Philip Grimley - Academia.edu (original) (raw)

Papers by Philip Grimley

Laboratory Investigation, 2006

Clinical Cancer Research, Oct 1, 2006

PL-11 In both the clinical development of new anticancer drugs and for patient care with current ... more PL-11 In both the clinical development of new anticancer drugs and for patient care with current therapy options, the need for defining which patients are likely to respond to a given drug is paramount. This is because most oncology drugs are only effective in 10-30% of the patients and even potent responses are often short-lived and fail to produce a cure. There are a few molecular biomarkers, e.g. her2, and CD20 for trastuzumab and rituximab, respectively, that can be used for pre-selecting likely responders. However, for the majority of drugs, biomarkers which predict therapeutic efficacy do not exist. For such drugs, the only way to determine potential efficacy is through case-based trial and error or through expensive and time-consuming clinical trials, involving hundreds of patients. Therefore, methods of stratifying patients as likely "responders" or "non-responders" are needed.Our laboratory has recently developed a potential solution to this problem. We have patented and validated, a new cell biology platform technology, which allows real-time continuous monitoring of drug, induced optical changes in freshly explanted human tumors. The technology is called Kinetics of Optical Response, or KOR. We believe that, when combined with our knowledge of the hormone and viability factor requirements of cancer cells, the KOR system offers an unprecedented opportunity for evaluating drugs on fresh human tumor explants --- or cell lines and xenographs derived from the explants. The impressive correlation between KOR drug profiling results in vitro and the clinical outcomes in our patient research studies give us confidence that selection of the best available therapy for patients on an individual basis will soon be possibleFor example, a 4-year, multi-institutional study indicated the clinical potential of this technology by establishing a remarkable correlation between KOR chemosensitivity tests on individual9s explanted leukemia cells and the clinical outcome when that patient received treatment. Thus, the KOR results had significant predictive value for both chemotherapy response and survival in patients with acute myelogenous leukemia (AML). In a typical assay, single cell suspensions from normal or abnormal tissues are seeded at a pre-determined density and, following the addition of putative toxic compounds (either alone or in combination at t = 0 or sequentially at later times) plates are placed into the KOR instruments that are programmed for 24 to 72 hours of incubation. By reading OD of each well every 5 minutes OD profiles are generated, which allow a determination of the complete time course of apoptosis and rate of apoptosis which varies as a function of drug dose. Depending on the nature of the curves induced by the added drug or agent, continuous monitoring of any of 4 kinds of responses-- apoptosis, necrosis, proliferation, cytostasis-- is possible, within a single experiment.The KOR technology and has been extensively validated on cell lines and primary tumor explants from cancer patients. Although published results have largely focused on the KOR assay for suspension cultures of hematopoietic cells, we have tested adherent cells with excellent results. For example, in collaboration with a major pharmaceutical company, we screened human colon cancer cell lines with chemotherapeutic agents that were tested in combinations of two or three at a time. These results showed that several combinations of agents were synergistic at several doses. Compared to KOR technology, other current cell biology methods for estimating cell death (apoptosis or necrosis), proliferation, or mitogenesis, are very labor-intensive, produce only indirect and retrospective information and, for the most part, measure a surrogate of death rather than the real time activity itself. Due to the expense and labor required, it is only feasible to use traditional methods (MTT, thymidine uptake, annexin V, DNA fragmentation, etc.) as single endpoint assays. Such assays therefore only provide a snapshot of drug actions at some arbitrary time without providing information regarding when, how often, and with what duration responses are generated. As far as we are aware, no assay other than KOR is easily amenable to continuous monitoring of apoptosis or necrosis.It should also be noted that KOR technology may ultimately permit high throughput screening of drug candidates on freshly explanted cells from virtually any organ. Again, the KOR platform has the potential to significantly impact the manner in which anti-cancer drugs are discovered, tested, achieve FDA approval, and brought into the clinical marketplace. Finally, since our conditions of tumor analysis, expansion and preservation emphasize maintenance of viable cells, the in vitro (KOR) stratification offers unique opportunities to sort out the mechanism(s) whereby some patient9s cells respond and other patient9s cells do not-- i.e. the heterogeneity of response. Of perhaps…

