Ventricular outflow tract obstruction secondary to leiomyosarcoma of the right ventricle

Primary leiomyosarcomas of the heart, particularly those affecting the right ventricle, are uncommon. We report the case of a 70-year-old Belgian woman presenting with the symptoms of progressive exertional dyspnea and left-sided pleuritic pain. A leiomyosarcoma which originated from the right lateral ventricle wall, causing pulmonary outflow obstruction, was diagnosed. Pathology revealed a neoplasm with a myxoid stroma, high mitotic activity and nuclei expressing atypia. Immunohistochemical staining was positive for vimentine and desmin. Seven months after complete surgical resection the tumor relapsed. This case demonstrates the poor outcome, the high relapse rate and inefficiency of treatment associated with primary cardiac leiomyosarcomas. The current literature regarding the incidence, diagnostic techniques, treatment strategies and survival rates of this rare but terminal disease is reviewed.     

Rapidly proliferating CD44hi peripheral T cells undergo apoptosis and delay posttransplantation T-cell reconstitution after allogeneic bone marrow transplantation

Delayed T-cell recovery is an important complication of allogeneic bone marrow transplantation (BMT). We demonstrate in murine models that donor BM-derived T cells display increased apoptosis in recipients of allogeneic BMT with or without GVHD. Although this apoptosis was associated with a loss of Bcl-2 and Bcl-X(L) expression, allogeneic recipients of donor BM deficient in Fas-, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)- or Bax-, or BM-overexpressing Bcl-2 or Akt showed no decrease in apoptosis of peripheral donor-derived T cells. CD44 expression was associated with an increased percentage of BM-derived apoptotic CD4(+) and CD8(+) T cells. Transplantation of RAG-2-eGFP-transgenic BM revealed that proliferating eGFP(lo)CD44(hi) donor BM-derived mature T cells were more likely to undergo to apoptosis than nondivided eGFP(hi)CD44(lo) recent thymic emigrants in the periphery. Finally, experiments using carboxyfluorescein succinimidyl ester-labeled T cells adoptively transferred into irradiated syngeneic hosts revealed that rapid spontaneous proliferation (as opposed to slow homeostatic proliferation) and acquisition of a CD44(hi) phenotype was associated with increased apoptosis in T cells. We conclude that apoptosis of newly generated donor-derived peripheral T cells after an allogeneic BMT contributes to delayed T-cell reconstitution and is associated with CD44 expression and rapid spontaneous proliferation by donor BM-derived T cells.     

Gain-of-function mutations of Ptpn11 (Shp2) cause aberrant mitosis and increase susceptibility to DNA damage-induced malignancies

