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PubMed2005

Selection of grip function in double free gracilis transfer procedures after complete paralysis of the brachial plexus.

Double free gracilis transfer (DFGT) procedures introduced by Doi et al have resulted in significant improvement in maintaining functional prehensile hand after total brachial plexus injury (TBPI). However, not all patients with satisfactory recovery of finger motion could improve their prehensile function. The use of reconstructed hand in daily activities was examined retrospectively to plan individual grip function, depending on the patient's own demand. Thirty patients who had had reconstruction with DFGT procedures were evaluated retrospectively according to total active motion (TAM), power grip, hook grip, and pinch function. Power grip was evaluated by holding a bottle and hook grip by lifting a weight. Only 11 patients (36%) had very light pulp-to-pulp pinch, 11 (36%) had power grip, and 25 (83%) had hook grip. The mean weight that could be carried by hook grip was 1.3 kg. The mean TAM was 43 degrees. Pain sensation was the only encouraging sensation recovery, radiating to the chest. Fine movements of the hand like pinching require well-developed exquisite control of movements. TBPI patients have the contralateral normal limb, which they always prefer, only using their reconstructed hand when the activity requires both hands, such as when holding a bottle to open its cap or lifting bags when the contralateral normal hand is already engaged. For performance of these actions, hook grip and power grip are the useful prehensile hand functions that can be obtained after DFGT. Selection of grip functions should be done according to patient needs, and the late-stage reconstructive hand operations should be decided according to preferred grip function.

Adolescent↗
PubMed1991

Effects of hormones on tumor growth and immunoreactive insulin-like growth factor-1 of estrogen receptor-positive human breast cancer (MCF-7) transplanted in nude mice.

The effects of estrogens and tamoxifen were analyzed on estrogen receptor-positive human breast cancer (MCF-7) transplanted into athymic nude mice. It was found that (1) the tumor growth and the proportion of 3H-thymidine-labeled cells were significantly increased in the 17 beta-estradiol dipropionate (E2) group, but significantly decreased in the tamoxifen (TAM) group with respect to the control group, and (2) the tumor content of insulin-like growth factor-1 (IGF-1) and the rate of IGF-1-positive cells were significantly lower in the E2 group, but significantly higher in the TAM group than in the control group. It was concluded that the tumor content of IGF-1 and the proportion of IGF-I-positive cells were inversely correlated to the tumor growth and the 3H-thymidine labeling index in vivo.

Animals↗
PubMed1992

32P-postlabeling analysis of DNA adducts in rats during estrogen-induced hepatocarcinogenesis and effect of tamoxifen on DNA adduct level.

DNA adduct formation in the liver, pancreas, kidneys and uterus in ethynylestradiol (EE)-induced carcinogenesis and the effect of tamoxifen (TAM) on DNA adduct formation were evaluated in female Wistar JCL rats using the 32P-postlabeling method. Hyperplastic nodules were noted in the liver of all rats 4 months after the first oral administration of 0.075 mg of EE, and hepatocellular carcinoma was detected in 8.1% of rats treated with EE for 12 months. DNA adducts increased in the liver for 4 months, reaching a level of 7.3 adducts/10(7) nucleotides and decreasing thereafter. Formation of DNA adducts was also noted in the pancreas and kidney, but the adduct levels were lower than those in the liver. TAM inhibited estrogen receptors (ER) in liver tissues and completely suppressed the development of hyperplastic nodules or hepatocellular carcinoma but did not affect DNA adduct formation in the liver. In this model, therefore, EE is considered to cause mutations of hepatocytes due to DNA adduct formation without mediation by ER and to induce initiated cells to develop into hepatocellular carcinoma in the presence of ER-mediated hormonal activities.

Animals↗
PubMed2002

Estrogen receptor expression and estrogen receptor-independent cytotoxic effects of tamoxifen on malignant rhabdoid tumor cells in vitro.

