Search PubMed⌕ Search

Biomedical subjects

S Marcus

Publications and source records attributed to S Marcus.

At least 55 records · Page 3Linked to original sources
PubMed1997

Thymidine kinase (TK) gene-transduced human lymphocytes can be highly purified, remain fully functional, and are killed efficiently with ganciclovir.

A graft-versus-leukemia (GVL) effect has been considered a major factor responsible for cures in patients with hematologic malignancies undergoing allogeneic bone marrow transplantation; however, associated graft-versus-host disease (GVHD) results in significant morbidity and mortality. T-cell depletion reduces the incidence and severity of GVHD but eliminates, at least partially, the GVL effect. Reinfusion of donor T lymphocytes at relapse posttransplantation can induce a potent antitumor response, but GVHD still occurs in the majority of patients. Prior transduction of T lymphocytes with the suicide gene, the viral thymidine kinase (TK), permits specific cell kill on administration of ganciclovir (GCV). Therefore, infusion of TK-transduced T lymphocytes may induce GVL effect and allow for their subsequent selective elimination in case GVHD develops. To evaluate the efficacy and feasibility of this promising approach, anti-CD3-stimulated primary human lymphocytes cultured in interleukin-2 were TK-transduced by a retroviral vector carrying both TK and neomycin-resistance genes. After selection in G418, more than 90% of the cells contained the TK gene as shown by a semiquantitative polymerase chain reaction. In addition, 1 to 5 days of GCV exposure, at clinically achievable concentrations of 20 to 50 micromol/L, induced > or = 90% killing of G418-selected cells without affecting nontransduced cells. Correlation of the extent of T-cell kill and the proportion of TK-gene-transduced cells is consistent with the absence of a bystander effect. Transduced cells were CD3+ and either CD8+ or CD4+ and retained functional properties of untransduced cells. In vivo administration of GCV prevented tumor development after subcutaneous injection of TK-transduced murine myeloma cells (MOPC-11), whereas such an effect was not observed on injection of untransduced cells into the opposite flank. Our studies provide critical information that (1) adequate numbers of TK-transduced lymphocytes can be selected efficiently with > or = 90% purity, (2) selected cells remain functional, (3) 24 hours of exposure to GCV at clinically achievable concentration effects > or = 90% killing of selected cells, and (4) GCV is effective in vivo in killing TK-transduced cells. Based on these data, a clinical study has been initiated in patients with multiple myeloma with persistent or relapsing disease after T-cell-depleted allogeneic transplants.

Animals↗
PubMed1997

Infertility in a cryptorchid bull: a case report.

A unilateral cryptorchid bull stationed in an AI center for 3.5 yr was studied to determine if maintaining such a bull could be justified. The following parameters were determined: quantity and quality of the ejaculates, basal and stimulated plasma testosterone concentrations, and the histology and testosterone concentrations of the testicles. The bull produced 232 ejaculates of which 125 (53.8%) were immediately discarded; the rest (107 ejaculations) were processed into pellets. Two of the 107 frozen ejaculates (2%) were found to be of excellent quality, 37 were (34.5%) of good quality, 45 were (42%) of satisfactory quality and 23 were (21.5%) of poor quality. Treatment of the calf with GnRH and hCG at 4 and 5 mo of age did not initiate the descent of the retained testicle. Testosterone concentrations measured at 14 mo, after hCG stimulus, indicated that the bull had impaired steroidogenesis when compared with 2 control bull calves. Post mortem examination revealed a small left testicle in the inguinal canal and a normal right testicle as well as normal secondary sex glands. During the breeding period at the AI center, the bull's peripheral testosterone concentrations decreased from 2.2 to 0.95 ng/ml Testosterone concentrations in the parenchymal tissue of the scrotal testicle were higher than in the parenchyma of the retained testicle (98.2 vs 53.9 ng/g). In contrast, the epididymis of the scrotal testicle had a lower testosterone concentration than the epididymis of the retained testicle (10.8 vs 33. 0 ng/g). On histological examination no spermatozoa were found in the retained testicle, the Sertoli cells showed fat degeneration, and fibrotic tissue surrounded the tubuli seminiferi. No pathological changes were found in the normal scrotal testicle. In conclusion, no justification was found for maintaining such a bull in the AI center for breeding purposes.

Journal Article↗
PubMed1997

Transrectal electroejaculation combined with in-vitro fertilization: effective treatment of anejaculatory infertility due to spinal cord injury.

