Gerald Colvin - Academia.edu (original) (raw)

Papers by Gerald Colvin

Research paper thumbnail of Quantitative tissue stem cell modeling - Response

Research paper thumbnail of low-dose whole-body irradiation Host marrow stem cell potential and engraftability at varying times after

Research paper thumbnail of Alteration of Marrow Cell Gene Expression, Protein Production, and Engraftment into Lung by Lung-Derived Microvesicles: A Novel Mechanism for Phenotype Modulation

Stem Cells, 2007

Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the c... more Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the cellular component of the lung. Lung injury is a major variable in this process; however, the mechanism remains unknown. We hypothesize that injured lung is capable of inducing epigenetic modifications of marrow cells, influencing them to assume phenotypic characteristics of lung cells. We report that under certain conditions, radiation-injured lung induced expression of pulmonary epithelial cell-specific genes and prosurfactant B protein in cocultured whole bone marrow cells separated by a cell-impermeable membrane. Lung-conditioned media had a similar effect on cocultured whole bone marrow cells and was found to contain pulmonary epithelial cell-specific RNA-filled microvesicles that entered whole bone marrow cells in culture. Also, whole bone marrow cells cocultured with lung had a greater propensity to produce type II pneumocytes after transplantation into irradiated mice. These findi...

Research paper thumbnail of Murine allogeneic in vivo stem cell homing

Journal of Cellular Physiology, 2007

Stem cell homing has been studied in syngeneic models and appears to be rapid (<1 h) and dependen... more Stem cell homing has been studied in syngeneic models and appears to be rapid (<1 h) and dependent on cellular adhesion and migration factors. We utilized a full H2-mismatched transplantation model to determine the basics of allogeneic homing. C57BL/6J Lin-Sca-1+ cells were labeled with CFSE and injected in non-myeloablated BALB/c mice. Fluorescent cell detection was via high-speed FACS analysis. Alternatively, B6.SJL whole bone marrow cells were injected in lethally irradiated BALB/ c mice (10 Gy). One, 3, 6, and 24 h after transplant, marrow was harvested and cells were either plated for high proliferative potential colony-forming cell (HPP-CFC) assay or secondarily injected into myeloablated (8 Gy) C57BL/6J mice using 10% competing C57BL/6J marrow. Chimerism was evaluated at 8 weeks. CFSE+ cells were detected in the bone marrow 1, 3, and 6 h after injection. The numbers were moderately lower when compared to syngeneic homing possibly due to strain effect. Conversely, utilizing a surrogate or secondary assay, we observed a decline of secondary engraftment of harvested cells over time, but not of HPP-CFC. Combining experiments and normalizing the 1-h time point to 100% (to allow comparison), we observed a mean relative engraftment of 87 ± 29%, 72 ± 21%, 84 ± 35% of the 1 h level at 3, 6, and 24 h respectively. HPP-CFC assay showed no significant variation as a homing surrogate over 1-6 h. These data indicate a rapid homing into allogeneic recipients with a plateau at 1 h. The decline of secondary engraftability over time may indicate a phenotype alteration of homed cells. Hematopoetic stem cells (HSC) are defined by their capacity to fully reconstitute marrow of lethally irradiated hosts and give rise to all marrow-derived hematopoietic elements. Stem cell transplantation is a clinical approach used to restore defective hematopoiesis due either to highdose chemoradiotherapy or to intrinsic marrow diseases. In this process, intravenously infused stem cells rapidly find their way to specific periendosteal location in the marrow-termed niches. The totality of this process defines homing (Quesenberry and Becker, 1998). Using syngeneic inbred mice, many aspects of stem cell homing have been described (