Acta Obstetricia et Gynecologica Scandinavica, Mar 18, 2021

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

American Journal of Clinical Pathology, Dec 1, 1978

In a cooperative intrastate program based upon experience with sickle-cell anemia screening, the ... more In a cooperative intrastate program based upon experience with sickle-cell anemia screening, the authors explored the feasibility of applying hemoglobin electrophoresis for detection of beta-thalassemia gene carriers. Initially, blood samples collected in capillary tubes were analyzed by cellulose acetate electrophoresis with densitometric quantitation of hemoglobin A2 (Hb A2), followed by selective spectrophotometric quantitation. This approach proved insufficiently specific or reproducible. Follow-up hematologic and family studies of presumptive beta-thalassemia gene carriers indicated that coordinate measurement of erythrocytic indices and Hb A2 values would have discriminated a subpopulation with a high incidence of beta-thalassemia trait more specifically. This approach was tested prospectively by the use of 731 venous blood samples collected in a county with a large population of Mediterranean ancestry. Of 31 individuals (4.2%) with presumptive thalassemia trait, 13 returned for a repeat testing, and the initial results for 11 were confirmed. These findings lend support to an empirical screening sequence suggested by Pearson (erythrocytic indices followed by Hb A2 quantitation), but they also indicate that a significant subpopulation of beta-thalassemia gene carriers with limited phenotypic expression may elude detection in any single-pass approach.

PubMed, Jun 1, 1985

Tubuloreticular inclusions (TRI) developed within the endoplasmic reticulum of peripheral blood m... more Tubuloreticular inclusions (TRI) developed within the endoplasmic reticulum of peripheral blood mononuclear cells (PBMC) sampled from eight patients with chronic type B hepatitis during cycles of therapy with DNA-recombinant human alpha-interferon (rIFN alpha A). Each cycle of therapy consisted of a series of six intramuscular injections (triweekly) of a fixed dose of rIFN alpha A (from 18 to 68 X 10(6) IU/dose). In PBMC examined by transmission electron microscopy, TRI were absent prior to therapy and developed during therapy in all cases. Peak serum levels of alpha-interferon (320 to 960 IU/ml) were achieved within 12 hours. At 24 hours. TRI were detected in 0.5 to 6.5% of PBMC sections, and they persisted in 1.4 to 6.8% of sections examined at 48 hours. After five sequential interferon doses, TRI were observed in 1.6 to 9.8% of PBMC sections. TRI could no longer be detected at 5 to 16 days after cessation of rIFN alpha A, but they reappeared during subsequent cycles of therapy. Subpopulations of the PBMC with TRI were differentiated by immunoelectron microscopy utilizing a battery of anti-Leu monoclonal antibodies: surface markers of T cells, helper/inducer or cytotoxic/suppressor T cell subsets, natural killer cells, or B-cells were identified by direct or indirect procedures utilizing avidin and biotinylated peroxidase. In cases analyzed with multiple monoclonal antisera, TRI were expressed in all of the major PBMC subpopulations. Monocytes with TRI were demonstrated by the endogenous peroxidase reaction. TRI were not found in circulating polymorphonuclear granulocytes. Lymphocytes isolated from healthy donors and exposed to rIFN alpha A (100 IU/ml), for 48 to 72 hours in vitro, developed TRI in proportions of PBMC sections (2.3 to 8.4%) comparable to those observed in the interferon-treated patients. Stimulation of lymphocytes with concanavalin A, for 72 hours before rIFN alpha A exposure, enhanced formation of TRI which could then be found in T blasts. Stimulation of donor lymphocytes with Sendai virus, a potent inducer of alpha-interferon, also resulted in formation of TRI by 48 hours. This suggested that lymphocytotrophic virus infections could exercise a primary role in the natural pathogenesis of TRI.

American Journal of Clinical Pathology, Apr 1, 1979

Definition of hemoglobin A in cellulose acetate electrophoretograms of eluate from air-dried spec... more Definition of hemoglobin A in cellulose acetate electrophoretograms of eluate from air-dried specimens of newborns' blood was improved by adding glycerine to the Tris--ethylenediametetraacetic acid--borate buffer system. Examination of 1,672 randomly received samples showed no reduction in ability to detect hemoglobin S with the modified buffer. The method may be adopted as a useful adjunct to current technics for rapid electrophoretic screening of neonatal dried blood samples.

