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L Silverman

Publications and source records attributed to L Silverman.

At least 19 recordsLinked to original sources
PubMed2002

Accelerated superfractionated radiotherapy with concomitant boost for locally advanced head-and-neck squamous cell carcinomas.

PURPOSE: A growing body of evidence supports the efficacy of accelerated superfractionated radiotherapy with concomitant boost for advanced head-and-neck carcinomas. This study represents a single-institution experience, performed to identify the factors influencing tumor control, survival, and toxicity. MATERIALS AND METHODS: Between 1988 and 1999, 133 patients with primary squamous cell head-and-neck carcinoma underwent accelerated superfractionated radiotherapy using a concomitant boost. The concomitant boost in this regimen was delivered using reduced fields delivered 3 times weekly in a twice-daily schedule during the final phase. The total radiation dose ranged from 64.8 Gy to 76.5 Gy (mean 71.1). Patients were evaluated in follow-up for local control and late toxicity. Multivariate analysis of treatment and patient parameters was performed to evaluate their influence on toxicity, local control, and overall survival. RESULTS: With a mean follow-up of 37 months, the actuarial overall survival rate for the entire group at 5 years was 24% and the local control rate was 57%. The tumor volume was the most significant predictor of local control, such that each 1-cm(3) increase in volume was associated with a 1% decrease in local control. For patients with tumor volumes </=30 cm(3) vs. >30 cm(3), the 5-year disease-specific survival rate was 52% and 27% (p = 0.004) and locoregional control rate was 76% and 26% (p <0.001), respectively. Seventy-six patients with a minimum of 12 months and median of 39 months toxicity follow-up were studied for late effects. None of these patients experienced Grade 4 or 5 toxicity. The actuarial rate of significant toxicity (Grade III or greater) was 32% at 5 years. Of the toxicities observed, xerostomia (19%) was the most common. Multivariate analysis revealed N stage and dose as independent predictors of Grade 3 effects. CONCLUSION: The locoregional control and survival for patients in this institutional experience compare favorably to other published reports. Tumors of the larynx had the best prognosis. Larger volume tumors were associated with significantly lower local control and survival. Significant late effects were related to dose and nodal status.

Analysis of Variance↗
PubMed2000

Outcome of treatment in children with Philadelphia chromosome-positive acute lymphoblastic leukemia.

BACKGROUND: Children with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) have a poor prognosis, and there is no consensus on the optimal treatment for this variant of ALL. METHODS: We reviewed the medical records of patients with Ph-positive ALL who were treated with intensive chemotherapy, with or without bone marrow transplantation, by 10 study groups or large single institutions from 1986 to 1996. Data on 326 children and young adults, who ranged in age from 0.4 to 19.9 years (median, 8.1), were analyzed to determine the rate of complete remission and the probability of event-free, disease-free and overall survival according to standard prognostic factors and type of treatment. RESULTS: The 267 patients who achieved a complete remission after induction chemotherapy (82 percent) were stratified into three subgroups according to the age and leukocyte count at the time of diagnosis: those with the best prognosis (a leukocyte count of less than 50,000 per cubic millimeter and an age of less than 10 years; 95 patients); those with an intermediate prognosis (intermediate-risk features; 92 patients); and those with the worst prognosis (a leukocyte count of more than 100,000 per cubic millimeter; 80 patients). The estimates of disease-free survival at five years (+/-SE) were 49+/-5 percent) for patients with the best prognosis), 30+/-5 percent (for those with an intermediate prognosis), and 20+/-5 percent (for those with the worst prognosis) (P<0.001 for the overall comparison). We also found that transplantation of bone marrow from an HLA-matched related donor offered significantly greater benefit than intensive chemotherapy alone in terms of protecting patients from relapse or other adverse events (relative risk, 0.3; 95 percent confidence interval, 0.2 to 0.5; P<0.001). This finding was consistent in all three groups. CONCLUSIONS: Unlike the usual type of all, Ph-positive ALL is associated with a poor prognosis. Nevertheless, in some patients with favorable prognosis features, the disease can be be controlled by intensive chemotherapy. Transplantation of bone marrow from an HLA-matched related donor is superior to other types of transplantation and to intensive chemotherapy alone in prolonging initial complete remissions.

Adolescent↗
PubMed1999

Selective A1-adenosine receptor antagonists identified using yeast Saccharomyces cerevisiae functional assays.

Evaluation of a biased "library" of pyrrolo[2,3-d]pyrimidines using yeast-based functional assays expressing human A1- and A2a-adenosine receptors, led to the A1 selective antagonist 4b. A direct correlation between yeast functional activity and binding data was established. Practical compounds with polar residues at C-4 of the pyrrolopyrimidine system required H-bond donor functionality for high potency.

Binding, Competitive↗
PubMed1998

New assay technologies for high-throughput screening.

The use of high-throughput screening for early stage drug discovery imposes several constraints on the format of assays for therapeutic targets of interest. Homogeneous cell-free assays based on energy transfer, fluorescence polarization spectroscopy or fluorescence correlation spectroscopy provide the sensitivity, ease, speed and resistance to interference from test compounds needed to function in a high-throughput screening mode. Similarly, novel cell-based assays are now being adapted for high-throughput screening, providing for in situ analysis of a variety of biological targets. Finally, recent advances in assay miniaturization mark a transition to ultra high-throughput screening, ensuring that identification of lead compounds will not be the rate-limiting step in finding new drugs.

