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D Straus

Publications and source records attributed to D Straus.

At least 19 recordsLinked to original sources
PubMed2004

Electronic transport in a controllably grown carbon nanotube-silicon heterojunction array.

A uniform array of a new type of heterojunction formed between carbon nanotubes and silicon is studied. The heterojunction array was controllably grown with parallel and uniform nanotubes vertically aligned to the silicon substrate using a self-organized nanopore array template. The pronounced rectifying characteristics of the heterojunction were measured with an on/off ratio as high as 10(5) at 4 V. The analysis shows a large and type-I band offset at the heterojunction. The charge transport in the nanotubes is found to be strongly coupled to and limited by the dielectric charging and polarization in the hosting alumina matrix surrounding the nanotubes.

Journal Article↗
PubMed2001

Chemotherapy for human immunodeficiency virus-associated non-Hodgkin's lymphoma in combination with highly active antiretroviral therapy.

PURPOSE: This study investigated the efficacy, toxicity, and pharmacokinetic interactions resulting from simultaneous combination chemotherapy and highly active antiretroviral therapy (HAART) for patients with human immunodeficiency virus (HIV)-associated non-Hodgkin's lymphoma (NHL). In addition, the effects on viral load, CD4 counts, and opportunistic infections were examined with the use of combination chemotherapy combined with HAART. PATIENTS AND METHODS: Sixty-five patients with previously untreated and measurable disease at any stage of HIV-associated NHL of intermediate or high grade were entered onto this study at 17 different centers. The first 40 patients entered onto the study received reduced doses of cyclophosphamide and doxorubicin, combined with vincristine and prednisone (modified CHOP [mCHOP]), whereas the subsequent 25 patients entered onto the study received full doses of CHOP combined with granulocyte colony-stimulating factor (G-CSF). All patients also received stavudine, lamivudine, and indinavir. RESULTS: The complete response rates were 30% and 48% among patients who received mCHOP and full-dose CHOP combined with HAART, respectively. Grade 3 or 4 neutropenia occurred in 25% of patients receiving mCHOP and 12% of those receiving full-dose CHOP combined with G-CSF (25% v 12%). There were similar numbers of patients with grade 3 or 4 hyperbilirubinemia (12% and 17%), constipation and abdominal pain (18% and 17%), and transaminase elevation (48% and 52%) on the modified and full-dose arms of the study, respectively. Doxorubicin clearance and indinavir concentration curves were similar among patients on this study and historical controls, whereas cyclophosphamide clearance was 1.5-fold reduced as compared with control values. Human immunodeficiency virus (HIV) load declined from a median baseline value of 29,000 copies/mL to a median minimum value on therapy of 500 copies/mL. CONCLUSION: Either modified-dose or full-dose CHOP chemotherapy for HIV-NHL, delivered with HAART, is effective and tolerable.

Adult↗
PubMed2001

A 2-step comprehensive high-dose chemoradiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model.

Salvage of patients with relapsed and refractory Hodgkin disease (HD) with high-dose chemoradiotherapy (HDT) and autologous stem cell transplantation (ASCT) results in event-free survival (EFS) rates from 30% to 50%. Unfortunately, the reduction in toxicity associated with modern supportive care has improved EFS by only 5% to 10% and has not reduced the relapse rate. Results of a comprehensive 2-step protocol encompassing dose-dense and dose-intense second-line chemotherapy, followed by HDT and ASCT, are reported. Sixty-five consecutive patients, 22 with primary refractory HD and 43 with relapsed HD, were treated with 2 biweekly cycles of ifosfamide, carboplatin, and etoposide (ICE). Peripheral blood progenitor cells from responding patients were collected, and the patients were given accelerated fractionation involved field radiotherapy (IFRT) followed by cyclophosphamide-etoposide and either intensive accelerated fractionation total lymphoid irradiation or carmustine and ASCT. The EFS rate at a median follow-up of 43 months, as analyzed by intent to treat, was 58%. The response rate to ICE was 88%, and the EFS rate for patients who underwent transplantation was 68%. Cox regression analysis identified 3 factors before the initiation of ICE that predicted for outcome: B symptoms, extranodal disease, and complete remission duration of less than 1 year. EFS rates were 83% for patients with 0 to 1 adverse factors, 27% for patients with 2 factors, and 10% for patients with 3 factors (P <.001). These results compare favorably with other series and document the feasibility and efficacy of giving uniform dose-dense and dose-intense cytoreductive chemotherapy and integrating accelerated fractionation radiotherapy into an ASCT treatment program. This prognostic model provides a basis for risk-adapted HDT.

