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Michael Weinstein

Publications and source records attributed to Michael Weinstein.

31 records · Page 2Linked to original sources
PubMed2003

Rb function in extraembryonic lineages suppresses apoptosis in the CNS of Rb-deficient mice.

Retinoblastoma (Rb)-deficient embryos show severe defects in neurogenesis, erythropoiesis, and lens development and die at embryonic day 14.5. Our recent results demonstrated a drastic disorganization of the labyrinth layer in the placenta of Rb-deficient embryos, accompanied by reduced placental transport function. When these Rb-/- embryos were supplied with a wild-type placenta by using either tetraploid aggregation or genetic approaches, animals survived until birth. Here we analyze the role of extraembryonic Rb in regulating proliferation, apoptosis, and differentiation in the rescued animals at different developmental stages. Many of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-/- animals, including the ectopic apoptosis in the CNS, were virtually absent in rescued Rb-/- pups. However, rescued animals died at birth with severe skeletal muscle defects. Like in Rb knockout embryos, rescued animals showed a marked increase in DNA replication and cell division in the CNS. In sharp contrast, the typical widespread neuronal apoptosis was absent in Rb-deficient embryos reconstituted with a normal placenta. In lens fiber cells, however, the inappropriate proliferation and apoptosis that is normally observed in Rb-/- embryos continued unabated in rescued animals. These results demonstrate that Rb function in extraembryonic lineages plays an important role in the survival of neuronal cells and in the differentiation of the erythroid lineage, providing mechanistic insight into the cell autonomous and nonautonomous functions of Rb during development.

Animals↗
PubMed2003

Extra-embryonic function of Rb is essential for embryonic development and viability.

The retinoblastoma (Rb) gene was the first tumour suppressor identified. Inactivation of Rb in mice results in unscheduled cell proliferation, apoptosis and widespread developmental defects, leading to embryonic death by day 14.5 (refs 2-4). However, the actual cause of the embryonic lethality has not been fully investigated. Here we show that loss of Rb leads to excessive proliferation of trophoblast cells and a severe disruption of the normal labyrinth architecture in the placenta. This is accompanied by a decrease in vascularization and a reduction in placental transport function. We used two complementary techniques-tetraploid aggregation and conditional knockout strategies-to demonstrate that Rb-deficient embryos supplied with a wild-type placenta can be carried to term, but die soon after birth. Most of the neurological and erythroid abnormalities thought to be responsible for the embryonic lethality of Rb-null animals were virtually absent in rescued Rb-null pups. These findings identify and define a key function of Rb in extra-embryonic cell lineages that is required for embryonic development and viability, and provide a mechanism for the cell autonomous versus non-cell autonomous roles of Rb in development.

Animals↗
PubMed2003

Pemphigus vulgaris: the eyes have it.

Pemphigus vulgaris is a potentially fatal autoimmune blistering disease that is rare in childhood. We report 2 recent cases seen contemporaneously in adolescents who presented with chronic oral mucosal lesions and conjunctivitis. The previously unemphasized ocular manifestations are described and the importance of a biopsy in establishing the diagnosis in instances of unexplained chronic mucositis is stressed.

Adolescent↗
PubMed2002

Using PSA, biopsy Gleason score, clinical stage, and the percentage of positive biopsies to identify optimal candidates for prostate-only radiation therapy.

PURPOSE: An identification of prostate cancer patients most likely to benefit from prostate-only radiation was made based upon the pretreatment prostate-specific antigen (PSA), biopsy Gleason score, clinical stage, percentage of positive biopsies, and the 5-year postoperative PSA outcome. METHODS: Between 1989 and 2000, 2099 patients underwent radical prostatectomy for clinically localized prostate cancer. The primary end points were pathologic evidence of seminal vesicle invasion 2(SVI), extracapsular extension (ECE) with or without positive surgical margins, and the 5-year postoperative PSA outcome. RESULTS: Pretreatment PSA, biopsy Gleason score, and clinical stage were used to assign patients to low-, intermediate-, and high-risk groups. These risk groups were stratified by the percentage of positive biopsies and the primary pathologic and biochemical outcomes examined. The rates of SVI, ECE with positive margin, and no biochemical evidence of disease (bNED) for low-risk patients with < or =50% positive biopsies were 2%, 7%, and 93%, respectively. Patients with >50% positive biopsies had higher rates of SVI and ECE (5% and 11%, respectively) and 52% bNED (p < 0.0001). For intermediate-risk patients with < or =17% positive biopsies, the rates of SVI, ECE with positive margin, and bNED were 3%, 9%, and 90%, respectively. As the percentage of positive biopsies increased above 17% in intermediate-risk patients, there was a statistically significant increase in SVI and ECE and a significant decrease in bNED. CONCLUSIONS: Low-risk patients with < or =50% positive biopsies and intermediate-risk patients with < or =17% positive biopsies had a very low risk of SVI and ECE with positive surgical margins. Given that the presence of SVI and ECE with positive surgical margins was uncommon (<10%) with a > or =90% PSA failure-free survival after radical prostatectomy, these patients may be optimal candidates for radiation therapy directed at the prostate only (prostate gland + 1.5-cm margin).

Biopsy↗
PubMed2002

Expression of fibroblast growth factors 4, 8, and 10 in limbs, flanks, and blastemas of Ambystoma.

