Re: Surgeon-controlled ultrasound-guided core biopsies in the breast-a prospective study and a new use for surgeons in the clinic.
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Biopsy, Needle↗
Biomedical subjects
C M Rubin
Publications and source records attributed to C M Rubin.
Genome-wide chromatin remodeling modulates the Alu heat shock response.
During heat shock recovery in Hela cells, the level of Alu RNA transiently increases with kinetics that approximately parallel the transient expression of heat shock protein mRNAs. Coincidentally, there is a transient increase in the accessibility of Alu chromatin to restriction enzyme cleavage suggesting that an opening and re-closing of chromatin regulates the Alu stress response. Similar changes occur in alpha satellite and LINE1 chromatin showing that heat shock induces a genome-wide remodeling of chromatin structure which is independent of transcription. The increased accessibility of restriction sites within these repetitive sequences is inconsistent with a simple lengthening of the nucleosome linker region but instead suggests a scrambling of nucleosome positions. Chromatin structure and its dynamics account for many of the principal features of SINE transcriptional regulation potentially providing a functional rationale for the dispersion and high copy number of SINEs.
Alu Elements↗
Improving the sensitivity of stereotactic core biopsy to diagnose ductal carcinoma in situ of the breast: a mathematical model.
Stereotactic core biopsy (SCB) is performed on mammographically suspicious, non-palpable lesions of the breast. Reported sensitivities of SCB for the detection of ductal carcinoma in situ (DCIS) vary from 41% to 93%. We have developed a simple mathematical model to predict the probability of retrieving at least one diagnostic core from a focus of DCIS. We make recommendations of the number of samples needed for different sized areas of microcalcification. The sensitivity of SCB is affected by needle placement accuracy, diameter of the area of microcalcification (d), histological density of DCIS (x) (calculated as 7.5% by previous studies) and number of core samples (n) removed. The probability of achieving at least one representative core sufficient for diagnosis (P(core)) is defined as: P(core) = 1-(1 + p ([1- (x/100)]d - 1 ))n, where rho is the probability of a SCB accurately targeting the area of microcalcification. At least seven core samples should be removed in small foci (<5 mm) of DCIS to achieve a 0.75 probability of an accurate diagnosis. The probability of a diagnostic biopsy of larger areas of DCIS (>10 mm) is 0.95 when five cores are removed. This formula serves as an explanation to patients why SCB may fail to diagnose DCIS, and justifies the retrieval of more core samples to increase the probability of an accurate diagnosis and to reduce the chance of a non-representative core. In the absence of sufficient samples, a wire-guided open biopsy is necessary to exclude DCIS.
Biopsy↗
K562 cells implicate increased chromatin accessibility in Alu transcriptional activation.
Alu repeats in K562 cells are unusually hypomethylated and far more actively transcribed than those in other human cell lines and somatic tissues. Also, the level of Alu RNA in K562 cells is relatively insensitive to cell stresses, namely heat shock, adenovirus infection and treatment with cycloheximide, which increase the abundance of Alu RNA in HeLa and 293 cells. Recent advances in understanding the interactions between DNA methylation, transcriptional activation and chromatin conformation reveal reasons for the constitutively high level of Alu expression in K562 cells. Methylation represses transcription of transiently transfected Alu templates in all cell lines tested but cell stresses do not relieve this repression suggesting that they activate Alu transcription through another pathway. A relatively large fraction of the Alus within K562 chromatin is accessible to restriction enzyme cleavage and cell stresses increase the chromatin accessibility of Alus in HeLa and 293 cells. Cell stress evidently activates Alu transcription by rapidly remodeling chromatin to recruit additional templates.
Adenoviridae↗
Nineteen cases of the t(1;22)(p13;q13) acute megakaryblastic leukaemia of infants/children and a review of 39 cases: report from a t(1;22) study group.
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Child, Preschool↗
Physiological stresses increase mouse short interspersed element (SINE) RNA expression in vivo.