Journal of the National Cancer Institute, Apr 1, 1969

Continuous single layer tissue cultures were established with explants from a metastatic nodule o... more Continuous single layer tissue cultures were established with explants from a metastatic nodule of medullary carcinoma primary in the thyroid gland. Some cultures were infected with simian virus 40 and the cells acquired morphologic and growth characteristics associated with viral transformation. Thyrocalcitonin activity was detected by radioimmunoassay of culture fluids as late as 7 months after initiation of the single layers. Substances with the chemical and biological properties of (PG) prostaglandins E2 and F2alpha were extracted from culture fluids after 4 months. The original carcinoma cells contained abundant cyctoplasmic secretory granules, which were demonstrated by electron microscopy. These granules disappeared during subculture of the monolayers, and electron-dense secretory substance accumulated within dilated cisternae of the ribosome-bound endoplasmic reticulum. Ultrastructural differences in surface organization of the virus transformed and uninfected culture cells were noted. Amyloid was present in the original tumor stroma and tissue culture explants, but could not be identified in those serial subcultures derived from the monolayer outgrowths.

Nature, Dec 1, 1997

... Emanuel F. Petricoin, III 1 , Satoshi Ito 1 , Brandi L. Williams 2 , Susette Audet 1 , Louis ... more ... Emanuel F. Petricoin, III 1 , Satoshi Ito 1 , Brandi L. Williams 2 , Susette Audet 1 , Louis F. Stancato 1 , Ana Gamero 3 , Kathleen Clouse 1 , Philip Grimley 4 , Arthur Weiss 5 , Judy Beeler 1 , David S. Finbloom 1 , Elizabeth W. Shores 1 , Robert Abraham 2 & Andrew C. Larner 3, 3. ...

Biorheology, Mar 1, 1977

The results of a screening program for heterozygous thalassemia involving 1039 subjects are repor... more The results of a screening program for heterozygous thalassemia involving 1039 subjects are reported. Identification of possible thalassemia carriers was made on the basis of standard blood indices and quantitative hemoglobin A2 measurements. Various mathematical relationships reported as discriminant functions for possible thalassemia carriers were tested using these data. None of the currently proposed methods suitable for use in a mass screening program performed successfully. Besides the normal hematological parameters, hemorheological variables including shear viscometry, erythrocyte sedimentation rate and osmotic fragility were also studied.

Cell Biology International Reports, Jul 1, 1989

Annals of Internal Medicine, Mar 1, 1967

AIDS research, 1983

ABSTRACT

Journal of the National Cancer Institute, Jul 1, 1973

Journal of Virology, Jul 1, 1974

Production of particles with the ultrastructural appearance of C-type virions persisted for at le... more Production of particles with the ultrastructural appearance of C-type virions persisted for at least 6 h in actinomycin D-treated cells infected with murine leukemia virus. This phenomenon occurred despite severe inhibition of viral RNA synthesis. Virus particles present in a 6-h harvest sedimented in sucrose gradients with the buoyant density characteristic of RNA tumor viruses (1.16 g/cm') and exhibited high levels of reverse transcriptase activity in response to the exogenous template polyriboadenylic acid-oligo deoxythymidylic acid in the range of untreated controls. However, RNase-sensitive endogenous activity was only Y/5 the level found in controls. This observation correlated with a marked