Adolescent↗
PubMed2000

The tyrosine kinase p56lck is essential in coxsackievirus B3-mediated heart disease.

Infections are thought to be important in the pathogenesis of many heart diseases. Coxsackievirus B3 (CVB3) has been linked to chronic dilated cardiomyopathy, a common cause of progressive heart disease, heart failure and sudden death. We show here that the sarcoma (Src) family kinase Lck (p56lck) is required for efficient CVB3 replication in T-cell lines and for viral replication and persistence in vivo. Whereas infection of wild-type mice with human pathogenic CVB3 caused acute and very severe myocarditis, meningitis, hepatitis, pancreatitis and dilated cardiomyopathy, mice lacking the p56lck gene were completely protected from CVB3-induced acute pathogenicity and chronic heart disease. These data identify a previously unknown function of Src family kinases and indicate that p56lck is the essential host factor that controls the replication and pathogenicity of CVB3.

Animals↗
PubMed1999

Heat-shock protein 72 protects against oxidant-induced injury of barrier function of human colonic epithelial Caco2/bbe cells.

BACKGROUND & AIMS: Barrier function of the inflamed intestinal mucosa can be compromised by reactive oxygen metabolites that increase mucosal permeability and disrupt the actin cytoskeleton, the integrity of which is important for maintaining tight epithelial junctions. Because heat-shock protein 72 (hsp72) protects intestinal epithelial cells against injury, we determined whether resistance of Caco2/bbe (C2) intestinal monolayer barrier function was related to their high endogenous hsp72 expression. METHODS: hsp72 anti-sense (C2/AS) and vector-only transfected C2 (C2/CEP4) clones, lines that exhibit low and high hsp72 expression, respectively, were studied. Permeability was assessed by measuring electrical resistance and mannitol fluxes and actin organization by confocal fluorescein isothiocyanate-phalloidin analysis. RESULTS: Basal transepithelial electrical resistance (TER) and mannitol fluxes were not significantly different between groups. However, the oxidant monochloramine rapidly decreased TER and increased mannitol permeability of C2/AS monolayers compared with C2/CEP4 (50% effective doses at 30 minutes were 0.53 +/- 0.11 and 2.06 +/- 0.34 mmol/L, respectively). Associated with these changes, decreased cell viability, dissociation and aggregation of perijunctional and stress actin filaments, loss of cell height, and increased intercellular separation were observed only in C2/AS cells treated with monochloramine. CONCLUSIONS: hsp72 protects intestinal epithelial barrier function against oxidant-induced stress, in part, by protecting the integrity of the actin cytoskeleton.

Actins↗
PubMed1998

Molecular basis of T cell inactivation by CTLA-4.

CTLA-4, a negative regulator of T cell function, was found to associate with the T cell receptor (TCR) complex zeta chain in primary T cells. The association of TCRzeta with CTLA-4, reconstituted in 293 transfectants, was enhanced by p56(lck)-induced tyrosine phosphorylation. Coexpression of the CTLA-4-associated tyrosine phosphatase, SHP-2, resulted in dephosphorylation of TCRzeta bound to CTLA-4 and abolished the p56(lck)-inducible TCRzeta-CTLA-4 interaction. Thus, CTLA-4 inhibits TCR signal transduction by binding to TCRzeta and inhibiting tyrosine phosphorylation after T cell activation. These findings have broad implications for the negative regulation of T cell function and T cell tolerance.

Abatacept↗
PubMed1998

Dexamethasone protection of rat intestinal epithelial cells against oxidant injury is mediated by induction of heat shock protein 72.