The possible functionality of short interspersed elements (SINEs) is investigated by assaying the effects of physiological stress on their RNA polymerase-III-directed transcriptional expression in vivo. B2 RNA is expressed at moderately high levels in all mouse tissues investigated, namely liver, spleen, kidney and testis. B1 RNA is expressed in testis but is nearly undetectable in the other tissues. Following hyperthermic shock, the amounts of B1 and B2 SINE RNAs transiently increase in all tissues by as much as 40-fold in certain cases. The kinetics of these increases resemble those of heat shock protein mRNAs. An acute dose of ethanol also transiently increases the abundance of B1 and B2 RNA in liver, showing that other physiological stresses increase SINE RNA expression. The constitutive expression of B2 RNA in all tissues and tissue-specific differences in expression of B1 RNA imply that these transcripts serve a normal physiological function(s). Moreover, increased SINE RNA expression is a vital response to stress and by the criterion of their inducibility, mammalian SINEs behave like regulated cell stress genes.
Animals↗
Association between liver transplantation for Langerhans cell histiocytosis, rejection, and development of posttransplant lymphoproliferative disease in children.
OBJECTIVE: Langerhans cell histiocytosis (LCH) is an unusual indication for orthotopic liver transplantation in children. Data from limited case reports suggest that orthotopic liver transplantation for LCH is associated with excellent survival rates and a low incidence of disease recurrence. However, in our experience, children who have transplantation for LCH appeared to experience a high incidence of refractory rejection and posttransplant lymphoproliferative disease (PTLD). STUDY DESIGN: Data from 398 liver transplants performed in 298 children younger than 16 years of age were reviewed to determine the presence of risk factors for PTLD in patients with LCH and other causes of liver failure. RESULTS: The incidence of PTLD was significantly higher in children who received transplants for LCH compared with all indications (p < 0.001) and specific indications that were associated with the development of PTLD (p < 0.002). Among patients in whom PTLD developed, there was no significant difference in the incidence of primary Epstein-Barr virus infections in patients who receive transplantation for LCH (4/4, 100%) versus all other indications (12/14, 86%). Children who had transplantation for LCH were older than those who had transplantation for other indications (LCH median age 3.1 years, other indications 1 year). The incidence of rejection, especially refractory rejection, was greater in patients who had transplantation for LCH (100% and 50%, respectively) compared with those who had transplantation for other indications (70% and 10%, p < 0.02 for refractory rejection). CONCLUSIONS: Patients who had transplantation for liver disease related to LCH experienced a 67% long-term survival (median follow up 5.8 years, range 2.1 to 7.5 years). Recurrent LCH occurred in only 33% of patients and was easily managed. However, PTLD developed in two thirds of these patients, perhaps in part because of the high incidence of refractory rejection. This series therefore demonstrates an association between a primary disease process and the development of PTLD. Although the data indicate that children with LCH-induced liver failure benefit from transplantation, special care must be exercised in screening for and preemptive treatment of PTLD.
Adolescent↗
Complete lymphoid chimerism and chronic graft-versus-host disease in an infant recipient of a hepatic allograft from an HLA-homozygous parental living donor.
Living-related donor liver transplantation (LDLT) is an accepted approach to pediatric liver transplantation. Parental donation imposes a significant risk of chimerism with graft-versus-host disease (GVHD) because donors homozygous at all HLA loci (1.6% of the population) present no mismatched HLA antigens to be recognized by their offspring's immune system. The case of a 9-month-old who underwent LDLT with her 23-year-old HLA-homozygous mother as a donor demonstrates the consequences of this occurrence. The patient developed GVHD with aplastic anemia; the patient's nucleated peripheral blood elements were shown to be entirely derived from the donor. Later, after some marrow recovery, the patient's circulating lymphocytes had a donor origin, while the marrow-derived neutrophils had a recipient origin. The patient suffers from chronic GVHD and debilitating skin disease several years posttransplant. Our current protocol calls for HLA typing to eliminate parents who are homozygous at all HLA loci as donors of hepatic allografts to their children.
Chronic Disease↗
Posttransplant lymphoproliferative disease in pediatric liver transplantation. Interplay between primary Epstein-Barr virus infection and immunosuppression.