Journal of Clinical Oncology, May 20, 2009

e16506 Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct... more e16506 Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct patterns of gene expression or mutations to high or low tumor grade. This heterogeneity appears to be mirrored in two population subgroups delineated by age-specific incidence rates (ASIR) stratified by grade. We aimed to determine whether serous adenocarcinomas of the peritoneum (PSC) or fallopian tubes (FSC) comprised grade-related subgroups comparable to OSC. Methods: Data for women with invasive OSC (25,997 cases), PSC (2,157), and/or FSC (618) registered in the NCI's Surveillance, Epidemiology, and End Results program (1976–2005) were analyzed. Incidence rates (IR) stratified by grade were compared by year or age of diagnosis. Descriptive analyses were supplemented with tests for trend or age interaction by grade. Cancer-specific survival also was compared by grade (Kaplan-Meier estimator). Results: We observed trend interactions by grade for OSC, PSC, and FSC (p < 0.001); age-adjusted incidence rates rose more rapidly for high than low grade tumors over time. ASIR for OSC/PSC were higher for low than high grade tumors prior to age 40 years, after which rates became higher for high grade (p < 0.001 for age interaction by grade). ASIR were similar for FSC but interpretation was limited by small sample sizes. Unilateral carcinomas were far more common for FSC than OSC (90.9% versus 40.6%). Actuarial cancer-specific cumulative survival was worse for high than low grade tumors (all anatomic sites). Conclusions: Trend and survival analyses both were consistent with a biologically significant high/low grade stratification of OSC, PSC, and FSC. For PSC, significant correlations to ASIR by high/low grade were consistent with two population subgroups as defined for OSC; and also appeared congruent with molecular models that project dual pathways of carcinogenesis. For FSC, definitive correlations will require larger sample sizes. No significant financial relationships to disclose.

Proceedings ... annual meeting, Electron Microscopy Society of America, Aug 1, 1971

Appearance of an eccentric nucleoid within developing poxvirus envelopes is the first ultrastruct... more Appearance of an eccentric nucleoid within developing poxvirus envelopes is the first ultrastructural evidence of core differentiation. Subsequently, the nucleoid elongates and is flanked by lenticular densities known as lateral bodies. When mature, it collapses into a biconcave form. In ultrathin sections, the eccentric nucleoid usually appears compact; although in the elongate stage central spaces may be apparent. Normally, the stages of poxvirus maturation are asynchronous and difficult to examine in order. Treatment of infected cells with rifampin provides a useful experimental approach for examining the development of nucleoid material.HeLa cells were treated with rifampin (100µg/ml) during an 8 hr. infection with vaccinia virus. Rifampin interrupts vaccinia morphogenesis at a stage prior to the formation of coated envelopes, and membranous precursors of envelopes accumulate. When the drug is washed out, large numbers of virus envelopes form simoultaneously (Fig. 1).

Laboratory Investigation, 2006

Clinical Cancer Research, Oct 1, 2006

PL-11 In both the clinical development of new anticancer drugs and for patient care with current ... more PL-11 In both the clinical development of new anticancer drugs and for patient care with current therapy options, the need for defining which patients are likely to respond to a given drug is paramount. This is because most oncology drugs are only effective in 10-30% of the patients and even potent responses are often short-lived and fail to produce a cure. There are a few molecular biomarkers, e.g. her2, and CD20 for trastuzumab and rituximab, respectively, that can be used for pre-selecting likely responders. However, for the majority of drugs, biomarkers which predict therapeutic efficacy do not exist. For such drugs, the only way to determine potential efficacy is through case-based trial and error or through expensive and time-consuming clinical trials, involving hundreds of patients. Therefore, methods of stratifying patients as likely "responders" or "non-responders" are needed.Our laboratory has recently developed a potential solution to this problem. We have patented and validated, a new cell biology platform technology, which allows real-time continuous monitoring of drug, induced optical changes in freshly explanted human tumors. The technology is called Kinetics of Optical Response, or KOR. We believe that, when combined with our knowledge of the hormone and viability factor requirements of cancer cells, the KOR system offers an unprecedented opportunity for evaluating drugs on fresh human tumor explants --- or cell lines and xenographs derived from the explants. The impressive correlation between KOR drug profiling results in vitro and the clinical outcomes in our patient research studies give us confidence that selection of the best available therapy for patients on an individual basis will soon be possibleFor example, a 4-year, multi-institutional study indicated the clinical potential of this technology by establishing a remarkable correlation between KOR chemosensitivity tests on individual9s explanted leukemia cells and the clinical outcome when that patient received treatment. Thus, the KOR results had significant predictive value for both chemotherapy response and survival in patients with acute myelogenous leukemia (AML). In a typical assay, single cell suspensions from normal or abnormal tissues are seeded at a pre-determined density and, following the addition of putative toxic compounds (either alone or in combination at t = 0 or sequentially at later times) plates are placed into the KOR instruments that are programmed for 24 to 72 hours of incubation. By reading OD of each well every 5 minutes OD profiles are generated, which allow a determination of the complete time course of apoptosis and rate of apoptosis which varies as a function of drug dose. Depending on the nature of the curves induced by the added drug or agent, continuous monitoring of any of 4 kinds of responses-- apoptosis, necrosis, proliferation, cytostasis-- is possible, within a single experiment.The KOR technology and has been extensively validated on cell lines and primary tumor explants from cancer patients. Although published results have largely focused on the KOR assay for suspension cultures of hematopoietic cells, we have tested adherent cells with excellent results. For example, in collaboration with a major pharmaceutical company, we screened human colon cancer cell lines with chemotherapeutic agents that were tested in combinations of two or three at a time. These results showed that several combinations of agents were synergistic at several doses. Compared to KOR technology, other current cell biology methods for estimating cell death (apoptosis or necrosis), proliferation, or mitogenesis, are very labor-intensive, produce only indirect and retrospective information and, for the most part, measure a surrogate of death rather than the real time activity itself. Due to the expense and labor required, it is only feasible to use traditional methods (MTT, thymidine uptake, annexin V, DNA fragmentation, etc.) as single endpoint assays. Such assays therefore only provide a snapshot of drug actions at some arbitrary time without providing information regarding when, how often, and with what duration responses are generated. As far as we are aware, no assay other than KOR is easily amenable to continuous monitoring of apoptosis or necrosis.It should also be noted that KOR technology may ultimately permit high throughput screening of drug candidates on freshly explanted cells from virtually any organ. Again, the KOR platform has the potential to significantly impact the manner in which anti-cancer drugs are discovered, tested, achieve FDA approval, and brought into the clinical marketplace. Finally, since our conditions of tumor analysis, expansion and preservation emphasize maintenance of viable cells, the in vitro (KOR) stratification offers unique opportunities to sort out the mechanism(s) whereby some patient9s cells respond and other patient9s cells do not-- i.e. the heterogeneity of response. Of perhaps…