Gain-of-function (GOF) mutations of protein tyrosine phosphatase nonreceptor type 11 Ptpn11 (Shp2), a protein tyrosine phosphatase implicated in multiple cell signaling pathways, are associated with childhood leukemias and solid tumors. The underlying mechanisms are not fully understood. Here, we report that Ptpn11 GOF mutations disturb mitosis and cytokinesis, causing chromosomal instability and greatly increased susceptibility to DNA damage-induced malignancies. We find that Shp2 is distributed to the kinetochore, centrosome, spindle midzone, and midbody, all of which are known to play critical roles in chromosome segregation and cytokinesis. Mouse embryonic fibroblasts with Ptpn11 GOF mutations show a compromised mitotic checkpoint. Centrosome amplification and aberrant mitosis with misaligned or lagging chromosomes are significantly increased in Ptpn11-mutated mouse and patient cells. Abnormal cytokinesis is also markedly increased in these cells. Further mechanistic analyses reveal that GOF mutant Shp2 hyperactivates the Polo-like kinase 1 (Plk1) kinase by enhancing c-Src kinase-mediated tyrosine phosphorylation of Plk1. This study provides novel insights into the tumorigenesis associated with Ptpn11 GOF mutations and cautions that DNA-damaging treatments in Noonan syndrome patients with germ-line Ptpn11 GOF mutations could increase the risk of therapy-induced malignancies.Src homology 2 domain-containing protein tyrosine phosphatase 2 (Shp2), a ubiquitously expressed protein tyrosine phosphatase (PTP), plays multiple roles in cellular processes. This phosphatase is best known to be involved in growth factors, cytokines, and other extracellular protein-induced signal transduction (1, 2). It is normally self-inhibited by hydrogen bonding of the backside of the N-terminal SH2 (N-SH2) domain to the deep pocket of the PTP domain. Ligands with phosphorylated tyrosine (pY) residues activate Shp2 by binding the SH2 domains (primarily N-SH2) and disrupting the inhibitory interaction between N-SH2 and PTP domains. Shp2 is involved in multiple cell signaling pathways and plays an overall positive role in transducing signals initiated from receptor and cytosolic kinases (1, 2). The underlying mechanisms are not completely understood. Shp2 interacts with a number of cell signaling intermediates. Of these signaling partners, some are the targets of its enzymatic activity. However, Shp2 can also function as an adaptor protein independent of its catalytic activity (3, 4). In addition to growth factor/cytokine-induced signaling, Shp2 regulates genotoxic stress-triggered signaling and cellular responses (5, 6). More recently, Shp2 has been found to be required for optimal activation of Polo-like kinase 1 (Plk1) and maintenance of chromosomal stability, although the detailed signaling mechanisms remain unclear (7).The critical role of Shp2 in cell signaling and other activities is further underscored by its direct association with human diseases. Germ-line or somatic heterozygous mutations in Ptpn11 (encoding Shp2) have been identified in the developmental disorder Noonan syndrome (8), juvenile myelomonocytic leukemia (JMML) (9, 10), acute leukemias (11, 12), and sporadic solid tumors (13). These mutations cause amino acid changes at the interphase formed between N-SH2 and PTP domains, disrupting the inhibitory intramolecular interaction and leading to hyperactivation of Shp2 catalytic activity (8, 9). In addition, disease-associated Ptpn11 mutations enhance the binding of mutant Shp2 to signaling partners (14–16). Recent studies have demonstrated that these gain-of-function (GOF) mutations of Ptpn11 are sufficient to drive the development of Noonan syndrome and leukemias in mice (15, 17, 18). Nevertheless, as the biochemical basis for the role that Shp2 plays in cell signaling is not well understood, the mechanisms of the tumorigenesis induced by Ptpn11 GOF mutations remain poorly defined.     

Rate of spontaneous mutation at human loci encoding protein structure.

The techniques of electrophoresis were used in a search for evidence of mutation affecting protein structure, the indicators being hemoglobin and a set of serum proteins and erythrocyte enzymes. Among 94,796 locus tests on Amerindians from Central and South America, there was no evidence for mutation. Among 105,649 locus tests on newborn infants in Ann Arbor, Michigan, there was also no evidence for mutation. We have previously failed to encounter any mutations in a series of 208,196 locus tests involving Japanese children [Neel, J. V., Satoh, C., Hamilton, H. B., Otake, M., Goriki, K., Kageoka, T., Fugita, M., Neriishi, S & Asakawa,J. (1980) Proc. Natl. Acad. Sci. USA 77, 4221-4225], and H. Harris, D. A. Hopkinson, and E. B. Robson [(1974) Ann. Hum. Genet. 37, 237-253] found no mutations in 113,478 locus tests on inhabitants of the United Kingdom. This failure to demonstrate any mutations of this type in a total of 522,119 locus tests excludes, at the 95% level of probability, a mutation rate greater than 0.6 X 10(-5)/locus per generation in this combination of populations.     

Mitochondrial DNA "clock" for the Amerinds and its implications for timing their entry into North America.