Research paper thumbnail of ‘Weighing in’ on screening mammography

Breast Cancer Research and Treatment, 2008

Obesity is associated with increased post-menopausal breast cancer risk. Overweight and obese wom... more Obesity is associated with increased post-menopausal breast cancer risk. Overweight and obese women also tend to have a poorer prognosis when diagnosed with breast cancer compared with their matched normal weight peers. In previous studies obesity was associated with decreased utilization of screening mammography. We present a study examining the association between Body Mass Index (BMI) and compliance with recommended mammographic screening using data from the 2004 Behavioral Risk Factor Surveillance Survey (BRFSS). We included 130,185 female participants, aged 40 and older, who were randomly selected to participate in the world largest telephone survey. After weighted analysis, this is representative of 56,226,220 non-institutionalized US women. The primary outcome was the proportion of women who underwent screening mammography within the last 2 years preceding the survey stratified by BMI. The mammography screening behavior of normal weight women (BMI 18.5-24.99) was compared with underweight (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;18.5), overweight (25-29.99), and women with obesity class I (30-34.99), class II (35-39.99), and class III (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=40) using logistic regression analysis and weighted to provide estimates of women in the United States (US). Our sample included 1.91% underweight, 37.91% normal weight, 30.15% overweight and 14.36%, 5.44%, and 3.49% women with obesity classes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; I-III respectively. Approximately 7% of women age 40 and older had insufficient information to calculate their BMI. Adjusting for age, race, smoking status, general health perception, level of education, and income level, underweight women had lower odds of complying with regular screening mammography (OR 0.57; 95% CI, 0.48-0.68). Women with obesity class III (OR 0.97; 95% CI, 0.84-1.13) showed a trend towards underutilization of screening mammograms which was not clinically significant. In contrary, in overweight women a significantly higher association with appropriate mammography utilization was identified OR 1.08 (95% CI, 1.01-1.15). Although not statistically significant, women with class I and II obesity showed a trend towards a higher utilization 1.08 (95% CI, 0.99-1.18) and 1.10 (95% CI, 0.98-1.25) respectively, when compared to women at desired weight. We present a weighted analysis of the BRFSS, evaluating the association of BMI and appropriate screening mammography among women 40 years and older. These results are generalizable to the US population of women in this age range. Underweight women had significantly lower odds of utilizing screening mammography appropriately when compared with women at desired weight. Results from previous studies reporting underutilization of screening mammography in high risk, obese, and overweighed women were not confirmed in this largest population based analysis performed to date.

Research paper thumbnail of Consolidation Therapy Following Autologous Stem Cell Transplantation For Non-Hodgkins And Hodgkins Lymphomas

Biology of Blood and Marrow Transplantation, 2010

chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunother... more chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunotherapy consisted of rituximab 375 mg/M 2 IV weekly and sargramostim 250 ug s.c. TIW during weeks 5 to 8 and 24 to 27 post transplant. Results: Seven patients had successful mobilization (mean CD34/kg collected 12.5E6 and infused 9E6) and underwent transplant. Median time to neutrophil and platelet engraftment was 9 and 10 days respectively. Six patients are alive with no evidence of disease from 3 to 18 months post transplant. One patient relapsed at 11 months. 4/4 patients receiving at least once cycle of adjuvant immunotherapy developed grade 1 to 4 neutropenia from 3 to 34 weeks post adjuvant rituximab. Neutrophil counts recovered following treatment with G-CSF, but recurred in all 4 patients without additional exposure to rituximab. One patient who had engrafted platelets developed grade 2 thrombocytopenia on day 33 post transplant. Platelets spontaneously recovered. Conclusions: Delayed-onset neutropenia is a known complication of rituximab. The incidence may be higher when rituximab is used following ASCT. It is not clear if the timing of rituximab administration post transplant or the concomitant use of sargramostim contributed to the high incidence of delayed neutropenia in this study. Larger studies and longer followup will be needed to determine if adjuvant immunotherapy decreases relapse.

Research paper thumbnail of Conversion Potential of Marrow Cells into Lung Cells Fluctuates with Cytokine-Induced Cell Cycle

Stem Cells and Development, 2008

Green fluorescent protein (GFP)-labeled marrow cells transplanted into lethally irradiated mice c... more Green fluorescent protein (GFP)-labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung-specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit the cell cycle by exposure to interleukin-3 (IL-3), IL-6, IL-11, and Steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G 1 /S interface of the cell cycle have a threefold increase in cells that assume a nonhematopoietic or pulmonary epithelial cell phenotype and that this increase is no longer seen in late S/G 2. These cells have been characterized as GFP ؉ CD45 ؊ and GFP ؉ cytokeratin ؉. Thus, marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine-induced cell cycle transit. Previous studies have shown that the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse the cell cycle, leading to a continuum model of stem cell regulation. The present study indicates that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum.

Research paper thumbnail of The Good Neighbor Alliance

Cover: "Cross Country Trail," pastel, 56" x 40", by Regina Partridge, a Rhode Island artist who h... more Cover: "Cross Country Trail," pastel, 56" x 40", by Regina Partridge, a Rhode Island artist who has exhibited in RI, MA, and CT. Currently her work is at the Bert Gallery and Gallery Z. Her artwork appears in banks, hospitals, restaurants, insurance companies and offices around the country. She is a partner in Studio Goddard Partridge and on the boards of the Rhode Island State Council on the Arts and the Pawtucket Arts Collaborative. www.studiogoddardpartridge.com.

