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Biomedical subjects

M Goodman

Publications and source records attributed to M Goodman.

At least 19 recordsLinked to original sources
PubMed2007

Lack of survival benefit of post-operative radiation therapy in prostate cancer patients with positive lymph nodes.

Randomized data from SWOG 8794 and EORTC 22911 confirm the benefit of post-operative radiation therapy (RT) for selected patients with pT3 prostate cancer (CaP) after radical prostatectomy (RP). However, data regarding the potential benefit of RT for patients post-RP with positive lymph node (+LN) involvement are limited. We analyzed the Surveillance Epidemiology End Results (SEER) registry for population-based data on efficacy of post-operative RT for +LN patients after RP. As LN data have only been captured by SEER since 1988, we analyzed data for 1988-1992, with specific attention to 10-year relative survival (defined as observed survival divided by the survival of a gender-, age- and race-matched population cohort without disease). Specifically analyzed were data for 1921 patients with nonmetastatic prostate cancer who underwent surgery alone, or surgery followed by RT, and who had +LNs documented. SEER does not code the interval between surgery and RT, so the ratio of patients receiving salvage versus adjuvant therapy is unknown. Using follow-up data through 2002, post-diagnosis survival was examined by number of +LNs. There was no significant relative survival benefit for +LN patients receiving post-operative RT (chi(2)P=0.270). These data do not support routine use of post-operative RT for patients with +LNs in the surgical specimen.

Combined Modality Therapy↗
PubMed2006

Occupational trichloroethylene exposure and non-Hodgkin's lymphoma: a meta-analysis and review.

METHODS: Meta-analysis and review of 14 occupational cohort and four case-control studies of workers exposed to trichloroethylene (TCE) to investigate the relation between TCE exposure and the risk of non-Hodgkin's lymphoma (NHL). Studies were selected and categorised based on a priori criteria, and results from random effects meta-analyses are presented. RESULTS: The summary relative risk estimates (SRRE) for the group of cohort studies that had more detailed information on TCE exposure was 1.29 (95% CI 1.00 to 1.66) for the total cohort and 1.59 (95% CI 1.21 to 2.08) for the seven studies that identified a specific TCE exposed sub-cohort. SRREs for three studies with cumulative exposure information were 1.8 (95% CI 0.62 to 5.26) for the lowest exposure category and 1.41 (95% CI 0.61 to 3.23) for the highest category. Comparison of SRREs by levels of TCE exposure did not indicate exposure-response trends. The remaining cohort studies that identified TCE exposure but lacked detailed exposure information had an SRRE of 0.843 (95% CI 0.72 to 0.98). Case-control studies had an SRRE of 1.39 (95% CI 0.62 to 3.10). Statistically significant findings for the Group 1 studies were driven by the results from the subgroup of multiple industry cohort studies (conducted in Europe) (SRRE = 1.86; 95% CI 1.27 to 2.71). The SRRE for single industry cohort studies was not significantly elevated (SRRE = 1.25; 95% CI 0.87 to 1.79). CONCLUSIONS: Interpretation of overall findings is hampered by variability in results across the Group 1 studies, limited exposure assessments, lack of evidence of exposure response trends, lack of supportive information from toxicological and mechanistic data, and absence of consistent findings in epidemiologic studies of exposure and NHL. Although a modest positive association was found in the TCE sub-cohort analysis, a finding attributable to studies that included workers from multiple industries, there is insufficient evidence to suggest a causal link between TCE exposure and NHL.

Case-Control Studies↗
PubMed2005

Synthesis and biologic activity of conformationally constrained analogs of L-363,301.

We report the synthesis, biological activity and conformational analysis of analogs of the cyclic hexapeptide L-363,301, c[Pro6-Phe7-D-Trp8-Lys9-Thr10-Phe11] (numbering as in the native hormone somatostatin-14). The d-Trp in position 8 was replaced with (2R,3S)- and (2R,3R)-beta-MeTrp respectively, with an added methyl group in the beta position of Trp. The objective of our study was to determine the potency and selectivity generated by the added constraint in the beta position of the d-Trp upon binding to human somatostatin receptors hsst1-5. We synthesized the building blocks enantioselectively and incorporated them into the peptides by SPPS. Competition binding assays revealed that both compounds 2 and 3 were selective for hsst2 over hsst5. The (2R,3S) analog 2 was approximately 30 times more potent at hsst2 than the (2R,3R) analog 3. Interestingly, the (2R,3R) compound showed no binding affinity at hsst5.

