Citations

The decrease in abundance of a subset of highly conserved basic nuclear proteins is established to correlate with the loss of proliferative potential in association with the process of terminal differentiation in murine mesenchymal stem cells and human keratinocytes. These proteins, designated P2Ps for proliferation potential proteins, have apparent molecular masses of 30-40 kD, are associated with the 30-40S substructures of nuclear hnRNP complexes, and are recognized by antibodies made against core proteins of hnRNP particles. They also share an epitope in common with heat shock protein-90 (hsp90) and are recognized by two mAbs against hsp90. Two-dimensional electrophoretic Western blots furthermore show that P2Ps make up a subset of hnRNP proteins. Cells that possess these proteins express the potential to proliferate whether or not they are traversing the cell cycle. These include rapidly growing cells, reversibly growth-arrested cells, and nonterminally differentiated cells. In contrast, cells that have irreversibly lost their proliferative potential, such as terminally differentiated cells, show a marked reduction in the abundance of P2Ps as determined by immunodetection on Western blots. A correlation, therefore, exists between the presence of this subset of nuclear proteins and the proliferative potential in two cell types. These results raise the possibility that as a subset of hnRNP proteins, P2Ps may mediate posttranscriptional control of the processing of specific RNAs required for cell proliferation.

The morphology of the canine cardiac myosin molecule has been investigated in the electron microscope with Hall's mica-replica technique. The molecule is an elongated rod (shaft) of nonuniform diameter with a globular expansion (head) on one end. Statistical analysis of the lengths of 1908 molecules showed that the mean length was 1610 ± 250 A; the mean length of the head was 210 ± 20 A; and the diameter of the head and that of the shaft were 35 to 40 and 15 to 20 A, respectively. About one-third of the molecules had single or multiple, fairly sharp, angulations along their shafts. Rarely, some details of the substructure of the molecule have been observed. Large, spindle-shaped aggregates, measuring 0.5 to 1 µ in length and 50 to 100 A in diameter, were produced by dilution of the myosin solutions. These aggregates were readily visualized in the electron microscope by means of Huxley's negative-staining technique. Projections often were visible along the length of the aggregates except at a central zone where they were frequently absent. The aggregates resembled the thick myofilaments of the myocardium and appeared similar to those produced by Huxley from skeletal myosin solutions.

AbstractAlthough palpable axillary lymphadenopathy is most often related to benign disorders, it may be a harbinger of an underlying advanced malignancy. Fewer than 1% of patients diagnosed with breast cancer initially present with axillary metastases as their only clinical manifestation. This study represents the Mayo Clinic experience with women with occult breast cancer who presented with axillary metastases. Among a group of 44 women undergoing axillary biopsy for a palpable mass, 35 had histologic evidence of a metastatic carcinoma of primary breast cancer origin. Our retrospective analysis focused on the workup, identification, treatment, and outcome of these 35 women. All 35 women had a palpable axillary nodule, no dominant breast mass, and normal mammograms and chest radiographs. Histologic analysis of the axillary node revealed a probable breast cancer in all patients. Long‐term follow‐up was available for 33 patients (mean 71.5 months, range 4–252 months). Mastectomy was performed as part of the primary treatment in 18 patients (51%), and among them a primary breast tumor was found in 6 (33%). Of the women who underwent mastectomy (n = 18) and for whom follow‐up data were available (n = 17), six developed tumor recurrence (35%), and four died of their disease (24%). Among the patients who did not undergo mastectomy (n = 17) as their primary treatment, follow‐up revealed that 12 (of 16) patients developed recurrent disease (75%), and 11 patients died of breast carcinoma (69%). Despite extensive clinical and radiologic evaluation, a primary tumor was not initially located in any of the 35 women with axillary metastases from a presumed occult breast carcinoma. As a consequence of aggressive surgical intervention, six primary breast cancers were located in mastectomy specimens, and those 17 patients followed after mastectomy fared significantly better than the 16 patients without mastectomy (p = 0.047).