Research paper thumbnail of Directed Differentiation: Evolution towards Human Application

Blood

Directed differentiation is defined as the ability to program a stem cell at the most primitive l... more Directed differentiation is defined as the ability to program a stem cell at the most primitive level while it still has its reproductive and full proliferative potential. This is in contrast to ex-vivo expansion where the stem cells are forced into specific lineage commitments, limiting the overall therapeutic utility. We have reproducibly induced directed stem cell differentiation towards megakaryopoiesis by capitalizing on inherent changes in sensitivities to inductive cytokine signals in the context of cell cycle position. Murine experiments have been performed on highly purified quiescent G0–1 lineagenegative rhodaminelowHoeschtlow (LRH) marrow stem cells. When exposed to thrombopoietin, FLT3-ligand and steel factor (TFS), they synchronously pass through cell cycle. Megakaryopoiesis is focused at early to mid S-phase, returning to baseline before initial cell division. Population based differentiation cultures after 14-days produced up to 49% megakaryocytes with stem cells sub-...

Research paper thumbnail of Circadian Rhythms of Whole Bone Marrow and Lineage Negative Stem Cells of the Mouse

Blood

Circadian rhythms underlie most biological processes. In mammals circadian control of physiology ... more Circadian rhythms underlie most biological processes. In mammals circadian control of physiology and behavior is mediated via a central master oscillator, in the supra-schismatic nuclei of the hypothalamus. At the cellular level this oscillator is composed of an auto-regulatory transcription-translation loop of clock genes. The Period2 (Per2) gene is one of the clock genes which plays a key role in controlling the circadian rhythm in mammals. Mice with mutations in Per2 become arrhythmic. Expression of clock genes is also present in many peripheral tissues, including the bone marrow. Stem cell engraftment has been shown to vary with cell cycle transit (Habibian et al, 1998). A diurnal circadian variation in the ability of bone marrow to engraft sub-lethally irradiated mice has been previously shown by our laboratory. An increase in numbers of progenitors in S-phase underlined the engraftment nadirs. The host’s ability to accept incoming cells did not show circadian variation. To fur...

Research paper thumbnail of Classroom Counseling in Secondary Schools: An Old Idea That's New Again

American Secondary Education, Oct 1, 2004

Research paper thumbnail of Method and apparatus for broadcasting software update information to mobile phones over a wireless communications network

Research paper thumbnail of Eosinophilia Secondary To Strongyloides

With an increase in travel and an influx of immigrants and refugees from the tropics over the las... more With an increase in travel and an influx of immigrants and refugees from the tropics over the last few decades, clinicians in Rhode Island are more commonly encountering tropical diseases. The Federation for American Immigration Reform estimated that the average annual rate of increase in the for- eign-born population in Rhode Island to be 2400 persons, with the Dominican Republic and Guatemala two of the larg- est countries from which people emigrate. 1 As a result, hema- tologic abnormalities such as eosinophilia can arise without any other symptoms, perplexing clinicians as to the proper workup. Hematologists at The Rhode Island Hospital have noticed a significant increase in referrals of eosinophilia with mild leuko- cytosis or anemia, making it important to discuss major causes in immigrant populations. Infections such as hookworm and Strongyloides stercoralis (Strongyloides) are the most common parasitic nematodes to cause eosinophilia in tropical and sub- tropical areas. 2 We...

Research paper thumbnail of Abstract 2806: A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2 + or Her2 - high risk breast cancer (more than 10+ nodes): Table 1

