in ZNRF3/RNF43 LOF mice or with recombinant RSPO1 protein expanded the hepatic Wnt/β-catenin signalling gradient in a reversible and LGR4/5-dependent manner. Recombinant RSPO1 protein increased liver size and improved liver regeneration, whereas LGR4/5 LOF caused the opposite effects, resulting in hypoplastic livers. Furthermore, we show that LGR4(+) hepatocytes throughout the lobule contribute to liver homeostasis without zonal dominance. Taken together, our results indicate that the RSPO-LGR4/5-ZNRF3/RNF43 module controls metabolic liver zonation and is a hepatic growth/size rheostat during development, homeostasis and regeneration

BRCA1 expression modulates chemosensitivity of BRCA1-defective HCC1937 human breast cancer cells

Germline mutations of the tumour suppressor gene BRCA1 are involved in the predisposition and development of breast cancer and account for 20–45% of all hereditary cases. There is an increasing evidence that these tumours are characterised by a specific phenotype and pattern of gene expression. We have hypothesised that differences in chemosensitivity might parallel molecular heterogeneity of hereditary and sporadic breast tumours. To this end, we have investigated the chemosensitivity of the BRCA1-defective HCC1937 breast cancer cell line, and the BRCA1-competent MCF-7 (hormone-sensitive) and MDA-MB231 (hormone-insensitive) breast cancer cell lines using the MTT assay. The 50% inhibitory concentration (IC50) for the individual compounds were derived by interpolate plot analysis of the logarithmic scalar concentration curve after a 48 h exposure. HCC1937 cells were significantly (P<0.005) more sensitive to cisplatin (CDDP) (IC50 : 30–40 μM) compared with MCF-7 (IC50 : 60–70 μM) and MDA-MB231 (IC50 : 90–100 μM) cells. On the other hand, BRCA1-defective breast cancer cells were significantly less sensitive to doxorubicin (Dox) (IC50 : 45–50 μM) compared with MCF-7 (IC50 : 1–5 μM) and MDA-MB231 (IC50 : 5–10 μM) (P<0.02), as well as to paclitaxel (Tax) (IC50 : >2 μM for HCC1937, 0.1–0.2 μM for MCF-7 and 0.01–0.02 μM for MDA-MB231) (P<0.001). Full-length BRCA1 cDNA transfection of BRCA1-defective HCC1937 cells led to the reconstituted expression of BRCA1 protein in HCC1937/WTBRCA1-derived cell clone, but did not reduce tumour cell growth in soft agar. BRCA1 reconstitution reverted the hypersensitivity to CDDP (P<0.02), and restored the sensitivity to Dox (P<0.05) and Tax (P<0.001), compared with parental HCC1937 cells. Taken together, our findings suggest a specific chemosensitivity profile of BRCA1-defective cells in vitro, which is dependent on BRCA1 protein expression, and suggest prospective preclinical and clinical investigation for the development of tailored therapeutical approaches in this setting