Amino Acids↗
PubMed2003

Acute graft-versus-host disease (aGVHD) presenting with an acquired lupus anticoagulant.

There are few reports describing the association between antiphospholipid antibodies, including the lupus anticoagulant, and bone marrow or peripheral stem cell transplantation. Autoimmune syndromes and autoantibodies such as lupus anticoagulant and anticardiolipin antibodies have been described following allogeneic bone marrow or peripheral blood stem cell transplantation, particularly in patients who develop chronic graft-versus-host disease (GVHD). The association between Lupus anticoagulant and acute GVHD has not been previously described. We report a patient who developed a de novo lupus anticoagulant on day +34 after a matched-related allogeneic peripheral stem cell transplant. No clinical evidence of systemic thrombosis was observed and the lupus anticoagulant disappeared following immunosuppressive therapy with a combination of steroids and infliximab.

Acute Disease↗
PubMed2001

Suicide, impulsive aggression, and HTR1B genotype.

BACKGROUND: Suicidality and impulsive aggression are partially heritable, and postmortem brain studies suggest that abnormalities in serotonin 1B may be associated with suicide. Studies of serotonin 1B "knockout" mice show an increase in aggressive behavior relative to wild-type mice. METHODS: We assessed the relationship between genotype at the HTR1B locus and both suicide history and impulsive aggression in personality disorders. RESULTS: The "G" allele of a polymorphic gene at the HTR1B locus was associated with a history of suicide attempts in white patients with personality disorders [chi(2)(1) = 9.3, p =.01, n = 90]. No relationship was found between HTR1B genotype and self-reported impulsive aggression. CONCLUSIONS: This preliminary finding suggests that allelic variability at the HTR1B locus may be associated with the susceptibility to suicide attempts in patients with personality disorders.

Adult↗
PubMed2001

A novel traceless resin-bound guanidinylating reagent for secondary amines to prepare N,N-disubstituted guanidines.

[reaction: see text]. We report the development of a solid support-linked guanidinylating reagent. This reagent consists of a urethane-protected triflyl guanidine attached to the resin via a carbamate linker. It allows for rapid synthesis of guanidines from a variety of amines. It provides access to N-alkyl/aryl- or N,N-dialkylguanidines under mild conditions. Cleavage with 50% TFA produces target molecules in high yields and purity. The ability to guanidinylate secondary amines is a significant feature of this guanidinylating reagent.

Amines↗
PubMed2001

An orphaned mammalian beta-globin gene of ancient evolutionary origin.

Mammals possess multiple, closely linked beta-globin genes that differ in the timing of their expression during development. These genes have been thought to be derived from a single ancestral gene, by duplication events that occurred after the separation of the mammals and birds. We report the isolation and characterization of an atypical beta-like globin gene (omega-globin) in marsupials that appears to be more closely related to avian beta-globin genes than to other mammalian beta-globin genes, including those previously identified in marsupials. Phylogenetic analyses indicate that omega-globin evolved from an ancient gene duplication event that occurred before the divergence of mammals and birds. Furthermore, we show that omega-globin is unlinked to the previously characterized beta-globin gene cluster of marsupials, making this the first report of an orphaned beta-like globin gene expressed in a vertebrate.

Amino Acid Sequence↗
PubMed2001

New reagents, reactions, and peptidomimetics for drug design.

It has been a major focus in our laboratories to prepare novel reagents and peptidomimetic structures for drug design. We have designed and prepared novel guanidinylation reagents that can be employed in solution or as solid phase reagents. We and others have utilized the reagent 3-(diethoxyphosphoryloxy)-1,2,3-benzotriazin-4(3H)-one (DEPBT) for amide bond formation to couple sterically hindered structures. These couplings proceed with remarkably strong resistance to racemization. In the area of peptidomimetics, we have incorporated novel building blocks to create biologically active compounds. These building blocks include thioether and alkylamine bridges, beta-methylated, and beta,beta-dimethylated amino acid residues. These mimetic structures have been incorporated into specific target molecules such as opioids to obtain cyclic peptidomimetics with potent and selective biological activity.