Animals↗
PubMed1997

Acceptance of home and clinic-based cystic fibrosis carrier education and testing by first, second, and third degree relatives of cystic fibrosis patients.

We contacted and offered free cystic fibrosis (CF) carrier education and testing to the first, second, and third degree relatives of individuals with CF followed at a large Southeastern US CF Clinic. Relatives were offered CF carrier education and testing either in their homes or in a genetic counseling clinic. Overall, of 514 relatives offered free CF carrier education and testing, 299 (58%) accepted. Significantly more (67%) of those offered education and testing in their homes accepted than those offered education and testing in a genetic counseling clinic (45%). Regression analyses identified several factors, including education, income, gender, perceived chance of being a carrier, and perceived chance of having a child who is a CF carrier, as predictors of acceptance of education and testing in both home and clinic sites. A smaller set of factors was identified that predicted acceptance of education and testing unique to each site. Within the limits of this study and its design, even when CF carrier testing is offered free of charge, including education and testing in the home, acceptance of education and testing, while higher than in general population samples, is not universal among at-risk relatives. Several factors which may have contributed to the observations reported in this study are discussed.

Adolescent↗
PubMed1996

Cisplatin-based chemotherapy in renal transplant recipients. A case report and a review of the literature.

BACKGROUND: Renal transplant recipients have a high incidence of cancer. The main side effect of cisplatin, nephrotoxicity, has special implications in renal transplant recipients. This is particularly true in view of the routine use of cyclosporine as an immunosuppresant. Nephrotoxicity is also one of the main side effects of cyclosporine. METHODS: We report a patient with a renal allograft who was receiving cyclosporine for immunosuppression and developed metastatic transitional cell carcinoma of the bladder and was treated with cisplatin-based chemotherapy. The literature regarding cisplatin-containing chemotherapy in patients with different cancers and a single transplanted kidney is reviewed. RESULTS: The patient received four cycles of methotrexate, vinblastine, doxorubicin, and cisplatin while on continuous cyclosporine therapy. His renal function remained stable. He responded to chemotherapy initially, but this response was short. Ten patients with renal transplants and cancer who were treated with cisplatin have been reported previously. Two were maintained on cyclosporine for immunosuppression throughout chemotherapy. No patient developed renal failure during or shortly after administration of cisplatin. Two of five patients treated for testicular cancer developed renal failure at 3 and 6 years after completion of chemotherapy. However, in both cases the cause of renal failure was attributed to chronic rejection of the transplanted kidney. CONCLUSION: Renal transplant recipients usually tolerate cisplatin-based chemotherapy well. It should be offered to patients with potentially curable cancer (e.g., germ cell tumor). This case and a review of the literature suggest that these patients retain baseline renal function even if cisplatin-based chemotherapy and cyclosporine are given simultaneously.

Adult↗
PubMed1993

Effect of melanin, oxyhemoglobin and bilirubin on transcutaneous bilirubinometry.

To determine the effect of skin pigments on transcutaneous bilirubinometer readings, we measured the effect of bilirubin, melanin, and oxyhemoglobin solutions on transcutaneous bilirubinometer readings in vitro. Our results showed that the variability of the readings in vitro was related to the instrument's non-linear response to bilirubin and melanin concentration and an inaccurate oxyhemoglobin correction factor. These factors should be considered in developing a more accurate non-invasive method of monitoring serum bilirubin concentration.

Bilirubin↗
PubMed1993

Members of the src family of nonreceptor tyrosine kinases share a common mechanism for membrane binding.

The src family of nonreceptor protein tyrosine kinases share extensive sequence homology, except for 80 NH2-terminal amino acids, thought to comprise a "unique" domain. This region is presumed to mediate interactions specific to each kinase. Recently, we identified three NH2-terminal lysine residues, crucial for pp60v-src membrane association. Surprisingly, these lysines are conserved among several src family members. Since their mechanism of membrane association is unknown, it was of interest to determine whether other tyrosine kinases also utilize their NH2-terminal domain. Here, we demonstrate that pp60v-src, p62c-yes, and p59fyn polypeptides compete with each other for membrane binding, whereas p56lck, which lacks the NH2-terminal lysine motif, has no effect. Moreover, myristylated peptides corresponding to the NH2 termini of src, yes, lyn, and fyn inhibit membrane association of pp60c-src, p62c-yes, and p59fyn. Our results suggest that src family members share a common mechanism for membrane binding, and they provide a molecular explanation for the ability of other src family members to complement pp60c-src function.

Alkylation↗
PubMed1992

del(5q) in acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype.