Acta Obstetricia et Gynecologica Scandinavica, Mar 18, 2021

This is an open access article under the terms of the Creative Commons Attribution-NonCommercial ... more This is an open access article under the terms of the Creative Commons Attribution-NonCommercial License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.

American Journal of Clinical Pathology, Dec 1, 1978

In a cooperative intrastate program based upon experience with sickle-cell anemia screening, the ... more In a cooperative intrastate program based upon experience with sickle-cell anemia screening, the authors explored the feasibility of applying hemoglobin electrophoresis for detection of beta-thalassemia gene carriers. Initially, blood samples collected in capillary tubes were analyzed by cellulose acetate electrophoresis with densitometric quantitation of hemoglobin A2 (Hb A2), followed by selective spectrophotometric quantitation. This approach proved insufficiently specific or reproducible. Follow-up hematologic and family studies of presumptive beta-thalassemia gene carriers indicated that coordinate measurement of erythrocytic indices and Hb A2 values would have discriminated a subpopulation with a high incidence of beta-thalassemia trait more specifically. This approach was tested prospectively by the use of 731 venous blood samples collected in a county with a large population of Mediterranean ancestry. Of 31 individuals (4.2%) with presumptive thalassemia trait, 13 returned for a repeat testing, and the initial results for 11 were confirmed. These findings lend support to an empirical screening sequence suggested by Pearson (erythrocytic indices followed by Hb A2 quantitation), but they also indicate that a significant subpopulation of beta-thalassemia gene carriers with limited phenotypic expression may elude detection in any single-pass approach.