Infertility due to spinal cord injury (SCI) in young men is a frequent complication of their injury. When the simpler methods of management of the erectile and ejaculatory dysfunction that invariably follow the more severe types of SCI are not effective, then semen production by transrectal electroejaculation (TREE) combined with in-vitro fertilization (IVF) and embryo transfer is effective. A retrospective analysis is presented of data on the treatment and outcome of 35 couples who wished to have a family but in whom the male partner had suffered SCI. These 35 couples had 71 attempts at IVF with spermatozoa obtained following TREE. Normal fertilization and cleavage of the embryos occurred in 48.2% of the oocytes. Fresh embryos were transferred in 54 cycles and frozen-thawed embryos in 14 cycles. In all, 18 clinical pregnancies were achieved in 54 fresh and 14 frozen embryo transfer cycles, with a live birth rate of 16.5% (14/85) per treatment cycle started, 20.6% (14/68) per transfer cycle and 40.0% (14/35) per couple who started treatment, in a mean of 1.9 transfer cycles. We conclude that TREE combined with IVF and embryo transfer is an effective treatment for the infertility problems associated with SCI.

Cryopreservation↗
PubMed1997

Domestic violence and children: prevalence and risk in five major U.S. cities.

OBJECTIVE: Children witnessing domestic violence is a major national concern. The present study provided data on the prevalence of children's exposure to substantiated cases of adult female assaults in five U.S. cities. METHOD: Data for this study were drawn from the Spouse Assault Replication Program (SARP) database, collected from police officers and female victims of misdemeanor domestic violence. In addition, household demographic data and data on involvement of children in the violent incidents were collected. Data from the SARP households were compared with census data from each city. RESULTS: Results indicated that children were disproportionately present in households with domestic violence and that young children were disproportionately represented among these children. Moreover, these children were exposed to excessive levels of additional developmental risk factors and they were involved in the incidents to varying degrees. CONCLUSIONS: These findings underscore the importance of establishing a more rigorous interdisciplinary, scientific research agenda to inform assessment and treatment efforts for a very vulnerable group of children who witness domestic violence, children aged 0 through 5 years.

Adolescent↗
PubMed1996

The highly conserved skb1 gene encodes a protein that interacts with Shk1, a fission yeast Ste20/PAK homolog.

The Shk1 protein kinase, a homolog of Saccharomyces cerevisiae Ste20 and mammalian p21Cdc42/Rac-activated kinases, is an essential component of a Ras- and Cdc42-dependent signaling cascade required for cell viability, normal morphology, and mitogen-activated protein kinase-mediated sexual responses in the fission yeast, Schizosaccharomyces pombe. To identify S. pombe proteins that modulate or mediate Shk1 functions, we conducted a two-hybrid screen for Shk1-interacting proteins. One of the genes identified as a result of this screen was skb1. We show that Skb1 interacts with a region of the N-terminal regulatory domain of Shk1 distinct from that to which Cdc42 binds, and that Shk1, Cdc42, and Skb1 are able to form a ternary complex in vivo. S.pombe cells carrying an skb1 null mutation are less elongate in morphology than wild-type cells and exhibit a moderate growth defect. The morphology defect of the skb1 deletion mutant is suppressed by overexpression of Shk1. Overexpression of Skb1 causes wild-type S. pombe cells to become hyperelongated. Additional genetic analyses described herein suggest that Skb1 is a component of the morphology control branch of the Ras signaling cascade in S. pombe and that it positively modulates Shk1 function. Homologs of Skb1 are encoded by open reading frames in the genomes of S. cerevisiae and Caenorhabditis elegans and by an uncharacterized human cDNA sequence. Thus, skb1 may be the first well-characterized member of a highly conserved family of genes encoding potential p21Cdc42/Rac-activated kinase regulators.

Amino Acid Sequence↗
PubMed1996

The obstetric outcome of in vitro fertilization and embryo transfer in women with congenital uterine malformation.

OBJECTIVE: Our purpose was to analyze 3 obstetric outcomes according to the various forms of congenital uterine malformation after in vitro fertilization and embryo transfer. STUDY DESIGN: We conducted a retrospective analysis of data from 24 patients with the following types of congenital uterine malformation: 6 unicomuate, 9 bicomuate, 5 septate, and 4 uterus didelphys. All patients underwent in vitro fertilization and embryo transfer at Boum Hall Clinic, a tertiary infertility referral center. RESULTS: Twenty-four patients conceived a total of 19 clinical pregnancies in 51 embryo transfer cycles. The clinical pregnancy rate was 19 of 51 (37.3%) per embryo transfer and 17 of 24 (70.8%) per patient. There were no significant differences in the clinical pregnancy rates when the various forms of uterine malformation were compared. There was a trend for the group with unicomuate uteri and uterus didelphys to have the highest rate of term delivery (6/9, 66.7%) and the lowest rate of first-trimester miscarriages (0/9, 0%) as compared with the group with septate and bicomuate uteri, in whom the term delivery rate was 1 of 10 (10%) and the spontaneous abortion rate was 3 of 10 (30%). The multiple pregnancy rate was 6 of 15 (40%) for women who had three embryos transferred, as compared with 0 in women who had two embryos or one embryo transferred. There was a high rate of preterm delivery (6/13, 46.2%) and cesarean section (10/13, 76.9%). CONCLUSION: In vitro fertilization and embryo transfer in women with congenital uterine malformation is associated with good pregnancy rates, and the patients should be counseled about the risks involved, in particular, the increased rate of preterm delivery and cesarean section.