The incidence, risk factors, and outcome of posttransplant lymphoproliferative disease (PTLD) were examined for 298 children undergoing liver transplantation. The overall incidence of PTLD was 8.4% (25 of 298). Intensity of immunosuppression was found to be a major risk factor for the development of PTLD. Cyclosporine and tacrolimus when used as primary immunosuppression were associated with the development of PTLD in 4.3% and 6.6% of cases (P=NS). OKT3 and tacrolimus, when used as rescue therapy for steroid-resistant rejection, were associated with a comparable increase in the risk of developing PTLD (10.9% and 11.1%, P=NS). Patients requiring both OKT3 and tacrolimus to treat refractory rejection were at significantly increased risk for PTLD (28.1% vs. 4.3% or 6.6%, P<0.0001). PTLD was more common in patients who received transplants for Langerhans cell histiocytosis relative to other indications for transplantation (66% vs. 8.4%, P=0.0005). The data also support an association between primary Epstein-Barr virus (EBV) infections following transplantation and the development of PTLD. While only three patients were EBV seropositive before transplantation (14%), 19 patients were EBV seropositive at the time of diagnosis of PTLD (90%), confirming a high incidence of primary EBV infections in patients with PTLD (21 patients had both pre- and posttransplant EBV serologies). In this series, PTLD was associated with a mortality rate of 60%, and 12 of the 15 patients who died had persistent tumor at the time of death. Five of the 13 patients rendered disease-free developed ductopenic rejection. Of the four with severe liver dysfunction, two have undergone successful retransplantation and are alive without evidence of PTLD. In conclusion, intense immunosuppression using OKT3 and tacrolimus as rescue agents was associated with a significant increase in the incidence of PTLD. Primary EBV infection after transplantation further accentuated this risk. Independent of these risk factors, patients with Langerhans cell histiocytosis were at significantly increased risk for PTLD. The identification of high-risk patients should allow the development of protocols to screen patients for primary EBV infections and early indications of PTLD, as well as the institution of preemptive antiviral and antitumor therapies.
Adolescent↗
Standardized nomenclature for Alu repeats.
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Animals↗
Lineage involvement by BCR/ABL in Ph+ lymphoblastic leukemias: chronic myelogenous leukemia presenting in lymphoid blast vs Ph+ acute lymphoblastic leukemia.
Chronic myelogenous leukemia (CML) can sometimes present in lymphoid blast phase (L-BP), and can be difficult to distinguish from Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). Some have suggested that the determination of cell lineages involved by the Ph chromosome may be used for distinguishing CML presenting in L-BP (presumably multilineage disease) from Ph+ ALL (presumably lymphoid-restricted), although others have suggested the term 'stem cell ALL' for the multilineage process. Because it has been difficult to perform lineage studies of the Ph chromosome, we investigated the use of fluorescence in situ hybridization (FISH) with probes for BCR (on chromosome 22) and ABL (on chromosome 9) to study lineage involvement in Ph+ lymphoblastic malignancies. We analyzed routine blood and marrow specimens from eight patients who presented with Ph+ lymphoblastic leukemia and found that FISH recognized the 9;22 translocation, distinguished between the two common molecular variants, and readily identified multilineage vs lymphoblast-restricted disease. In our series, four patients had multilineage and four had lymphoblast-restricted disease. Multilineage disease was associated with morphologic features of CML at diagnosis and/or reversion to chronic phase CML after treatment leading us to consider it as CML presenting in L-BP. Patients with lymphoid-restricted disease lacked such findings. The survival of three of our four patients with multilineage disease was prolonged, at 25, 28+, and 126+ months, and when data from our entire series are added to those of 18 previously reported cases that were studied for lineage involvement (reviewed in Leukemia 1993; 7: 147), the difference in overall survival between patients with multilineage and lymphoblast-restricted disease is significant (median overall survival of 47 months vs 8 months, respectively; P=0.013, log rank). Our findings illustrate that FISH analysis can be used to recognize lineage involvement in patients presenting with Ph+ lymphoblastic malignancies, and they provide further support to the notion that multilineage and lymphoblast-restricted disease are distinct clinically as well as biologically.
Adolescent↗
Bone marrow transplantation for the treatment of haematological disorders in Down's syndrome: toxicity and outcome.