Although the therapeutic actions of glucocorticoids are largely attributed to their anti-inflammatory and immunosuppressive effects, they have been implicated in enhancing tissue and cellular protection. In this study, we demonstrate that dexamethasone significantly enhances viability of IEC-18 rat small intestinal cells against oxidant-induced stress in a dose-dependent fashion. This protective action is mediated by induction of hsp72, the major inducible heat shock protein in intestinal epithelial cells. Dexamethasone stimulates a time- and dose-dependent response in hsp72 protein expression that parallels its effects on cell viability. Furthermore, the induction of hsp72 is tissue dependent, as nonintestinal epithelioid HeLa cells show differential induction of hsp72 expression in response to the same dexamethasone treatment. Antisense hsp72 cDNA transfection of IEC-18 cells abolishes the dexamethasone-induced hsp72 response, without significantly affecting constitutive expression of its homologue, hsc73. Dexamethasone treatment also significantly induces hsp72 protein expression in rat intestinal mucosal cells in vivo. These data demonstrate that glucocorticoids protect intestinal epithelial cells against oxidant-induced stress by inducing hsp72.

Animals↗
PubMed1998

Positional cloning without a genome map: using 'Targeted RFLP Subtraction' to isolate dense markers tightly linked to the regA locus of Volvox carteri.

The ability to isolate genes defined by mutant phenotypes has fueled the rapid progress in understanding basic biological mechanisms and the causes of inherited diseases. Positional cloning, a commonly used method for isolating genes corresponding to mutations, is most efficiently applied to the small number of model organisms for which high resolution genetic maps exist. We demonstrate a new and generally applicable positional cloning method that obviates the need for a genetic map. The technique is based on Restriction Fragment Length Polymorphism (RFLP) Subtraction, a method that isolates RFLP markers spanning an entire genome. The new method, Targeted RFLP Subtraction (TRS), isolates markers from a specific region by combining RFLP Subtraction with a phenotypic pooling strategy. We used TRS to directly isolate dense markers tightly linked to the regA gene of the eukaryotic green alga Volvox. As a generally applicable method for saturating a small targeted region with DNA markers, TRS should facilitate gene isolation from diverse organisms and accelerate the process of physically mapping specific regions in preparation for sequence analysis.

Algal Proteins↗
PubMed1998

Regulation of PAK activation and the T cell cytoskeleton by the linker protein SLP-76.

Tyrosine phosphorylation of linker proteins enables the T cell antigen receptor (TCR)-associated protein tyrosine kinases to phosphorylate and regulate effector molecules that generate second messengers. We demonstrate here that the SLP-76 linker protein interacts with both nck, an adaptor protein, and Vav, a guanine nucleotide exchange factor for Rho-family GTPases. The assembly of this tri-molecular complex permits the activated Rho-family GTPases to regulate target effectors that interact through nck. In turn, assembly of this complex mediates the enzymatic activation of the p21-activated protein kinase 1 and facilitates actin polymerization. Hence, phosphorylation of linker proteins not only bridges the TCR-associated PTK, ZAP-70, with downstream effector proteins, but also provides a scaffold to integrate distinct signaling complexes to regulate T cell function.

Actins↗
PubMed1998

Genetic evidence of a role for Lck in T-cell receptor function independent or downstream of ZAP-70/Syk protein tyrosine kinases.

T-cell antigen receptor (TCR) engagement results in sequential activation of the Src protein tyrosine kinases (PTKs) Lck and Fyn and the Syk PTKs, ZAP-70 and Syk. While the Src PTKs mediate the phosphorylation of TCR-associated signaling subunits and the phosphorylation and activation of the Syk PTKs, the lack of a constitutively active Syk PTK has prohibited the analysis of Lck function downstream of these initiating signaling events. We describe here the generation of an activated Syk family PTK by substituting the kinase domain of Syk for the homologous region in ZAP-70 (designated as KS for kinase swap). Expression of the KS chimera resulted in its autophosphorylation, the phosphorylation of cellular proteins, the upregulation of T-cell activation markers, and the induction of interleukin-2 gene synthesis in a TCR-independent fashion. The KS chimera and downstream ZAP-70 or Syk substrates, such as SLP-76, were still phosphorylated when expressed in Lck-deficient JCaM1.6 T cells. However, expression of the KS chimera in JCaM1.6 cells failed to rescue downstream signaling events, demonstrating a functional role for Lck beyond the activation of the ZAP-70 and Syk PTKs. These results indicate that downstream TCR signaling pathways may be differentially regulated by ZAP-70 and Lck PTKs and provide a mechanism by which effector functions may be selectively activated in response to TCR stimulation.