Adult↗
PubMed1996

Cost reduction by combined carotid endarterectomy and coronary artery bypass grafting.

A significant cost reduction is likely if patients who require coronary artery bypass grafting with significant carotid stenosis have simultaneous carotid endarterectomy and bypass grafting, provided risk is not increased. To investigate this issue, we retrospectively identified cases from February 1977 to May 1994 with first-time isolated carotid endarterectomy, coronary bypass, or combined procedures. In the isolated carotid endarterectomy population, median age was 69 years and 58% (85/146) were male, as compared with 68 years and 68% (68/100) male in the combined group; median age of the coronary bypass cohort was 65 years and 76% (381/500) male. A significantly higher percentage of patients in the coronary bypass versus combined group were in New York Heart Association functional class IV. In the combined group there was a significantly higher incidence of older age, diabetes, hypertension, hyperlipidemia, renal failure, and congestive heart failure. There was no difference among the three groups with respect to hospital mortality (0%, 3.4%, and 4.0%, respectively) and permanent stroke (0.7%, 1.2%, and 0%, respectively). Hospital costs were $4,896, $10,959 and $11,089, respectively, with a savings of $4,766 (30%), and Medicare hospital reimbursement was $8,575, $23,071, and $23,071, respectively, with a savings of $10,077 (25.3%). Thus, in appropriate patients, a combined procedure is cost effective, eliminating a second surgical procedure and the cost of the postoperative stay (3.7 +/- 2.4 days) associated with isolated carotid endarterectomy. Risk of permanent stroke or death is not increased.

Aged↗
PubMed1996

Actions of Rho family small G proteins and p21-activated protein kinases on mitogen-activated protein kinase family members.

The mitogen-activated protein (MAP) kinases are a family of serine/threonine kinases that are regulated by distinct extracellular stimuli. The currently known members include extracellular signal-regulated protein kinase 1 (ERK1), ERK2, the c-Jun N-terminal kinase/stress-activated protein kinases (JNK/SAPKs), and p38 MAP kinases. We find that overexpression of the Ste20-related enzymes p21-activated kinase 1 (PAK1) and PAK2 in 293 cells is sufficient to activate JNK/SAPK and to a lesser extent p38 MAP kinase but not ERK2. Rat MAP/ERK kinase kinase 1 can stimulate the activity of each of these MAP kinases. Although neither activated Rac nor the PAKs stimulate ERK2 activity, overexpression of either dominant negative Rac2 or the N-terminal regulatory domain of PAK1 inhibits Ras-mediated activation of ERK2, suggesting a permissive role for Rac in the control of the ERK pathway. Furthermore, constitutively active Rac2, Cdc42hs, and RhoA synergize with an activated form of Raf to increase ERK2 activity. These findings reveal a previously unrecognized connection between Rho family small G proteins and the ERK pathway.

Animals↗
PubMed1995

Isolation of MEK5 and differential expression of alternatively spliced forms.

The prototype mitogen-activated protein (MAP) kinase module is a three-kinase cascade consisting of the MAP kinase, extracellular signal-regulated protein kinase (ERK) 1 or ERK2, the MAP/ERK kinase (MEK) MEK1 or MEK2, and the MEK kinase, Raf-1 or B-Raf. This and other MAP kinase modules are thought to be critical signal transducers in major cellular events including proliferation, differentiation, and stress responses. To identify novel mammalian MAP kinase modules, polymerase chain reaction was used to isolate a new MEK family member, MEK5, from the rat. MEK5 is more closely related to MEK1 and MEK2 than to the other known mammalian MEKs, MKK3 and MKK4. MEK5 is thought to lie in an uncharacterized MAP kinase pathway, because MEK5 does not phosphorylate the ERK/MAP kinase family members ERK1, ERK2, ERK3, JNK/SAPK, or p38/HOG1, nor will Raf-1, c-Mos, or MEKK1 highly phosphorylate it. Alternative splicing results in a 50-kDa alpha and a 40-kDa beta isoform of MEK5. MEK5 beta is ubiquitously distributed and primarily cytosolic. MEK5 alpha is expressed most highly in liver and brain and is particulate. The 23 amino acids encoded by the 5' exon in the larger alpha isoform are similar to a sequence found in certain proteins believed to associate with the actin cytoskeleton; this alternatively spliced modular domain may lead to the differential subcellular localization of MEK5 alpha.