We report 18 patients with Down's syndrome who underwent bone marrow transplantation, and review nine previously published patients. The indications for transplant in the combined group of 27 patients were acute lymphoblastic leukaemia in 14 cases (52%), acute myeloid leukaemia in 11 cases (41%) and aplastic anemia in two cases (7%). Transplants were autologous in five cases (19%) and allogeneic in 22 cases (81%); of the 22 allogeneic transplants, 16 donors were HLA-matched siblings. In all patients the conditioning regimen included total body irradiation of 7.5 Gy or more, and/or contained cyclophosphamide of 120 mg/kg or more. Seven patients (26%) had fatal pulmonary disease including pneumonitis and pulmonary hemorrhage. Five patients (19%) had significant airway problems including three with severe mucositis who required intubation for airway protection, one with severe mucositis with partial airway obstruction that required observation in the intensive care unit but did not require intubation, and one with Candida albicans laryngitis with development of a glottic web. Nineteen patients (70%) survived beyond 100 days post-transplant. There was no clear association between 100-day survival and the use of any particular agent or regimen used for conditioning or graft-versus-host disease prophylaxis, and the majority of patients tolerated high-dose cyclophosphamide, high-dose cytosine arabinoside, high-dose busulfan, total body irradiation, cyclosporin A, and methotrexate. There appeared to be more early deaths in patients who received the combination of cyclophosphamide and total body irradiation, compared with those receiving the combination of busulfan and cyclophosphamide or those receiving the combination of cytosine arabinoside and total body irradiation. Also, the use of methotrexate was associated with a greater number of early deaths, compared with cyclosporin A. At 3 years, life table estimates of freedom from relapse, relapse-free survival and survival were 75%, 44% and 48%, respectively. The estimated cumulative risk of death due to a non-leukaemic cause at 3 years was 39%. The data show that Down syndrome patients can tolerate the commonly used transplant conditioning regimens with acceptable toxicity; however, there is a strong suggestion in the data that the rates of life-threatening and fatal toxicity are higher than would be expected to occur in patients without Down's syndrome. Patients with Down's syndrome may have a predisposition to fatal pulmonary complications and reversible airway problems during the immediate post-transplant period.
Adolescent↗
Dispersion and insertion polymorphism in two small subfamilies of recently amplified human Alu repeats.
Newly isolated members of two recently propagated (young) Alu subfamilies were examined for sequence diversity and insertion polymorphism in primate genomes. The smaller subfamily (termed HS-2) is comprised of approximately 5 to 25 members, while the larger (termed Sb2) includes approximately 125 to 600 members. Individual members of these Alu subfamilies share distinguishing sets of diagnostic mutations, are well-conserved relative to each other, and have expanded in the human lineage. At least one member from each subfamily is known to be polymorphic in humans. Three newly characterized HS-2 Alu family members as well as three Sb2 Alu repeats are monomorphic (fixed) in humans. The existence of a number of Alu subfamilies that have amplified in parallel within the human genome provides compelling evidence for the simultaneous activity of multiple dispersed Alu source genes.
Alleles↗
Sclerosing lymphocytic lobulitis of the breast.
Eight patients are described who had palpable breast lumps with clinical and imaging features suspicious of malignancy which proved to be sclerosing lymphocytic lobulitis on histological examination. In this series the typical mammographic appearance of this condition was increased parenchymal density and/or localized stromal distortion while on ultrasound, the typical appearance was an ill-defined mass with distal acoustic shadowing. This rare benign condition has been described in association with longstanding insulin-dependent diabetes or autoimmune disease, but four of our eight patients had no such medical history.
Adult↗
Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo.