PubMed, Jun 1, 1985

Tubuloreticular inclusions (TRI) developed within the endoplasmic reticulum of peripheral blood m... more Tubuloreticular inclusions (TRI) developed within the endoplasmic reticulum of peripheral blood mononuclear cells (PBMC) sampled from eight patients with chronic type B hepatitis during cycles of therapy with DNA-recombinant human alpha-interferon (rIFN alpha A). Each cycle of therapy consisted of a series of six intramuscular injections (triweekly) of a fixed dose of rIFN alpha A (from 18 to 68 X 10(6) IU/dose). In PBMC examined by transmission electron microscopy, TRI were absent prior to therapy and developed during therapy in all cases. Peak serum levels of alpha-interferon (320 to 960 IU/ml) were achieved within 12 hours. At 24 hours. TRI were detected in 0.5 to 6.5% of PBMC sections, and they persisted in 1.4 to 6.8% of sections examined at 48 hours. After five sequential interferon doses, TRI were observed in 1.6 to 9.8% of PBMC sections. TRI could no longer be detected at 5 to 16 days after cessation of rIFN alpha A, but they reappeared during subsequent cycles of therapy. Subpopulations of the PBMC with TRI were differentiated by immunoelectron microscopy utilizing a battery of anti-Leu monoclonal antibodies: surface markers of T cells, helper/inducer or cytotoxic/suppressor T cell subsets, natural killer cells, or B-cells were identified by direct or indirect procedures utilizing avidin and biotinylated peroxidase. In cases analyzed with multiple monoclonal antisera, TRI were expressed in all of the major PBMC subpopulations. Monocytes with TRI were demonstrated by the endogenous peroxidase reaction. TRI were not found in circulating polymorphonuclear granulocytes. Lymphocytes isolated from healthy donors and exposed to rIFN alpha A (100 IU/ml), for 48 to 72 hours in vitro, developed TRI in proportions of PBMC sections (2.3 to 8.4%) comparable to those observed in the interferon-treated patients. Stimulation of lymphocytes with concanavalin A, for 72 hours before rIFN alpha A exposure, enhanced formation of TRI which could then be found in T blasts. Stimulation of donor lymphocytes with Sendai virus, a potent inducer of alpha-interferon, also resulted in formation of TRI by 48 hours. This suggested that lymphocytotrophic virus infections could exercise a primary role in the natural pathogenesis of TRI.

American Journal of Clinical Pathology, Apr 1, 1979

Definition of hemoglobin A in cellulose acetate electrophoretograms of eluate from air-dried spec... more Definition of hemoglobin A in cellulose acetate electrophoretograms of eluate from air-dried specimens of newborns' blood was improved by adding glycerine to the Tris--ethylenediametetraacetic acid--borate buffer system. Examination of 1,672 randomly received samples showed no reduction in ability to detect hemoglobin S with the modified buffer. The method may be adopted as a useful adjunct to current technics for rapid electrophoretic screening of neonatal dried blood samples.

Journal of the National Cancer Institute, Apr 1, 1969

Continuous single layer tissue cultures were established with explants from a metastatic nodule o... more Continuous single layer tissue cultures were established with explants from a metastatic nodule of medullary carcinoma primary in the thyroid gland. Some cultures were infected with simian virus 40 and the cells acquired morphologic and growth characteristics associated with viral transformation. Thyrocalcitonin activity was detected by radioimmunoassay of culture fluids as late as 7 months after initiation of the single layers. Substances with the chemical and biological properties of (PG) prostaglandins E2 and F2alpha were extracted from culture fluids after 4 months. The original carcinoma cells contained abundant cyctoplasmic secretory granules, which were demonstrated by electron microscopy. These granules disappeared during subculture of the monolayers, and electron-dense secretory substance accumulated within dilated cisternae of the ribosome-bound endoplasmic reticulum. Ultrastructural differences in surface organization of the virus transformed and uninfected culture cells were noted. Amyloid was present in the original tumor stroma and tissue culture explants, but could not be identified in those serial subcultures derived from the monolayer outgrowths.

Nature, Dec 1, 1997

... Emanuel F. Petricoin, III 1 , Satoshi Ito 1 , Brandi L. Williams 2 , Susette Audet 1 , Louis ... more ... Emanuel F. Petricoin, III 1 , Satoshi Ito 1 , Brandi L. Williams 2 , Susette Audet 1 , Louis F. Stancato 1 , Ana Gamero 3 , Kathleen Clouse 1 , Philip Grimley 4 , Arthur Weiss 5 , Judy Beeler 1 , David S. Finbloom 1 , Elizabeth W. Shores 1 , Robert Abraham 2 & Andrew C. Larner 3, 3. ...