Recent studies have shown that the antiestrogen tamoxifen (TAM) can be used in the treatment of malignant neoplasms other than breast cancer. In the present study, we investigated the expression of estrogen receptor (ER) in six malignant rhabdoid tumor (MRT) cell lines. Alterations in MRT cell growth in response to estrogen or antiestrogens (4-hydroxytamoxifen (4-OHT), TAM, and ICI 182 780) were also investigated. RT-PCR and western blotting showed that ER-alpha was expressed in three of the six MRT cell lines. While 17-beta-estradiol (E2) did not significantly alter MRT cell line proliferation, the hydroxylated tamoxifen metabolite 4-OHT significantly inhibited the growth of all 6 MRT cell lines. However, the steroidal antiestrogen ICI 182 780 did not alter the proliferation of any of the MRT cell lines. 4-OHT induced apoptosis in both ER-alpha-negative and ER-alpha-positive MRT cell lines, as assessed by nuclear morphology and DNA fragmentation. Neither growth inhibition nor induction of apoptosis due to 4-OHT was blocked by the addition of excess E2. Our data suggested that 4-OHT induced cytotoxic effects against MRT cells, and that these effects were independent of ER expression.

Apoptosis↗
PubMed2005

Optimizing therapy for myeloid disorders of Down syndrome.

Children with Down syndrome (DS) are at increased risk of leukaemia. Myeloid disorders include transient abnormal myelopoiesis (TAM), myelodysplasia (MDS) and acute myeloid leukaemia (AML). Mutations in the GATA-1 gene, which encodes for a transcription factor central to the normal development of the erythroid and megakaryocytic lineages, are found in cases of TAM, MDS and AML in DS children. DS children with MDS/AML mostly present between the ages of 1 and 4 years, and have a large predominance of megakaryoblastic disease (French-American-British type M7). The MDS and AML are part of a single disease entity (myeloid leukaemia of Down syndrome) that is extremely sensitive to chemotherapy. Resistant disease and relapse are rare, but treatment-related toxicity is high, and deaths in remission have exceeded those due to disease in most series. Accordingly, controlled dosage reduction is the focus of contemporary treatment studies.

Acute Disease↗
PubMed1992

cAMP effect on extracellular matrix synthesis in human breast cancer cells.

The effect of a cAMP derivative (N6, O2-dibutyryl cyclic adenosine 3',5'-monophosphate: dBcAMP) on the cell cycle and on the synthesis of typical extracellular matrix (ECM) components, i.e. collagen and glycosaminoglycans (GAG), was studied in two hormone-responsive human breast cancer cell lines VHB-1 and MCF-7. The data showed that dBcAMP induced a decrease in the proportion of cells in S + G2 + M phases due to an increase of the non-cycling (G0 phase) cell number as revealed by the Ki-67 antigen immunocytochemical study. The collagen synthesis, estimated by [3H] proline incorporation into the cellular proteins followed by an enzymatic digestion with highly purified bacterial collagenase, was not modified by dBcAMP. In contrast, the GAG synthesis, analysed by [3H] glucosamine incorporation, was increased two-fold in the dBcAMP treated cells. As a comparison we also tested 4-hydroxy-Tamoxifen (4-OH-Tam) since it induces similar cell cycle perturbations as dBcAMP. However, we did not observe a stimulation of the GAG synthesis following 4-OH-Tam treatment. These data demonstrated that the increased GAG synthesis is due to cAMP and is not a consequence of perturbations in the cell cycle. We can therefore assume that the ECM modifications induced by dBcAMP may contribute to the growth inhibition of the hormone-responsive human breast cancer cells.

Breast Neoplasms↗
PubMed2000

Isolated pericardial effusion and transient abnormal myelopoiesis in a fetus with Down's syndrome.

Isolated pericardial effusion was detected in a fetus at 34 weeks of gestation. A male infant weighing 2,044 g was born by cesarean section because of a non-assuring fetal heart rate pattern at 35 weeks of gestation. Transient leukocytosis (36,100/microl) with 49% blast cells was seen in this neonate. The infant's karyotype was 47, XY + 21. The pericardial effusion disappeared after treatment with prednisolone at a dose of 2 mg/kg/day. Hypothyroidism was subsequently found. Thus, the subject patient with Down's syndrome developed isolated pericardial effusion, transient abnormal myelopoiesis (TAM), and hypothyroidism. Because more than 20% of the infants with TAM and Down's syndrome develop acute nonlymphocytic leukemia in early childhood, he is being closely observed.