The expression of the apolipoprotein A-I (apo A-I) gene was investigated in the myelinating sciatic nerve. Hybridization analysis with an apo A-I cDNA probe obtained from a cDNA library of mRNA isolated from rapidly myelinating chick sciatic nerve indicated that apo A-I coding transcripts increase during development in the chick sciatic nerve in parallel with the increase of myelin lamellae. Substantial apo A-I-like immunoreactivity in chick sciatic nerve homogenates was detected by Western blotting. The amount of antigen increased from the 15-d embryonic stage to 1 d posthatch and then decreased. Two subcellular fractions corresponding to the cytoplasmic compartments were particularly enriched in apo A-I. apo A-I immunoreactivity was also found in highly purified myelin preparations. Immunohistochemical staining provided further evidence for the presence of apo A-I in the endoneurial compartment of the sciatic nerve. Electron microscopic examination of these fractions after negative staining showed the presence of spherical and disc-shaped particles resembling high density lipoproteins. The presence of apo A-I, cholesterol esters, phospholipids, and triacylglycerols in ultracentrifugal fractions corresponding to serum lipoproteins and the behavior of apo A-I on nondenaturing gradient gels implied that apo A-I was associated with lipid. Studies with short-term organ cultures of sciatic nerves from 1-d chicks strengthened the evidence for local synthesis and secretion of apo A-I and apo A-I-containing lipoproteins by this tissue. These results establish that the apo A-I gene is actively expressed in developing sciatic nerve during the period of rapid myelination. These findings support the hypothesis that apo A-I synthesized within the nerve participates in the local transport of lipids used in myelin biosynthesis.

Purpose To evaluate the spectrum of and determine the risk factors for the development of liver toxicity (hepatopathy) after therapy with vincristine, dactinomycin, and cyclophosphamide (VAC) for rhabdomyosarcoma in children and adolescents. Patients and Methods We prospectively captured all events of hepatopathy occurring on the ongoing Children's Oncology Group intermediate risk protocol, D9803, for children with rhabdomyosarcoma. Patients enrolled onto this trial were randomly assigned to receive either VAC alone or VAC alternating with vincristine, topotecan, and cyclophosphamide. In addition, we reviewed the toxicity database and requested additional information for all patients with elevated bilirubin or transaminase levels. Risk factors were analyzed. Results Of 339 patients enrolled through August 2002, 18 developed hepatopathy. All events were captured by mandated toxicity reporting and filing of MedWatch forms, with no additional cases found after the additional search of the database. Four children died after developing this toxicity. All cases occurred after cycles of VAC (n = 16) or vincristine and cyclophosphamide with concomitant abdominal radiotherapy (n = 2). The onset of hepatopathy was 5 to 16 days from the start of a treatment cycle. For the 89 patients under 36 months of age, the risk of hepatopathy was 15%, with two deaths. For the 239 children 3 years of age or older, the risk for hepatopathy was 4%, with two deaths. Conclusion The greatest risk factor for development of hepatopathy after VAC therapy was age. Dose modifications for younger children receiving VAC therapy are recommended.

OBJECTIVESThere are options available to patients newly diagnosed with vestibular schwannoma. Our institution employs stereotactic radiosurgery, microsurgical removal, and watchful waiting. There are no studies in the literature examining which of these treatment options patients are choosing.STUDY DESIGN AND SETTINGUsing retrospective chart review from January 2000 through December 2001, we noted several variables and patients’ initial treatment choices.RESULTSDuring the 24‐month study period, 139 patients were seen at our institution with a new diagnosis of vestibular schwannoma and made a clear initial treatment choice. Of these, 32 (23%) patients elected watchful waiting; 51 (36%) underwent stereotactic radiosurgery, and 56 (40%) underwent surgical removal. Surgical excision correlated with younger age and larger tumor size.CONCLUSIONSOur initial hypothesis, that patients choosing treatment would choose stereotactic radiosurgery more than 50% of the time, was untrue for the time course studied.SIGNIFICANCEThis is the first study to examine patient choice in treatment of vestibular schwannoma.

ABSTRACTThe ability of interleukin-7 (IL-7) and IL-15 to expand and/or augment effector cell functions may be of therapeutic benefit to human immunodeficiency virus (HIV)-infected patients. The functional effects of these cytokines on innate HIV-specific immunity and their impact on cells harboring HIV are unknown. We demonstrate that both IL-7 and IL-15 augment natural killer (NK) function by using cells (CD3−CD16+CD56+) from both HIV-positive and -negative donors. Whereas IL-7 enhances NK function through upregulation of Fas ligand, the effect of IL-15 is mediated through upregulation of tumor necrosis factor-related apoptosis-inducing ligand. The difference in these effector mechanisms is reflected by the ability of IL-15-treated but not IL-7-treated NK cells to reduce the burden of replication-competent HIV in autologous peripheral blood mononuclear cells (PBMC) (infectious units per million for control NK cells, 6.79; for IL-7-treated NK cells, 236.17; for IL-15-treated cells, 1.01;P= 0.01 versus control). In addition, the treatment of PBMC with IL-15-treated but not IL-7-treated NK cells causes undetectable HIV p24 (five of five cases), HIV RNA (five of five cases), or HIV DNA (three of five cases). These results support the concept of adjuvant immunotherapy of HIV infection with either IL-7 or IL-15 but suggest that the NK-mediated antiviral effect of IL-15 may be superior.