Cancer Research, 2014

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Anti-CD3 x anti... more Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Anti-CD3 x anti-HER2Bi bispecific antibody (HER2Bi) targeted monoclonal antibody (mAb) activated T cells (ATC) exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement. This study reports a phase I immunotherapy trial in 9 women with locally advanced breast cancer consisting of infusions of HER2Bi armed ATC (aATC) in combination with interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) to evaluate safety, feasibility, time to progression (TTP), overall survival (OS), T cell trafficking, and immune responses. Methods: ATC were produced by stimulating peripheral blood mononuclear cells (PBMC) obtained by leukapheresis with anti-CD3 monoclonal antibody and expanding the ATC in IL-2. ATC were harvested, armed with HER2Bi and cryopreserved in aliqouts. Groups of 3 patients received 20, 40, 80 or 160 x 109 aATC per infusion twice a week for four weeks(Table 1). Results: Eight of 9 patients were ER positive, 2 of 9 were Her 2 overexpressing tumors. The median OS for all patients was 103.5 months (14.3 to 134.7months). Six of 9 patients are alive. Four out of the six patients have no evidence of disease and 2 patients relapsed (one at 77.27 months and the other at 104.67months). It was feasible to grow up to 160 x 109 ATC and both patients assigned to this dose level were able to reach it. There were no cell-based dose limiting toxicities. aATC persisted in the blood for at least a week. aATC infusions induce cellular anti-tumor responses and cytokine responses. Interpretation: Targeting Her2 positive and negative tumors induced cytotoxic anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels, clinical responses that suggest aATC infusions provided a survival benefit. These results are being confirmed in a phase II trial for metastatic breast cancer. View this table: Table 1 Citation Format: Deepa B. Jagtap, Ritesh Rathore, Archana Thakur, Gerald Colvin, Nicola Kouttab, Abby Maizel, Abhinav Deol, Lawrence G. Lum. A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2+ or Her2- high risk breast cancer (more than 10+ nodes). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2014-2806

Research paper thumbnail of Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells – A Review for the Clinician

New Advances in Stem Cell Transplantation, 2012

Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells-A Review for the Clinician 233... more Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells-A Review for the Clinician 233 primarily focus on the recent developments in the field of cryopreservation of hematopoietic stem cells, but also outline some of the similarities and differences between the cryopreservation of HSCs and non-hematopoietic stem cells. 3. Processing prior to cryostorage 3.1 Liquid phase storage Several centers, particularly in remote rural settings rely on the performance of autologous bone marrow transplantation without a local croypreservation expertise. Along with that, umbilical cord blood processing is only performed in highly specialized cell processing facilities, which are often geographically remote from the place of collection. In such clinical settings, the initial cell collections have to be transported to a center with the necessary expertise in a liquid form (Fleming & A Hubel, 2006; Rodrigues et al., 2008). Liquid storage, either for transport purposes or to bridge a short time span prior to definitive clinical use has been successfully used for different clinical indications (Corato et al.,

Research paper thumbnail of The Stem Cell Continuum: A New Model of Stem Cell Regulation

Handbook of Experimental Pharmacology, 2006

Most models of hematopoiesis have been hierarchical in nature. This is based on a large volume of... more Most models of hematopoiesis have been hierarchical in nature. This is based on a large volume of correlative data. Recent work has indicated that, at least at the stem/progenitor level, hematopoiesis may, in fact, be a continuum of transcriptional opportunity. The most primitive hematopoietic stem cells are either continually cycling at a slow rate or entering and exiting cell cycle. Associated with this cycle passage are changes in functional phenotype including reversible alterations in engraftment, adhesion protein expression, cytokine receptor expression, homing to marrow, and progenitor cell numbers. Global gene expression, as measured in one point in cycle, is also markedly altered. The differentiation potential of the marrow as it transits cell cycle in response to a set differentiation stimulus also shows marked variations. This cycle-related plasticity has been clearly established for hematopoiesis. It also holds for the ability of murine marrow stem cells to home to lung and to convert to pulmonary cells. These data indicate that bone marrow stem cells can probably not be defined as discrete entities but must rather be studied on a population basis. They also indicate that mathematical modeling will become progressively more important in this field.

Research paper thumbnail of Eosinophilia secondary to strongyloides in Rhode Island

Medicine and health, Rhode Island, 2010

Research paper thumbnail of The marrow cell continuum: stochastic determinism

Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society, 2005

Traditional models of hematopoiesis have been hierarchical in nature. Over the past 10 years, we ... more Traditional models of hematopoiesis have been hierarchical in nature. Over the past 10 years, we have developed data indicating that hematopoiesis is regulated in a continuum with deterministic and stochastic components. We have shown that the most primitive stem cells, as represented by lineage negative rhodamine(low) Hoechst(low) murine marrow cells are continuously or intermittently cycling as determined by in vivo BrdU labeling. When marrow stem cells are induced to transit cell cycle by in vitro exposure to cytokines, either IL-3, IL-6, IL-11, and steel factor or thrombopoietin, FLT3 ligand, and steel factor, they progress through cycle in a highly synchronized fashion. We have determined that when the stem cells progress through a cytokine stimulated cell cycle the homing, engraftment, adhesion protein, global gene expression, and hematopoietic differentiation phenotypes all change in a reversible fashion. This has led to the continuum model, in which, with cycle transit, chro...