Adult↗
PubMed1997

Significant reduction of human monocyte chemotactic response to monocyte-chemotactic protein 1 in patients with primary and metastatic malignant melanoma.

The recruitment of leukocytes from the peripheral blood is a key event for the development and composition of the inflammatory infiltrate in solid tumors and tumor metastases like malignant melanoma. Tumor-infiltrating lymphocytes (TIL) and tumor-associated macrophages (TAM) are thought to play a crucial rôle in tumor immunosurveillance. In malignant melanoma expression and secretion of monocyte-chemotactic protein 1 (MCP-1) have been demonstrated. MCP-1 serves as an attractant for monocytes and activated T-cells. In this study we addressed the question whether circulating monocytes show altered chemotaxis to MCP-1. Therefore the chemotactic responsiveness of monocytes towards MCP-1 was investigated in patients with primary and metastatic melanoma and compared to patients with basal cell carcinoma and healthy persons. The results show that monocytes from melanoma patients showed a significantly decreased chemotactic migration towards MCP-1 while chemotaxis to the stimulus N-formyl-methionyl-leucyl-phenylalanine (FMLP) remained normal. Patients with basal cell carcinoma showed normal monocyte chemotaxis to all stimuli tested. In primary melanoma, there was no relation of the number of TAM or TIL to the decreased chemotaxis of circulating monocytes to MCP-1. From these data it can be concluded that circulating monocytes from patients with primary and metastatic melanoma show a MCP-1-specific decrease in chemotactic migration. This may be due to deactivation or modulation of the MCP-1-receptor expression on these cells.

Adult↗
PubMed2004

Interactions of the stereoisomers of alpha-hydroxytamoxifen with human hydroxysteroid sulfotransferase SULT2A1 and rat hydroxysteroid sulfotransferase STa.

Tamoxifen (TAM) is a nonsteroidal antiestrogenic drug that is widely used for the treatment of estrogen receptor-dependent breast cancer. An increased risk of endometrial cancer in some patients treated with TAM has been linked to the metabolic formation of alpha-hydroxytamoxifen (alpha-OHTAM) and its subsequent sulfation. Alpha-OHTAM has been found to be a substrate for rat and human hydroxysteroid sulfotransferases (STa and SULT2A1, respectively). Since stereochemistry plays an important role in the interactions of hydroxysteroid sulfotransferases with their substrates, we have now investigated the interactions of each of the stereoisomers of alpha-OHTAM with highly purified recombinant STa and SULT2A1. Methods for the preparation of the enantiomers of E- and Z-alpha-OHTAM were developed. When each of the four enantiomers was examined with rat STa, E-(+)-alpha-OHTAM was the only substrate for the enzyme, whereas E-(-)-alpha-OHTAM, Z-(+)-alpha-OHTAM, and Z-(-)-alpha-OHTAM were inhibitors of the sulfation of E-(+)-alpha-OHTAM catalyzed by STa. The dissociation constants for the alpha-OHTAM enantiomers indicated that they bound to STa with similar affinity, but only the E-(+)-enantiomer was a substrate. In contrast to the results obtained with rat hydroxysteroid sulfotransferase STa, all enantiomers of alpha-OHTAM were substrates for the human SULT2A1. Moreover, kcat/Km values with SULT2A1 were higher with the Z enantiomers than with the E enantiomers. As a result of the potential for interconversion of the E and Z geometric isomers upon metabolism, the sulfation of the Z isomers may be of greater concern in human tissues than has been previously assumed.

Animals↗
PubMed2006

Molecular mechanism by which the K70E mutation in human immunodeficiency virus type 1 reverse transcriptase confers resistance to nucleoside reverse transcriptase inhibitors.