We report three patients with acute lymphoblastic leukemia with biphenotypic and early progenitor phenotype who had del(5q). In the first patient, the del(5q) was the sole abnormality; in the second patient, the del(5q) was interpreted as subclonal evolutionary event; while in the third patient, the rearrangement was transiently present 7 months following the diagnosis of Ph-positive ALL, while the patient was in clinical remission. Review of the literature indicates that del(5q) is rare in ALL. In contrast to its presence in AML, del(5q) in ALL is not an adverse prognostic indicator, and it appears to be more frequent in children.

Adolescent↗
PubMed1992

Crystal structure of the phosphotyrosine recognition domain SH2 of v-src complexed with tyrosine-phosphorylated peptides.

Three-dimensional structures of complexes of the SH2 domain of the v-src oncogene product with two phosphotyrosyl peptides have been determined by X-ray crystallography at resolutions of 1.5 and 2.0 A, respectively. A central antiparallel beta-sheet in the structure is flanked by two alpha-helices, with peptide binding mediated by the sheet, intervening loops and one of the helices. The specific recognition of phosphotyrosine involves amino-aromatic interactions between lysine and arginine side chains and the ring system in addition to hydrogen-bonding interactions with the phosphate.

Amino Acid Sequence↗
PubMed1992

Chromosome 21 rearrangement in acute biphenotypic leukemia.

A patient with myelodysplastic syndrome (MDS) and a 47,XY,+21 karyotype at diagnosis, was documented to have a clonal chromosome 21 rearrangement, i(21q), four months before transformation to acute biphenotypic leukemia. For 4 months after transformation, isochromosome 21 persisted while the patient was receiving treatment with zidovudine. Vitamin D3 was added to zidovudine for an additional month, during which time the trisomy 21 clone reappeared as the predominant cell population. The unique aspects of this patient are the atypical evolution of chromosome 21, the transformation to biphenotypic leukemia, and the occurrence of i(21q) associated with biphenotypic leukemia evolving from an MDS.

Anemia, Refractory, with Excess of Blasts↗
PubMed1992

Lysine residues form an integral component of a novel NH2-terminal membrane targeting motif for myristylated pp60v-src.

Association of pp60v-src with the plasma membrane is fundamental to generation of the transformed phenotype. Although myristylation of pp60v-src is required for interaction with a membrane-bound receptor, the importance of NH2-terminal amino acids in receptor binding has not yet been uncoupled from their role in signaling myristylation. Using chimeric src proteins, peptides identical or related to the NH2 terminus of src, and site-directed mutagenesis, we demonstrate that NH2-terminal lysines in conjunction with myristate are essential for membrane localization. Subsequent to NH2-terminal interaction with the "src receptor," internal regions of the src protein also participate in membrane binding. This novel NH2-terminal motif and internal contact mechanism may direct other members of the src family of tyrosine kinases to their membrane receptors.

Amino Acid Sequence↗
PubMed1991

Chemotherapy of metastatic Merkel cell cancer.

Out of 16 cases of Merkel cell cancer identified in the records of the Mt. Sinai Medical Center or affiliates, 11 patients developed systemic metastases. Literature review confirms the substantial possibility of dissemination. Both in our series and in the literature, cytotoxic chemotherapy produced a high rate of usually short-lived response, although one of our patients with disseminated metastases achieved complete remission for two years.

Adult↗
PubMed1989

Mechanisms of T cell activation by the calcium ionophore ionomycin.

We have investigated signaling mechanisms that may underlie the T cell mitogenic properties of the Ca2+ ionophore ionomycin. Ionomycin induces highly purified resting human T cells to proliferate in the presence of monocytes with accompanying IL-2R expression and IL-2 synthesis. Treatment of T cells with ionomycin triggers the hydrolysis of phosphoinositides, as evidenced by the accumulation of the hydrolytic by-products phosphatidic acid and inositol phosphates. Ionomycin also induces the activation of protein kinase C (PKC), as demonstrated by the auto-phosphorylation of PKC and the phosphorylation of the PKC target proteins CD4 and CD8. Ionomycin synergizes with PMA in enhancing the activation of PKC. It is concluded that, in addition to its putative activation of Ca2+/calmodulin-dependent signaling pathways, ionomycin induces the hydrolysis of phosphoinositides and the activation of PKC in human T cells. The synergy of ionomycin with phorbol esters in triggering T cell activation may relate, at least in part, to enhanced activation of PKC.

Calcium↗
PubMed1989

Increased permissivity of monkey cells to human adenovirus multiplication is affected by culturing conditions and correlates with both synthesis of virion fiber protein and altered splicing of its mRNA.

Human adenoviruses (Ad2) grow poorly in CV-1 (monkey) cells, resulting in an abortive infection. During abortive infections synthesis of the fiber protein is approximately 100-fold depressed compared to its synthesis in CV-1 cells productively infected with a host range mutant of adenovirus (Ad2hr400), while the corresponding mRNA is reduced only 10-fold. We found that passage of CV-1 cells under modified culture conditions resulted in loss of restrictiveness for Ad2 growth. As cells became more permissive, fiber polypeptide synthesis was enhanced although fiber mRNA levels did not necessarily increase. Analysis of the 5' ends of fiber message isolated from cells in various stages of permissivity showed a direct correlation between efficient synthesis of the fiber protein and an altered splicing pattern of the fiber message.

Adenoviruses, Human↗