Research paper thumbnail of The latest treatment advances for acute myelogenous leukemia

Medicine and health, Rhode Island, 2003

The research into pathogenesis and mechanisms behind AML is advancing rapidly, but in general, tr... more The research into pathogenesis and mechanisms behind AML is advancing rapidly, but in general, translation into global application for the majority of patients is wanting. As more becomes known about the cytogenetic and molecular characteristics of leukemia cells and the pathways of leukemogenesis are further elucidated, it is hoped that future therapies will be directed more specifically toward the least toxic method to eradicate clonal malignant cells. HLA-haploidentical and alloBMT using KIR mismatch may dramatically improve survival for many more patients.

Research paper thumbnail of Targeted T cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2015

This study reports a phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer c... more This study reports a phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3 activated T cells (ATC) in combination with low dose interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T cell trafficking, immune responses, time to progression, and overall survival (OS). ATC were expanded from leukapheresis product using IL-2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 x 10(9) armed ATC (aATC) per infusion. There were no dose limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 x 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in im...

Research paper thumbnail of Quantitative tissue stem cell modeling - Response

Research paper thumbnail of low-dose whole-body irradiation Host marrow stem cell potential and engraftability at varying times after

Research paper thumbnail of Alteration of Marrow Cell Gene Expression, Protein Production, and Engraftment into Lung by Lung-Derived Microvesicles: A Novel Mechanism for Phenotype Modulation

Stem Cells, 2007

Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the c... more Numerous animal studies have demonstrated that adult marrow-derived cells can contribute to the cellular component of the lung. Lung injury is a major variable in this process; however, the mechanism remains unknown. We hypothesize that injured lung is capable of inducing epigenetic modifications of marrow cells, influencing them to assume phenotypic characteristics of lung cells. We report that under certain conditions, radiation-injured lung induced expression of pulmonary epithelial cell-specific genes and prosurfactant B protein in cocultured whole bone marrow cells separated by a cell-impermeable membrane. Lung-conditioned media had a similar effect on cocultured whole bone marrow cells and was found to contain pulmonary epithelial cell-specific RNA-filled microvesicles that entered whole bone marrow cells in culture. Also, whole bone marrow cells cocultured with lung had a greater propensity to produce type II pneumocytes after transplantation into irradiated mice. These findi...

Research paper thumbnail of Murine allogeneic in vivo stem cell homing

Journal of Cellular Physiology, 2007

Stem cell homing has been studied in syngeneic models and appears to be rapid (<1 h) and dependen... more Stem cell homing has been studied in syngeneic models and appears to be rapid (<1 h) and dependent on cellular adhesion and migration factors. We utilized a full H2-mismatched transplantation model to determine the basics of allogeneic homing. C57BL/6J Lin-Sca-1+ cells were labeled with CFSE and injected in non-myeloablated BALB/c mice. Fluorescent cell detection was via high-speed FACS analysis. Alternatively, B6.SJL whole bone marrow cells were injected in lethally irradiated BALB/ c mice (10 Gy). One, 3, 6, and 24 h after transplant, marrow was harvested and cells were either plated for high proliferative potential colony-forming cell (HPP-CFC) assay or secondarily injected into myeloablated (8 Gy) C57BL/6J mice using 10% competing C57BL/6J marrow. Chimerism was evaluated at 8 weeks. CFSE+ cells were detected in the bone marrow 1, 3, and 6 h after injection. The numbers were moderately lower when compared to syngeneic homing possibly due to strain effect. Conversely, utilizing a surrogate or secondary assay, we observed a decline of secondary engraftment of harvested cells over time, but not of HPP-CFC. Combining experiments and normalizing the 1-h time point to 100% (to allow comparison), we observed a mean relative engraftment of 87 ± 29%, 72 ± 21%, 84 ± 35% of the 1 h level at 3, 6, and 24 h respectively. HPP-CFC assay showed no significant variation as a homing surrogate over 1-6 h. These data indicate a rapid homing into allogeneic recipients with a plateau at 1 h. The decline of secondary engraftability over time may indicate a phenotype alteration of homed cells. Hematopoetic stem cells (HSC) are defined by their capacity to fully reconstitute marrow of lethally irradiated hosts and give rise to all marrow-derived hematopoietic elements. Stem cell transplantation is a clinical approach used to restore defective hematopoiesis due either to highdose chemoradiotherapy or to intrinsic marrow diseases. In this process, intravenously infused stem cells rapidly find their way to specific periendosteal location in the marrow-termed niches. The totality of this process defines homing (Quesenberry and Becker, 1998). Using syngeneic inbred mice, many aspects of stem cell homing have been described (