We report on the chromosomal pattern of 120 patients with childhood AML de novo. One hundred and fifteen patients (96%) had adequate samples for analysis; 98 (85%) of these showed clonal karyotypic abnormalities. They were classified into cytogenetic subgroups which were closely correlated with FAB subtypes: t(8;21) and M2 (n = 9); t(15;17) and M3 (n = 12); inv(16) and M4Eo (n = 9); t(9;11) and M5a (n = 10); t(11q23) other than t(9;11) and M4-M5 (n = 11); and t(1;22) and M7 (n = 4). In patients with -7/del(7q) (n = 6), leukemia was preceded by MDS in half of the cases, although they had diverse FAB subtypes. Thirty-seven patients had miscellaneous abnormalities. Despite a high CR rate, patients with t(8;21) had a very poor survival: only one child was event-free at 3 years from diagnosis. One third of patients with t(15;17) died during induction. Those eight who achieved CR fared well: only two relapsed, and six were event-free survivors. Patients with inv(16) had a high remission rate and a long survival: five children were in CR 20 to 136 months. Both groups with t(9;11) and t(11q23) had a high remission rate: however, outcome was superior for the t(9;11) group when compared to either the t(11q23) group (EFS at 3 years +/- SE, 56 +/- 17% vs. 11 +/- 10%, p = 0.07) or to the remaining patients (p = 0.06). Both -7/del(7q) and t(1;22) groups had low CR rates (50%) and poor survival. Cytogenetic analysis identifies clinically distinct subsets of childhood AML and is useful in tailoring treatment for these patients. Favorable cytogenetic groups (t(15;17), inv(16), and t(9;11)) may do well with current therapy protocols, whereas unfavorable groups (t(11q23), t(8;21), -7/del(7q), and t(1;22)) require more effective therapies.
Child↗
Alu repeated DNAs are differentially methylated in primate germ cells.
A significant fraction of Alu repeats in human sperm DNA, previously found to be unmethylated, is nearly completely methylated in DNA from many somatic tissues. A similar fraction of unmethylated Alus is observed here in sperm DNA from rhesus monkey. However, Alus are almost completely methylated at the restriction sites tested in monkey follicular oocyte DNA. The Alu methylation patterns in mature male and female monkey germ cells are consistent with Alu methylation in human germ cell tumors. Alu sequences are hypomethylated in seminoma DNAs and more methylated in a human ovarian dysgerminoma. These results contrast with methylation patterns reported for germ cell single-copy, CpG island, satellite, and L1 sequences. The function of Alu repeats is not known, but differential methylation of Alu repeats in the male and female germ lines suggests that they may serve as markers for genomic imprinting or in maintaining differences in male and female meiosis.
Animals↗
Alu transcripts: cytoplasmic localisation and regulation by DNA methylation.
Full length Alu transcripts in HeLa cells are detected by primer extension using reverse transcriptase and are also analyzed as cloned cDNA sequences. The 5' end of these transcripts corresponds to the transcriptional start site for RNA polymerase III indicating that these RNAs are transcribed from their internal polymerase III promoters. The Alu transcripts found in cytoplasmic poly A+ RNAs appear to be organized into RNPs as assayed by sucrose gradient sedimentation. Present at about one hundred to one thousand copies per cell, the Alu transcripts are rare as compared to 7SL RNA. In agreement with previous reports that methylation inhibits Pol III-directed transcription of Alu in vitro, treatment of HeLa cells with 5-azacytidine results in Alu DNA hypomethylation and an increase in the abundance of the Alu transcript. Sequence analysis shows that many different Alu repeats including members of all subfamilies are transcribed by Pol III in vivo. cDNA sequences of the Pol III-directed transcripts exactly match the A box of the Pol III promoter element whereas in other Alu transcripts this element is not faithfully conserved.
Azacitidine↗
Paucity of novel short interspersed repetitive element (SINE) families in human DNA and isolation of a novel MER repeat.
An extensive compilation of renaturation rate data for human DNA is presented as an empirical guide for genomic hybridization studies and to document as accurately as possible the repetitive sequence content of the human genome. Approximately 15% of the genome renatures with heterogeneous rates characteristic of moderately repetitive sequences. Cross hybridization studies of this fraction with known repetitive sequences show that it is largely composed of known moderately repetitive sequences and contaminating highly repetitive sequences. These findings limit the maximum possible abundance of unidentified families of short interspersed elements (SINEs) in human DNA. Exhaustive analysis by subtractive hybridization of a small library constructed from short fragments of repetitive sequences yields few additional new SINEs, again suggesting the limited abundance of such sequences.
Base Sequence↗