Members of the fibroblast growth factor (FGF) family of molecules are critical to limb outgrowth. Here, we examine the expression of Fgfs in three types of limbs-embryonic (developing), mature (differentiated), and regenerating-as well as in the surrounding non-limb tissues in the Mexican axolotl, Ambystoma mexicanum. We have previously cloned partial cDNAs of Fgf4, 8, and 10 from the axolotl (Christensen et al., 2001); the complete Fgf10 cDNA sequence is presented here. Axolotl Fgf10 showed deduced amino acid sequence identity with all other vertebrate Fgf10 coding sequences of >62%, and also included conserved 5' and 3' untranslated regions in nucleotide sequence comparisons. Semiquantitative reverse transcriptase-polymerase chain reaction showed that fibroblast growth factors are differentially expressed in axolotl limbs. Only Fgf8 and 10 were highly expressed during axolotl limb development, although Fgf4, 8, and 10 are all highly expressed during limb development of other vertebrates. Fgf4 expression, however, was highly expressed in the differentiated salamander limb, whereas expression levels of Fgf8 and 10 decreased. Expression levels of Fgf8 and 10 then increased during limb regeneration, whereas Fgf4 expression was completely absent. In addition, axolotl limb regeneration contrasted to limb development of other vertebrates in that Fgf8 did not seem to be as highly expressed in the distal epithelium; rather, its highest expression was found in the blastema mesenchyme. Finally, we investigated the expression of these Fgfs in non-limb tissues. The Fgfs were clearly expressed in developing flank tissue and then severely downregulated in mature flank tissue. Differential Fgf expression levels in the limb and shoulder (limb field) versus in the flank (non-limb field) suggest that FGFs may be instrumental during limb field specification as well as instrumental in maintaining the salamander limb in a state of preparation for regeneration.

3' Untranslated Regions↗
PubMed2002

Primary intestinal and thoracic lymphangiectasia: a response to antiplasmin therapy.

Lymphangiectasia is a congenital or acquired disorder characterized by abnormal, dilated lymphatics with a variable age of presentation. We describe a case of lymphangiectasia with intestinal and pulmonary involvement in an adolescent female, who presented with many of the classic features including chylous pleural effusions, lymphopenia, hypogammaglobinemia, and a protein-losing enteropathy. She also presented with recurrent lower gastrointestinal bleeding, which is infrequently described. The patient did not improve with bowel rest and a low-fat medium-chain triglyceride diet and had little improvement with octreotide acetate therapy. However, she had a clinical response to antiplasmin therapy, trans-4-aminothylcyclohexamine carboxylic acid (tranexamic acid) in terms of serum albumin and gastrointestinal bleeding. She continues to have exacerbations of her condition, as well as persistent lymphopenia and chronic pleural effusions.

Adolescent↗
PubMed2002

Specificity of E2F1, E2F2, and E2F3 in mediating phenotypes induced by loss of Rb.

The Rb/E2F pathway plays a critical role in the control ofcellular proliferation. Here, we report that E2F1, E2F2, and E2F3 make major individual contributions toward the in vivo phenotypic consequences of Rb deficiency. In the developing lens of Rb(-/-) embryos, loss of E2F1, E2F2, or E2F3 reduces the unscheduled proliferation of fiber cells, with the loss of E2F3 having the most pronounced effect. In Rb-deficient retinas, all three E2Fs contribute equally to the ectopic proliferation of postmitotic neuronal cells. In contrast, E2F1 is unique in mediating apoptosis in both Rb(-/-) lenses and retinas. In the central nervous system, loss of E2F1 or E2F3 can almost completely eliminate the ectopic DNA replication and apoptosis observed in Rb(-/-) embryos, and loss of E2F2 partially reduces the unscheduled DNA replication and has no effect on apoptosis. These results provide clear evidence for functional specificity among E2Fs in the control of Rb-dependent proliferation and apoptosis in a tissue-specific manner.

Animals↗
PubMedDate not supplied

Can the core length involved with prostate cancer identify clinically insignificant disease in low risk patients diagnosed on the basis of a single positive core?

Clinically insignificant prostate cancer, defined as at most microscopic foci of Gleason grade < or = 3 disease in the radical prostatectomy specimen, has been recognized in some low risk (PSA < 10, biopsy Gleason score < or = 6, clinical Tlc, 2a) patients with minimal biopsy cancer volume. The purpose of this study is to determine if the fraction of cancer in a single positive core biopsy could identify a subset of low risk prostate cancer patients with clinically insignificant disease. Of 1100 patients with Tlc,2 prostate cancer that consecutively underwent radical prostatectomy at Brigham and Women's Hospital between 1989 to 2000, 130 low risk patients whose diagnoses were made on the basis of a single positive core comprised the study cohort. The pathologic findings at radical prostatectomy were enumerated for men with < or = 5% of a single core involved with prostate cancer in order to determine the rate of clinically insignificant prostate cancer in this population. Estimates of PSA survival were calculated using the actuarial method of Kaplan and Meier. Pairwise comparisons were made using the log rank test. For patients with < or = 5% (n = 14) and > 5% (n = 116) involvement of a single positive core, the 4 year PSA failure free survivals were 100% vs. 89% (P = 0.048), respectively. Within the subset of patients with < or = 5% of a single core involved, 7% (1/14) met the criteria for clinically insignificant disease. However, of the remaining 93%, 3, 8, and 2 patients had pathologic stage T2a, T2b, and T3a, respectively. Eleven patients had prostatectomy Gleason scores < or = 3 + 3, two patients had pathologic Gleason scores of 3 + 4, and one patient had a positive surgical margin. Given that only 7% of low risk patients in this cohort with < or = 5% involvement of a single positive core had clinically insignificant disease, the involved core length alone cannot be used to identify patients with clinically insignificant disease. Further studies are needed in order to delineate which patients may not benefit from treatment.

Adult↗