The K70E mutation in human immunodeficiency virus type 1 (HIV-1) reverse transcriptase (RT) has become more prevalent in clinical samples, particularly in isolates derived from patients for whom triple-nucleoside regimens that include tenofovir (TNV), abacavir, and lamivudine (3TC) failed. To elucidate the molecular mechanism by which this mutation confers resistance to these nucleoside RT inhibitors (NRTI), we conducted detailed biochemical analyses comparing wild-type (WT), K70E, and K65R HIV-1 RT. Pre-steady-state kinetic experiments demonstrate that the K70E mutation in HIV-1 RT allows the enzyme to discriminate between the natural deoxynucleoside triphosphate substrate and the NRTI triphosphate (NRTI-TP). Compared to the WT enzyme, K70E RT showed 2.1-, 2.3-, and 3.5-fold-higher levels of resistance toward TNV-diphosphate, carbovir-TP, and 3TC-TP, respectively. By comparison, K65R RT demonstrated 12.4-, 12.0-, and 13.1-fold-higher levels of resistance, respectively, toward the same analogs. NRTI-TP discrimination by the K70E (and K65R) mutation was primarily due to decreased rates of NRTI-TP incorporation and not to changes in analog binding affinity. The K65R and K70E mutations also profoundly impaired the ability of RT to excise 3'-azido-2',3'-dideoxythymidine monophosphate (AZT-MP) and other NRTI-MP from the 3' end of a chain-terminated primer. When introduced into an enzyme with the thymidine analog mutations (TAMs) M41L, L210W, and T215Y, the K70E mutation inhibited ATP-mediated excision of AZT-MP. Taken together, these findings indicate that the K70E mutation, like the K65R mutation, reduces susceptibility to NRTI by selectively decreasing NRTI-TP incorporation and is antagonistic to TAM-mediated nucleotide excision.

Adenine↗
PubMed2004

Evolution of human immunodeficiency virus type 1 (HIV-1) resistance mutations in nonnucleoside reverse transcriptase inhibitors (NNRTIs) in HIV-1-infected patients switched to antiretroviral therapy without NNRTIs.

We studied the evolution of nonnucleoside reverse transcriptase inhibitor (NNRTI) resistance mutations among 29 human immunodeficiency virus type 1 (HIV-1)-infected patients who experienced virologic failure when receiving an NNRTI-containing regimen (nevirapine, delavirdine, or efavirenz) and subsequently switched to antiretroviral therapy without NNRTIs. Genotypic resistance was determined from plasma samples collected at the time of NNRTI withdrawal (baseline) and during follow-up. At baseline, 83% of patients had more than two thymidine analog resistance mutations (TAMs), and all had NNRTI resistance mutations. Mutations at codons 103, 181, and 190 were found in 62, 62, and 34% of the patients, respectively. Follow-up samples were available after a median time of 6 months in all patients and at 12 months in 22 patients. The mean number of resistance mutations to NNRTIs was significantly lower at months 6 (1.34 +/- 1.04) and 12 (1.18 +/- 1.05) than at month 0 (2.03 +/- 1.02) (P < 0.009). The percentages of patients with at least one NNRTI resistance mutation were 100, 76, and 73% at baseline, month 6, and month 12, respectively (P < 0.0044). Overall, 70% of the patients had a mutation at codon 103 or 181 at month 12. The mean number of TAMs did not vary significantly during follow-up. Our data show that, in the context of maintained antiretroviral therapy, NNRTI resistance mutations persist in two-thirds of the patients in spite of NNRTI withdrawal. These results argue for the low impact of NNRTI resistance mutations on viral fitness and suggest that resistance mutations to different classes of drugs are associated on the same genome, at least in some of the resistant strains.

Antiretroviral Therapy, Highly Active↗
PubMed2005

luxS-dependent gene regulation in Escherichia coli K-12 revealed by genomic expression profiling.