Enzyme Activation↗
PubMed1997

Initial clinical trial of a selective retinoid X receptor ligand, LGD1069.

PURPOSE: The retinoid response is mediated by nuclear receptors, including retinoic acid receptors (RARs) and retinoid "X" receptors (RXRs). All-trans retinoic acid (RA) binds only RARs, while 9-cis RA is an agonist for both RARs and RXRs. Recently, LGD1069 was identified as a highly selective RXR agonist with low affinity for RARs. We undertook a dose-ranging study to examine the safety, clinical tolerance, and pharmacokinetics of LGD1069 in patients with advanced cancer. PATIENTS AND METHODS: Fifty-two patients received. LGD1069 administered orally once daily at doses that ranged from 5 to 500 mg/m2 for 1 to 41 weeks. Treatment proceeded from a starting dose of 5 mg/m2. Pharmacokinetic sampling was performed on selected patients on days 1, 15, and 29. RESULTS: Reversible, asymptomatic increases in liver biochemical tests were the most common dose-limiting adverse effect. Less prominent reactions included leukopenia, hypertriglyceridemia, and hypercalcemia. Characteristic retinoid toxicities, such as cheilitis, headache, and myalgias/arthralgias, were mild or absent. Two patients with cutaneous T-cell lymphoma experienced major antitumor responses. Pharmacokinetic studies obtained in 27 patients at eight dose levels showed that the day 1 area under the plasma concentration-times-time curves (AUCs) were proportional to dose. At all doses studied, the day 1 AUCs were similar to those on days 15 and 29, indicating a lack of induced metabolism. CONCLUSION: LGD1069 is a unique compound that exploits a newly identified pathway of retinoid receptor biology that may be relevant to tumor-cell proliferation and apoptosis. Further investigation of this drug is warranted. Based on the results of this study, a dose of 300 mg/m2 is recommended for single-agent trials.

Adult↗
PubMed1996

Three abundant germ line-specific transcripts in Volvox carteri encode photosynthetic proteins.

Volvox carteri is a multicellular eukaryotic green alga composed of about 2000 cells of only two differentiated types: somatic and germ line. To understand how embryonic cells are assigned either to somatic or germ line fates, we are investigating the regulation of transcripts that are abundant in only one cell type. Here we report the identity of three transcripts that are coordinately expressed at high levels in germ line cells but not in somatic cells. Surprisingly, all three transcripts encode photosynthetic chloroplast proteins (light-harvesting complex protein, oxygen-evolving enhancer protein 3, and ferredoxin-NADP+ reductase) that are transcribed from nuclear genes. We discuss why these mRNAs might be required at high levels in germ line cells and present a hypothesis, suggested by our results, on the evolution of cell specialization in the Volvocales.

Algal Proteins↗
PubMed1996

Distinct tyrosine phosphorylation sites in ZAP-70 mediate activation and negative regulation of antigen receptor function.

Biochemical and genetic evidence has implicated two families of protein tyrosine kinases (PTKs), the Src- and Syk-PTKs, in T- and B-cell antigen receptor signaling. ZAP-70 is a member of the Syk-PTKs that associates with the T-cell antigen receptor and undergoes tyrosine phosphorylation following receptor activation. Three tyrosine residues, Tyr-292, -492, and -493, have been identified as sites of phosphorylation following T-cell antigen receptor engagement. Utilizing ZAP-70- and Syk-deficient lymphocytes (Syk-DT40 cells), we provide biochemical and functional evidence that heterologous trans-phosphorylation of Tyr-493 by a Src-PTK is required for antigen receptor-mediated activation of both the calcium and ras pathways. In contrast, cells expressing mutations at Tyr-292 or -492 demonstrate hyperactive T- and B-cell antigen receptor phenotypes. Thus, phosphorylation of ZAP-70 mediates both activation and inactivation of antigen receptor signaling.