Students of the time of entry of the ancestors of the Amerinds into the New World are divided into two camps, one favoring an "early" entry [more than approximately 30,000 years before the present (YBP)], the other favoring a "late" entry (less than approximately 13,000 YBP). An "intermediate" date is unlikely for geological reasons. The correlation of the appropriate data on mtDNA variation in Amerinds with linguistic, archaeological, and genetic data offers the possibility of establishing a time frame for mtDNA evolution in Amerinds. In this paper, we estimate that the separation of the Chibcha-speaking tribes of Central America from other linguistic groups/nascent tribes began approximately 8000-10,000 YBP. Characterization of the mtDNA of 110 Chibcha speakers with 14 restriction enzymes leads on the basis of their time depth to an estimated mtDNA nucleotide substitution rate for Amerinds of 0.022-0.029% per 10,000 years. As a first application of this rate, we consider the mtDNA variation observed in 18 Amerind tribes widely dispersed throughout the Americas and studied by ourselves with the same techniques, and we estimate that if the Amerinds entered the New World as a single group, that entry occurred approximately 22,000-29,000 YBP. This estimate carries a large but indeterminate error. The mtDNA data are thus at present equivocal with respect to the most likely times of entry of the Amerind into the New World mentioned above but favor the "early" entry hypothesis.     

A practical approach to neurologic evaluation in the intensive care unit

Delirium and neurologic impairment are extremely common in the intensive care setting, and their delayed identification is an important contributor to patient morbidity. Even in comatose patients, the clinical neurologic examination remains the most accurate and effective tool in assessing nervous system function. Rapid identification of neurologic deficits with a practical and easily reproducible neurologic examination is a core skill for effectively caring for critically ill patients. The purpose of this tutorial is to discuss techniques of neurologic examination and localization with an emphasis on comatose patients. Commonly encountered cases of encephalopathy and coma along with clinical pearls are presented.     

Mortality among the offspring (F1) of atomic bomb survivors, 1946-85.

We compare the mortality in the years 1946-85 in a cohort of 31,159 children born to parents one or both of whom were exposed to the atomic bombing of Hiroshima and Nagasaki (a parental gonadal dose greater than or equal to 0.01 Sv) with that in a control group of 41,069 children. The average gonadal dose for the exposed parents was 0.435 Sv. The mean age of the cohorts was 28.8 years. In the greater than or equal to 0.01 Sv dose group 1,253 deaths were observed in the subset of children both of whose parents have been assigned DS86 doses. 3.2% were attributed to cancers, 72.9% to all diseases except neoplasms. These proportions in the 0 Sv dose group were about the same. Based on a linear relative risk model, no statistically significant increase in the mortality attributable to diseases other than neoplasms is noted following parental exposure, the excess relative risk being 0.030 (+/- 0.046) per sievert based on the DS86 doses (RBE of neutrons = 20). For fatal cancer, no statistically significant effect of parental radiation dose was also observed. An analysis based on the full sample, using not only the DS86 dose group but also ad hoc dose group, yields essentially the same results as the analysis restricted to the DS86 dose group.     

A methylated human 9-kb repetitive sequence on acrocentric chromosomes is homologous to a subtelomeric repeat in chimpanzees.

We have implemented an approach for the detection of DNA alterations in cancer by means of computerized analysis of end-labeled genomic fragments, separated in two dimensions. Analysis of two-dimensional patterns of neuroblastoma tumors, prepared by first digesting DNA with the methylation-sensitive restriction enzyme Not I, yielded a multicopy fragment which was detected in some tumor patterns but not in normal controls. Cloning and sequencing of the fragment, isolated from two-dimensional gels, yielded a sequence with a strong homology to a subtelomeric sequence in chimpanzees and which was previously reported to be undetectable in humans. Fluorescence in situ hybridization indicated the occurrence of this sequence in normal tissue, for the most part in the satellite regions of acrocentric chromosomes. A product containing this sequence was obtained by telomere-anchored PCR using as a primer an oligonucleotide sequence from the cloned fragment. Our data suggest demethylation of cytosines at the cloned Not I site and in neighboring DNA in some tumors, compared with normal tissue, and suggest a greater similarity between human and chimpanzee subtelomeric sequences than was previously reported.