The bacterial quorum-sensing autoinducer 2 (AI-2) has received intense interest because the gene for its synthase, luxS, is common among a large number of bacterial species. We have identified luxS-controlled genes in Escherichia coli under two different growth conditions using DNA microarrays. Twenty-three genes were affected by luxS deletion in the presence of glucose, and 63 genes were influenced by luxS deletion in the absence of glucose. Minimal overlap among these gene sets suggests the role of luxS is condition dependent. Under the latter condition, the metE gene, the lsrACDBFG operon, and the flanking genes of the lsr operon (lsrR, lsrK, tam, and yneE) were among the most significantly induced genes by luxS. The E. coli lsr operon includes an additional gene, tam, encoding an S-adenosyl-l-methionine-dependent methyltransferase. Also, lsrR and lsrK belong to the same operon, lsrRK, which is positively regulated by the cyclic AMP receptor protein and negatively regulated by LsrR. lsrK is additionally transcribed by a promoter between lsrR and lsrK. Deletion of luxS was also shown to affect genes involved in methionine biosynthesis, methyl transfer reactions, iron uptake, and utilization of carbon. It was surprising, however, that so few genes were affected by luxS deletion in this E. coli K-12 strain under these conditions. Most of the highly induced genes are related to AI-2 production and transport. These data are consistent with the function of LuxS as an important metabolic enzyme but appear not to support the role of AI-2 as a true signal molecule for E. coli W3110 under the investigated conditions.

Adaptation, Psychological↗
PubMed1997

Analysis of the internal replication sequence indicates that there are three elements required for efficient replication of minute virus of mice minigenomes.

Prior analysis of minigenomes of minute virus of mice carried out by our laboratory indicated that sequences within the region of nucleotides 4489 to 4695, inboard of the 5' palindrome, are required for efficient DNA replication of the virus and are the site of specific interactions with unidentified factors present in a host cell nuclear extract (P. Tam and C. R. Astell, Virology 193:812-824, 1993; P. Tam and C. R. Astell, J. Virology 68:2840-2848, 1994). In order to examine this region in finer detail, a comprehensive library of linker-scanning mutants spanning the region was tested for the ability to support replication of minigenome constructs and for the ability to interact with host cell factors. Three short discrete sequence elements critical for replication competence were observed. Binding of host cell nuclear factors was localized to four sites, with two major complexes each appearing to have two binding sites within the region. All factor binding sites were found to be directly adjacent to or overlapping with sequence elements contributing to replication competence, and evidence suggesting a correlation between factor binding and minigenome replication is presented. A possible model is proposed for function of a viral origin within the region of the internal replication sequence which addresses the still-unresolved problem of how parvoviruses overcome the thermodynamic energy barrier involved in the rearrangement of the 5'-terminal palindrome from an extended form to a hairpin conformation.

Animals↗
PubMed1997

Lack of a role for Jun kinase and AP-1 in Fas-induced apoptosis.

Cross-linking of Fas (CD95) induces apoptosis, a response that has been reported to depend upon the Ras activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activation pathway. Since many examples of apoptosis have been reported to involve AP-1 and/or the AP-1-activating enzyme Jun kinase (JNK), downstream effectors of Ras or Ras-like small GTP-binding proteins, we evaluated the role of these molecules in Fas-mediated apoptosis. Although cross-linking of Fas on Jurkat T cells did result in JNK activation, increased activity was observed relatively late, being detectable only after 60 min of stimulation. Expression of a dominant negative form of SEK1 that blocked Fas-mediated induction of JNK activity had no effect on Fas-mediated apoptosis. Furthermore, maximally effective concentrations of anti-Fas did not cause JNK activation if apoptosis was blocked by a cysteine protease inhibitor, suggesting that under these conditions, activation of JNK may be secondary to the stress of apoptosis rather than a direct result of Fas engagement. Despite the activation of JNK, there was no induction of AP-1 activity as determined by gel shift assay or induction of an AP-1-responsive reporter. The lack of a requirement for AP-1 induction in Fas-mediated death was further substantiated with Jurkat cells that were stably transfected with a dominant negative cJun, TAM-67. While TAM-67 effectively prevented AP-1-dependent transcription of both the interleukin-2 and cJun genes, it had no effect on Fas-induced cell death, even at limiting levels of Fas signaling. Thus, induction of JNK activity in Jurkat cells by ligation of Fas at levels sufficient to cause cell death is likely a result, rather than a cause, of the apoptotic response, and AP-1 function is not required for Fas-induced apoptosis.