Research paper thumbnail of ‘Weighing in’ on screening mammography

Breast Cancer Research and Treatment, 2008

Obesity is associated with increased post-menopausal breast cancer risk. Overweight and obese wom... more Obesity is associated with increased post-menopausal breast cancer risk. Overweight and obese women also tend to have a poorer prognosis when diagnosed with breast cancer compared with their matched normal weight peers. In previous studies obesity was associated with decreased utilization of screening mammography. We present a study examining the association between Body Mass Index (BMI) and compliance with recommended mammographic screening using data from the 2004 Behavioral Risk Factor Surveillance Survey (BRFSS). We included 130,185 female participants, aged 40 and older, who were randomly selected to participate in the world largest telephone survey. After weighted analysis, this is representative of 56,226,220 non-institutionalized US women. The primary outcome was the proportion of women who underwent screening mammography within the last 2 years preceding the survey stratified by BMI. The mammography screening behavior of normal weight women (BMI 18.5-24.99) was compared with underweight (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;lt;18.5), overweight (25-29.99), and women with obesity class I (30-34.99), class II (35-39.99), and class III (&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;gt;or=40) using logistic regression analysis and weighted to provide estimates of women in the United States (US). Our sample included 1.91% underweight, 37.91% normal weight, 30.15% overweight and 14.36%, 5.44%, and 3.49% women with obesity classes&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39; I-III respectively. Approximately 7% of women age 40 and older had insufficient information to calculate their BMI. Adjusting for age, race, smoking status, general health perception, level of education, and income level, underweight women had lower odds of complying with regular screening mammography (OR 0.57; 95% CI, 0.48-0.68). Women with obesity class III (OR 0.97; 95% CI, 0.84-1.13) showed a trend towards underutilization of screening mammograms which was not clinically significant. In contrary, in overweight women a significantly higher association with appropriate mammography utilization was identified OR 1.08 (95% CI, 1.01-1.15). Although not statistically significant, women with class I and II obesity showed a trend towards a higher utilization 1.08 (95% CI, 0.99-1.18) and 1.10 (95% CI, 0.98-1.25) respectively, when compared to women at desired weight. We present a weighted analysis of the BRFSS, evaluating the association of BMI and appropriate screening mammography among women 40 years and older. These results are generalizable to the US population of women in this age range. Underweight women had significantly lower odds of utilizing screening mammography appropriately when compared with women at desired weight. Results from previous studies reporting underutilization of screening mammography in high risk, obese, and overweighed women were not confirmed in this largest population based analysis performed to date.

Research paper thumbnail of Consolidation Therapy Following Autologous Stem Cell Transplantation For Non-Hodgkins And Hodgkins Lymphomas

Biology of Blood and Marrow Transplantation, 2010

chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunother... more chemotherapy with rituximab, carmustine, etoposide, cytarabine and melphalan. Adjuvant immunotherapy consisted of rituximab 375 mg/M 2 IV weekly and sargramostim 250 ug s.c. TIW during weeks 5 to 8 and 24 to 27 post transplant. Results: Seven patients had successful mobilization (mean CD34/kg collected 12.5E6 and infused 9E6) and underwent transplant. Median time to neutrophil and platelet engraftment was 9 and 10 days respectively. Six patients are alive with no evidence of disease from 3 to 18 months post transplant. One patient relapsed at 11 months. 4/4 patients receiving at least once cycle of adjuvant immunotherapy developed grade 1 to 4 neutropenia from 3 to 34 weeks post adjuvant rituximab. Neutrophil counts recovered following treatment with G-CSF, but recurred in all 4 patients without additional exposure to rituximab. One patient who had engrafted platelets developed grade 2 thrombocytopenia on day 33 post transplant. Platelets spontaneously recovered. Conclusions: Delayed-onset neutropenia is a known complication of rituximab. The incidence may be higher when rituximab is used following ASCT. It is not clear if the timing of rituximab administration post transplant or the concomitant use of sargramostim contributed to the high incidence of delayed neutropenia in this study. Larger studies and longer followup will be needed to determine if adjuvant immunotherapy decreases relapse.