Alternative Splicing↗
PubMed1995

Activation of mitogen-activated protein kinase cascades by p21-activated protein kinases in cell-free extracts of Xenopus oocytes.

In the evolutionarily distant yeasts Saccharomyces cerevisiae and Schizosaccharomyces pombe, genetic evidence suggests that activation of pheromone-induced mitogen-activated protein kinase (MAPK) cascades involves the function of the p21cdc42/racl-activated protein kinases (PAKs) Ste20 and Shk1, respectively. In this report, we show that purified Ste20 and Shk1 were each capable of inducing p42MAPK activation in cell-free extracts of Xenopus laevis oocytes, while a mammalian Ste20/Shk1-related protein kinase, p65pak (Pak1), did not induce activation of p42MAPK. In contrast to p42MAPK, activation of JNK/SAPK in Xenopus oocyte extracts was induced by both the yeast Ste20 and Shk1 kinases, as well as by mammalian Pak1. Our results demonstrate that MAPK cascades that are responsive to PAKs are conserved in higher eukaryotes and suggest that distinct PAKs may regulate distinct MAPK modules.

Animals↗
PubMed1995

Shk1, a homolog of the Saccharomyces cerevisiae Ste20 and mammalian p65PAK protein kinases, is a component of a Ras/Cdc42 signaling module in the fission yeast Schizosaccharomyces pombe.

We describe a protein kinase, Shk1, from the fission yeast Schizosaccharomyces pombe, which is structurally related to the Saccharomyces cerevisiae Ste20 and mammalian p65PAK protein kinases. We provide genetic evidence for physical and functional interaction between Shk1 and the Cdc42 GTP-binding protein required for normal cell morphology and mating in S. pombe. We further show that expression of the STE20 gene complements the shk1 null mutation and that Shk1 is capable of signaling to the pheromone-responsive mitogen-activated protein kinase cascade in S. cerevisiae. Our results lead us to propose that signaling modules composed of small GTP-binding proteins and protein kinases related to Shk1, Ste20, and p65PAK, are highly conserved in evolution and participate in both cytoskeletal functions and mitogen-activated protein kinase signaling pathways.

Amino Acid Sequence↗
PubMed1995

New technique for lesser saphenous vein harvesting.

A new technique using the Thompson self-retaining retractor system (Thompson Surgical Instruments, Inc, Traverse City, MI) to harvest lesser saphenous veins is presented. This modification, used in 10 patients undergoing redo myocardial revascularization, provided a rapid, comfortable, and convenient method for harvesting lesser saphenous veins.

Coronary Artery Bypass↗
PubMed1995

Modulation of prostaglandin synthesis in mammalian sperm acrosome reaction.

Exogenous arachidonic acid induces the acrosome reaction and the production of the prostaglandins PGE2 and PGF2 alpha in bovine spermatozoa. Exogenous PGE2 also induces the acrosome reaction and PGF2 alpha synthesis. To understand better the role of PGE2 in the induction of PGF2 alpha synthesis through modulation of phospholipase A2, inhibitors of this enzyme were used. The effects of PGE2 were blocked by phospholipase A2 inhibitors and this inhibition was reversed by addition of arachidonic acid. These data indicate that PGE2 activates phospholipase A2 to produce arachidonic acid. To determine whether protein kinase C modulates phospholipase A2 activity in this process, staurosporin, an inhibitor of protein kinase C, was used. The effect of PGE2 on PGF2 alpha production is inhibited by staurosporin and this inhibition was reversed by addition of arachidonic acid indicating that protein kinase C is involved in phospholipase A2 activation. The effect of exogenous arachidonic acid or PGE2 on the acrosome reaction is blocked by lipoxygenase inhibitors but not by inhibitors of cyclo-oxygenase, indicating that lipoxygenase products are involved in the mechanism of the acrosome reaction. The presented data shed light on the cross-talk between cyclo-oxygenase and lipoxygenase and their involvement in the sperm acrosome reaction. It is suggested that cyclo-oxygenase products modulate the activity of lipoxygenase which is a key enzyme in the mechanism leading to the acrosome reaction. Stimulation of cyclo-oxygenase to synthesize PGE2 activates phospholipase A2 to release arachidonic acid which is the substrate for lipoxygenase activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acrosome↗