Alanine↗
PubMed2001

Synthesis, conformational analysis and biological activities of lanthionine analogs of a cell adhesion modulator.

Cell adhesion is critical for many biological processes, such as hemostasis, wound healing, tumor metastasis and inflammation. Integrins are important mediators of cell adhesion. The integrin alpha4beta1, also known as VLA-4, is a cell surface receptor involved in inflammation. A cyclic peptide, 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH, is a potent antagonist to VLA-4 with an IC50 of 2.4 nM. In the current study, we synthesized the lanthionine analogs of 1-FCA-Arg-c[Cys-Asp-Thz-Cys]-OH and determined the conformations of both the parent compound and its lanthionine analog in solution by NMR and computer simulations. The lanthionine analog retains its selectivity to VLA-4 with high nanomolar potency. Both molecules adopt similar topological arrangements in their conformations, while some important differences remain in the sulfur bridge region, which may cause the difference in potency.

Alanine↗
PubMed2001

A bioactive somatostatin analog without a type II' beta-turn: synthesis and conformational analysis in solution.

A cyclic somatostatin analog [structure: see text] (1) has been synthesized. Biological assays show that this compound has strong binding affinities to somatostatin hsst2 and hsst5 receptor subtypes (5.2 and 1.2 nM, respectively, and modest affinity to hsst4 (41.1 nM)). Our conformational analysis carried out in DMSO-d6 indicates that this compound exists as two structures arising from the trans and cis configurations of the peptide bond between Phe7 and N-alkylated Gly8. However, neither conformer exhibits a type II' beta-turn. This is the first report of a potent bioactive somatostatin analog that does not exhibit a type II' beta-turn in solution. Molecular dynamics simulations (500 ps) carried out at 300 K indicate that the backbone of compound 1 is more flexible than other cyclic somatostatin analogs formed by disulfide bonds.

Amino Acid Sequence↗
PubMed2001

Molecular evolution of aerobic energy metabolism in primates.

As part of our goal to reconstruct human evolution at the DNA level, we have been examining changes in the biochemical machinery for aerobic energy metabolism. We find that protein subunits of two of the electron transfer complexes, complex III and complex IV, and cytochrome c, the protein carrier that connects them, have all undergone a period of rapid protein evolution in the anthropoid lineage that ultimately led to humans. Indeed, subunit IV of cytochrome c oxidase (COX; complex IV) provides one of the best examples of positively selected changes of any protein studied. The rate of subunit IV evolution accelerated in our catarrhine ancestors in the period between 40 to 18 million years ago and then decelerated in the descendant hominid lineages, a pattern of rate changes indicative of positive selection of adaptive changes followed by purifying selection acting against further changes. Besides clear evidence that adaptive evolution occurred for cytochrome c and subunits of complexes III (e.g., cytochrome c(1)) and IV (e.g., COX2 and COX4), modest rate accelerations in the lineage that led to humans are seen for other subunits of both complexes. In addition the contractile muscle-specific isoform of COX subunit VIII became a pseudogene in an anthropoid ancestor of humans but appears to be a functional gene in the nonanthropoid primates. These changes in the aerobic energy complexes coincide with the expansion of the energy-dependent neocortex during the emergence of the higher primates. Discovering the biochemical adaptations suggested by molecular evolutionary analysis will be an exciting challenge.

Animals↗
PubMed2001

Catarrhine phylogeny: noncoding DNA evidence for a diphyletic origin of the mangabeys and for a human-chimpanzee clade.