Research paper thumbnail of Conversion Potential of Marrow Cells into Lung Cells Fluctuates with Cytokine-Induced Cell Cycle

Stem Cells and Development, 2008

Green fluorescent protein (GFP)-labeled marrow cells transplanted into lethally irradiated mice c... more Green fluorescent protein (GFP)-labeled marrow cells transplanted into lethally irradiated mice can be detected in the lungs of transplanted mice and have been shown to express lung-specific proteins while lacking the expression of hematopoietic markers. We have studied marrow cells induced to transit the cell cycle by exposure to interleukin-3 (IL-3), IL-6, IL-11, and Steel factor at different times of culture corresponding to different phases of cell cycle. We have found that marrow cells at the G 1 /S interface of the cell cycle have a threefold increase in cells that assume a nonhematopoietic or pulmonary epithelial cell phenotype and that this increase is no longer seen in late S/G 2. These cells have been characterized as GFP ؉ CD45 ؊ and GFP ؉ cytokeratin ؉. Thus, marrow cells with the capacity to convert into cells with a lung phenotype after transplantation show a reversible increase with cytokine-induced cell cycle transit. Previous studies have shown that the phenotype of bone marrow stem cells fluctuates reversibly as these cells traverse the cell cycle, leading to a continuum model of stem cell regulation. The present study indicates that marrow stem cell production of nonhematopoietic cells also fluctuates on a continuum.

Research paper thumbnail of The Good Neighbor Alliance

Cover: "Cross Country Trail," pastel, 56" x 40", by Regina Partridge, a Rhode Island artist who h... more Cover: "Cross Country Trail," pastel, 56" x 40", by Regina Partridge, a Rhode Island artist who has exhibited in RI, MA, and CT. Currently her work is at the Bert Gallery and Gallery Z. Her artwork appears in banks, hospitals, restaurants, insurance companies and offices around the country. She is a partner in Studio Goddard Partridge and on the boards of the Rhode Island State Council on the Arts and the Pawtucket Arts Collaborative. www.studiogoddardpartridge.com.

Research paper thumbnail of Directed Differentiation: Evolution towards Human Application

Blood

Directed differentiation is defined as the ability to program a stem cell at the most primitive l... more Directed differentiation is defined as the ability to program a stem cell at the most primitive level while it still has its reproductive and full proliferative potential. This is in contrast to ex-vivo expansion where the stem cells are forced into specific lineage commitments, limiting the overall therapeutic utility. We have reproducibly induced directed stem cell differentiation towards megakaryopoiesis by capitalizing on inherent changes in sensitivities to inductive cytokine signals in the context of cell cycle position. Murine experiments have been performed on highly purified quiescent G0–1 lineagenegative rhodaminelowHoeschtlow (LRH) marrow stem cells. When exposed to thrombopoietin, FLT3-ligand and steel factor (TFS), they synchronously pass through cell cycle. Megakaryopoiesis is focused at early to mid S-phase, returning to baseline before initial cell division. Population based differentiation cultures after 14-days produced up to 49% megakaryocytes with stem cells sub-...

Research paper thumbnail of Circadian Rhythms of Whole Bone Marrow and Lineage Negative Stem Cells of the Mouse

Blood

Circadian rhythms underlie most biological processes. In mammals circadian control of physiology ... more Circadian rhythms underlie most biological processes. In mammals circadian control of physiology and behavior is mediated via a central master oscillator, in the supra-schismatic nuclei of the hypothalamus. At the cellular level this oscillator is composed of an auto-regulatory transcription-translation loop of clock genes. The Period2 (Per2) gene is one of the clock genes which plays a key role in controlling the circadian rhythm in mammals. Mice with mutations in Per2 become arrhythmic. Expression of clock genes is also present in many peripheral tissues, including the bone marrow. Stem cell engraftment has been shown to vary with cell cycle transit (Habibian et al, 1998). A diurnal circadian variation in the ability of bone marrow to engraft sub-lethally irradiated mice has been previously shown by our laboratory. An increase in numbers of progenitors in S-phase underlined the engraftment nadirs. The host’s ability to accept incoming cells did not show circadian variation. To fur...

Research paper thumbnail of Classroom Counseling in Secondary Schools: An Old Idea That's New Again

American Secondary Education, Oct 1, 2004

Research paper thumbnail of Method and apparatus for broadcasting software update information to mobile phones over a wireless communications network

Research paper thumbnail of Eosinophilia Secondary To Strongyloides

With an increase in travel and an influx of immigrants and refugees from the tropics over the las... more With an increase in travel and an influx of immigrants and refugees from the tropics over the last few decades, clinicians in Rhode Island are more commonly encountering tropical diseases. The Federation for American Immigration Reform estimated that the average annual rate of increase in the for- eign-born population in Rhode Island to be 2400 persons, with the Dominican Republic and Guatemala two of the larg- est countries from which people emigrate. 1 As a result, hema- tologic abnormalities such as eosinophilia can arise without any other symptoms, perplexing clinicians as to the proper workup. Hematologists at The Rhode Island Hospital have noticed a significant increase in referrals of eosinophilia with mild leuko- cytosis or anemia, making it important to discuss major causes in immigrant populations. Infections such as hookworm and Strongyloides stercoralis (Strongyloides) are the most common parasitic nematodes to cause eosinophilia in tropical and sub- tropical areas. 2 We...