Amino Acid Chloromethyl Ketones↗
PubMed2004

Id2 is dispensable for Myc-induced epidermal neoplasia.

We have previously described a transgenic mouse model of epidermal neoplasia wherein expression of a switchable form of c-Myc, MycER(TAM), is targeted to the postmitotic suprabasal keratinocytes of murine epidermis via the involucrin promoter. Sustained activation of c-MycER(TAM) results in a progressive neoplastic phenotype characterized by aberrant ectopic proliferation and delayed differentiation of suprabasal keratinocytes, culminating in papillomatosis. Transcription of the Id2 gene is regulated by Myc family proteins. Moreover, Id2 is implicated as a pivotal determinant of cell fate in multiple lineages and has a demonstrated role in mediating Myc-dependent cell proliferation in vitro through its interaction with retinoblastoma protein. Using Id2 nullizygous mice, we assessed in vivo the requirement for Id2 in mediating Myc-induced papilloma formation in skin. We show that absence of Id2 has no discernible impact on any measurable attribute of Myc function or on the timing or extent of eventual tumor formation. Thus, our data argue against any essential role for Id2 in mediating Myc action in vivo.

Animals↗
PubMed1979

Plasma water shifts during thermal dehydration.

Changes in body water compartments during acute dehydration before and after acclimation to heat and the role of plasma proteins in body fluid dynamics were studied in the rat. Compartment volumes, plasma and interstitial protein concentrations, and colloid osmotic pressures (COP) were measured in anesthetized (with thiopental sodium) and, if necessary, nephrectomized rats. Albumin outfluxes, total protein mass (TPM), and total albumin mass (TAM) were calculated. Nonacclimated rats conserved plasma volume (PV) as long as dehydration did not exceed 15-16% body weight loss (18.6% total body water loss). This was associated with decreased albumin outflux, elevated plasma COP, and reduced subcutaneous COP. When water loss reached 25,5%, PV and extracellular fluid volume decreased by 45 and 34%, respectively. Albumin outflux recovered, TPM and TAM decreased, and plasma COP remained high. In acclimated dehydrated rats PV remained unchanged, albumin outflux decreased, TPM and COP increased, and interstitial COP decreased. Most of the water loss was intracellular in origin. It was concluded that PV changes during dehydration are related to changes in plasma protein distribution. PV conservation rate is different in rats as compared to desert PV conservers.

Acclimatization↗
PubMed2005

Breast cancer cells stimulate neutrophils to produce oncostatin M: potential implications for tumor progression.

Tumor-associated and tumor-infiltrating neutrophils (TAN) and macrophages (TAM) can account for as much as 50% of the total tumor mass in invasive breast carcinomas. It is thought that tumors secrete factors that elicit a wound-repair response from TAMs and TANs and that this response inadvertently stimulates tumor progression. Oncostatin M is a pleiotropic cytokine belonging to the interleukin-6 family that is expressed by several cell types including activated human T lymphocytes, macrophages, and neutrophils. Whereas oncostatin M can inhibit the proliferation of breast cancer cells in vitro, recent studies suggest that oncostatin M may promote tumor progression by enhancing angiogenesis and metastasis. In addition, neutrophils can be stimulated to synthesize and rapidly release large quantities of oncostatin M. In this article, we show that human neutrophils secrete oncostatin M when cocultured with MDA-MB-231 and T47D human breast cancer cells. Neutrophils isolated from whole blood or breast cancer cells alone express little oncostatin M by immunocytochemistry and ELISA, but neutrophils express and release high levels of oncostatin M when they are cocultured with breast cancer cells. In addition, we show that granulocyte-macrophage colony-stimulating factor produced by breast cancer cells and cell-cell contact are both necessary for the release of oncostatin M from neutrophils. Importantly, neutrophil-derived oncostatin M induces vascular endothelial growth factor from breast cancer cells in coculture and increases breast cancer cell detachment and invasive capacity, suggesting that neutrophils and oncostatin M may promote tumor progression in vivo.

Antibodies↗