Amino Acid Sequence↗
PubMed1995

Diverse spermatogenic defects in humans caused by Y chromosome deletions encompassing a novel RNA-binding protein gene.

We have detected deletions of portions of the Y chromosome long arm in 12 of 89 men with azoospermia (no sperm in semen). No Y deletions were detected in their male relatives or in 90 other fertile males. The 12 deletions overlap, defining a region likely to contain one or more genes required for spermatogenesis (the Azoospermia Factor, AZF). Deletion of the AZF region is associated with highly variable testicular defects, ranging from complete absence of germ cells to spermatogenic arrest with occasional production of condensed spermatids. We find no evidence of YRRM genes, recently proposed as AZF candidates, in the AZF region. The region contains a single-copy gene, DAZ (Deleted in AZoospermia), which is transcribed in the adult testis and appears to encode an RNA binding protein. The possibility that DAZ is AZF should now be explored.

Amino Acid Sequence↗
PubMed1994

"RFLP subtraction": a method for making libraries of polymorphic markers.

We developed a method, "RFLP subtraction," that isolates large numbers of unique sequence restriction fragment length polymorphisms (RFLPs) in a single experiment. The technique purifies small restriction fragments from one genome containing sequences that reside on large fragments in a related genome. We first isolate samples containing the small restriction fragments from two polymorphic strains. Subtractive hybridization then removes the fragments that are present in both samples. The remaining sequences are RFLPs: they occur on small fragments in one strain but not in the other. Here we use RFLP subtraction to make a library of hundreds of unique sequence RFLPs from two inbred mouse strains. We analyze and map a subset of the RFLPs and show that the genetic linkage of these markers can be rapidly determined by an efficient dot blot mapping technique. Several other potential applications of RFLP subtraction, including isolating region specific markers, are discussed.

Alleles↗
PubMed1993

Signal transduction events leading to T-cell lymphokine gene expression.

The expression of T-cell derived lymphokines is regulated by signal transduction events initiated by the T-cell antigen receptor and other T-cell surface molecules. Substantial progress has been made in characterizing the signal transduction events initiated at the plasma membrane of the T cell and their targets which control lymphokine gene expression in the nucleus. This review will summarize recent progress in this area of investigation.

Animals↗
PubMed1992

High incidence of disseminated intravascular coagulation during remission induction of adult patients with acute lymphoblastic leukemia.

We determined the incidence and complications of disseminated intravascular coagulation (DIC) at presentation and during remission induction of previously untreated adults with acute lymphoblastic leukemia (ALL) or de novo Philadelphia chromosome-positive ALL (PCALL) seen at Memorial Hospital between January 1, 1978 and December 31, 1989. DIC was diagnosed in the presence of (1) low fibrinogen (less than or equal to 160 mg/dL), (2) prolonged prothrombin time (PT) and falling fibrinogen, or (3) prolonged PT and positive fibrin split products (FSP). L-Asparaginase was not used during remission induction. Among adequately screened patients with ALL, DIC was detected in 7 of 58 (12%) before initiation of chemotherapy and in 35 of 45 (78%) during remission induction. DIC was not simply the result of infection because clinical and laboratory signs of infection were absent in 16 patients, whereas only 2 of the 22 febrile patients with DIC had positive cultures. Among the 38 patients with DIC at presentation or during remission induction, serious complications were seen in 13 in temporal association with DIC (pulmonary embolus in one, sagittal sinus thrombosis in three, and serious hemorrhage in nine) and were major factors in the deaths of three patients. Among the 10 patients with thorough screening but no evidence of DIC there was only one hemorrhage during the same time interval. In patients with PCALL, DIC was detected in 9% at presentation and in 80% during remission induction. We conclude that DIC is rare at presentation but common during remission induction of adult ALL and PCALL and may be associated with significant thrombotic and hemorrhagic complications. We suggest daily screening for DIC during the first 14 days of remission induction. The treatment of DIC in ALL and PCALL should be a subject of future clinical studies.

Adult↗