Maximum-parsimony and maximum-likelihood analyses of two of the serum albumin gene's intron sequences from 24 catarrhines (17 cercopithecid and 7 hominid) and 3 platyrrhines (an outgroup to the catarrhines) yielded results on catarrhine phylogeny that are congruent with those obtained with noncoding sequences of the gamma(1)-gamma(2) globin gene genomic region, using only those flanking and intergenic gamma sequences that in their history were not involved in gene conversion. A data set that combined in a tandem alignment these two sets of noncoding DNA orthologues from the two unlinked nuclear genomic loci yielded the following confirmatory results both on the course of cladistic branchings (the divisions in a cladistic classification of higher ranking taxa into subordinate taxa) and on the ages of the taxa (each taxon representing a clade). The cercopithecid branch of catarrhines, at approximately 14 Ma (mega annum) divided into Colobini (the leaf-eating Old World monkeys) and Cercopithecini (the cheek-pouched Old World monkeys). At approximately 10-9 Ma, Colobini divided into an African clade, Colobina, and an Asian clade, Presbytina; similarly at this time level, Cercopithecini divided into Cercopithecina (the guenons, patas, and green monkeys) and Papionina. At approximately 7 Ma, Papionina divided into Macaca, Cercocebus, and Papio. At approximately 5 Ma, Cercocebus divided subgenerically into C. (Cercocebus) for terrestrial mangabeys and C. (Mandrillus) for drills and mandrills, while at approximately 4 Ma Papio divided subgenerically into P. (Locophocebus) for arboreal mangabeys, P. (Theropithecus) for gelada baboons, and P. (Papio) for hamadryas baboons. In turn, the hominid branch of catarrhines at approximately 18 Ma divided into Hylobatini (gibbons and siamangs) and Hominini; at approximately 14 Ma, Hominini divided into Pongina (orangutans) and Hominina; at approximately 7 Ma, Hominina divided into Gorilla and Homo; and at approximately 6-5 Ma, Homo divided subgenerically into H. (Homo) for humans and H. (Pan) for common and bonobo chimpanzees. Rates of noncoding DNA evolution were assessed using a data set of noncoding gamma sequence orthologues that represented 18 catarrhines, 16 platyrrhines, 3 non-anthropoid primates (2 tarsiers and 1 strepsirhine), and rabbit (as outgroup to the primates). Results obtained with this data set revealed a faster rate of nucleotide substitutions in the early primate lineage to the anthropoid (platyrrhine/catarrhine) ancestor than from that ancestor to the present. Rates were slower in catarrhines than in platyrrhines, slower in the cheek-pouched than in the leaf-eating cercopithecids, and slower yet in the hominids. On relating these results to data on brain sizes and life spans, it was suggested that life-history strategies that favor intelligence and longer life spans also select for decreases in de novo mutation rates.

Albumins↗
PubMed2001

Ovulation timing. Concepts and controversies.

While the luteinizing hormone (LH) surge has long been accepted as the key event in the estrous cycle of the bitch, historically, there has been no practical way to identify it. In the past, the veterinary practitioner had to rely on general and/or subjective information received from vaginal cytology, physical examinations, and observations. With the recent development of in-clinic progesterone and LH assays, and the wider availability of laboratory quantitative progesterone assays, the LH surge can either be identified directly or estimated by the detection of changes in progesterone. As a result, ovulation time can now be predicted with high accuracy in a private practice setting.

Animals↗
PubMed2001

A bicyclic and hsst2 selective somatostatin analogue: design, synthesis, conformational analysis and binding.

A backbone bridged and disulfide bridged bicyclic somatostatin analogue, compound 1 (PTR-3205), was designed and synthesized by solid-phase methodology. The binding of compound 1 to the five different somatostatin receptors, expressed in CHO or COS-7 cells, indicate a high degree of selectivity towards hsstr2. The three-dimensional structure of this compound has been determined in DMSO-d(6) and in water by 1H NMR and by molecular dynamics simulations. Similar backbone conformations were observed in both solvents. We have established direct evidence that the backbone of this bicyclic somatostatin analogue assumes a 'folded' conformation in solution, where the lactam ring extends roughly in the plane of the beta-turn. The pharmacophoric region Phe-(D)-Trp-Lys-Thr of compound 1 is in accord with that of both the Veber compound L-363,301 (Merck) and sandostatin. We believe that the enhanced selectivity towards the hsst2 receptor, in comparison with other analogues, is due to its large hydrophobic region, composed of the lactam ring and the Phe side chains at positions 1 and 8.

Animals↗