Biorheology, Mar 1, 1977

The results of a screening program for heterozygous thalassemia involving 1039 subjects are repor... more The results of a screening program for heterozygous thalassemia involving 1039 subjects are reported. Identification of possible thalassemia carriers was made on the basis of standard blood indices and quantitative hemoglobin A2 measurements. Various mathematical relationships reported as discriminant functions for possible thalassemia carriers were tested using these data. None of the currently proposed methods suitable for use in a mass screening program performed successfully. Besides the normal hematological parameters, hemorheological variables including shear viscometry, erythrocyte sedimentation rate and osmotic fragility were also studied.

Cell Biology International Reports, Jul 1, 1989

Annals of Internal Medicine, Mar 1, 1967

AIDS research, 1983

ABSTRACT

Journal of the National Cancer Institute, Jul 1, 1973

Journal of Virology, Jul 1, 1974

Production of particles with the ultrastructural appearance of C-type virions persisted for at le... more Production of particles with the ultrastructural appearance of C-type virions persisted for at least 6 h in actinomycin D-treated cells infected with murine leukemia virus. This phenomenon occurred despite severe inhibition of viral RNA synthesis. Virus particles present in a 6-h harvest sedimented in sucrose gradients with the buoyant density characteristic of RNA tumor viruses (1.16 g/cm') and exhibited high levels of reverse transcriptase activity in response to the exogenous template polyriboadenylic acid-oligo deoxythymidylic acid in the range of untreated controls. However, RNase-sensitive endogenous activity was only Y/5 the level found in controls. This observation correlated with a marked

Journal of Clinical Oncology, May 20, 2009

e16506 Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct... more e16506 Background: Molecular studies of ovarian serous adenocarcinomas (OSC) have linked distinct patterns of gene expression or mutations to high or low tumor grade. This heterogeneity appears to be mirrored in two population subgroups delineated by age-specific incidence rates (ASIR) stratified by grade. We aimed to determine whether serous adenocarcinomas of the peritoneum (PSC) or fallopian tubes (FSC) comprised grade-related subgroups comparable to OSC. Methods: Data for women with invasive OSC (25,997 cases), PSC (2,157), and/or FSC (618) registered in the NCI's Surveillance, Epidemiology, and End Results program (1976–2005) were analyzed. Incidence rates (IR) stratified by grade were compared by year or age of diagnosis. Descriptive analyses were supplemented with tests for trend or age interaction by grade. Cancer-specific survival also was compared by grade (Kaplan-Meier estimator). Results: We observed trend interactions by grade for OSC, PSC, and FSC (p < 0.001); age-adjusted incidence rates rose more rapidly for high than low grade tumors over time. ASIR for OSC/PSC were higher for low than high grade tumors prior to age 40 years, after which rates became higher for high grade (p < 0.001 for age interaction by grade). ASIR were similar for FSC but interpretation was limited by small sample sizes. Unilateral carcinomas were far more common for FSC than OSC (90.9% versus 40.6%). Actuarial cancer-specific cumulative survival was worse for high than low grade tumors (all anatomic sites). Conclusions: Trend and survival analyses both were consistent with a biologically significant high/low grade stratification of OSC, PSC, and FSC. For PSC, significant correlations to ASIR by high/low grade were consistent with two population subgroups as defined for OSC; and also appeared congruent with molecular models that project dual pathways of carcinogenesis. For FSC, definitive correlations will require larger sample sizes. No significant financial relationships to disclose.

Proceedings ... annual meeting, Electron Microscopy Society of America, Aug 1, 1971

Appearance of an eccentric nucleoid within developing poxvirus envelopes is the first ultrastruct... more Appearance of an eccentric nucleoid within developing poxvirus envelopes is the first ultrastructural evidence of core differentiation. Subsequently, the nucleoid elongates and is flanked by lenticular densities known as lateral bodies. When mature, it collapses into a biconcave form. In ultrathin sections, the eccentric nucleoid usually appears compact; although in the elongate stage central spaces may be apparent. Normally, the stages of poxvirus maturation are asynchronous and difficult to examine in order. Treatment of infected cells with rifampin provides a useful experimental approach for examining the development of nucleoid material.HeLa cells were treated with rifampin (100µg/ml) during an 8 hr. infection with vaccinia virus. Rifampin interrupts vaccinia morphogenesis at a stage prior to the formation of coated envelopes, and membranous precursors of envelopes accumulate. When the drug is washed out, large numbers of virus envelopes form simoultaneously (Fig. 1).