Research paper thumbnail of Abstract 2806: A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2 + or Her2 - high risk breast cancer (more than 10+ nodes): Table 1

Cancer Research, 2014

Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Anti-CD3 x anti... more Proceedings: AACR Annual Meeting 2014; April 5-9, 2014; San Diego, CA Background: Anti-CD3 x anti-HER2Bi bispecific antibody (HER2Bi) targeted monoclonal antibody (mAb) activated T cells (ATC) exhibit anti-HER2 cytotoxicity, proliferate, and secrete immunokines upon tumor engagement. This study reports a phase I immunotherapy trial in 9 women with locally advanced breast cancer consisting of infusions of HER2Bi armed ATC (aATC) in combination with interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor (GM-CSF) to evaluate safety, feasibility, time to progression (TTP), overall survival (OS), T cell trafficking, and immune responses. Methods: ATC were produced by stimulating peripheral blood mononuclear cells (PBMC) obtained by leukapheresis with anti-CD3 monoclonal antibody and expanding the ATC in IL-2. ATC were harvested, armed with HER2Bi and cryopreserved in aliqouts. Groups of 3 patients received 20, 40, 80 or 160 x 109 aATC per infusion twice a week for four weeks(Table 1). Results: Eight of 9 patients were ER positive, 2 of 9 were Her 2 overexpressing tumors. The median OS for all patients was 103.5 months (14.3 to 134.7months). Six of 9 patients are alive. Four out of the six patients have no evidence of disease and 2 patients relapsed (one at 77.27 months and the other at 104.67months). It was feasible to grow up to 160 x 109 ATC and both patients assigned to this dose level were able to reach it. There were no cell-based dose limiting toxicities. aATC persisted in the blood for at least a week. aATC infusions induce cellular anti-tumor responses and cytokine responses. Interpretation: Targeting Her2 positive and negative tumors induced cytotoxic anti-tumor responses, increases in Th1 cytokines and IL-12 serum levels, clinical responses that suggest aATC infusions provided a survival benefit. These results are being confirmed in a phase II trial for metastatic breast cancer. View this table: Table 1 Citation Format: Deepa B. Jagtap, Ritesh Rathore, Archana Thakur, Gerald Colvin, Nicola Kouttab, Abby Maizel, Abhinav Deol, Lawrence G. Lum. A phase Ia/Ib trial of chemotherapy followed by infusions of activated T cells armed with OKT3 x trastuzumab bispecific antibody, IL-2 and GM-CSF for stage II/ III, Her2+ or Her2- high risk breast cancer (more than 10+ nodes). [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2806. doi:10.1158/1538-7445.AM2014-2806

Research paper thumbnail of Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells – A Review for the Clinician

New Advances in Stem Cell Transplantation, 2012

Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells-A Review for the Clinician 233... more Cryopreservation of Hematopoietic and Non-Hematopoietic Stem Cells-A Review for the Clinician 233 primarily focus on the recent developments in the field of cryopreservation of hematopoietic stem cells, but also outline some of the similarities and differences between the cryopreservation of HSCs and non-hematopoietic stem cells. 3. Processing prior to cryostorage 3.1 Liquid phase storage Several centers, particularly in remote rural settings rely on the performance of autologous bone marrow transplantation without a local croypreservation expertise. Along with that, umbilical cord blood processing is only performed in highly specialized cell processing facilities, which are often geographically remote from the place of collection. In such clinical settings, the initial cell collections have to be transported to a center with the necessary expertise in a liquid form (Fleming & A Hubel, 2006; Rodrigues et al., 2008). Liquid storage, either for transport purposes or to bridge a short time span prior to definitive clinical use has been successfully used for different clinical indications (Corato et al.,

Research paper thumbnail of The Stem Cell Continuum: A New Model of Stem Cell Regulation

Handbook of Experimental Pharmacology, 2006

Most models of hematopoiesis have been hierarchical in nature. This is based on a large volume of... more Most models of hematopoiesis have been hierarchical in nature. This is based on a large volume of correlative data. Recent work has indicated that, at least at the stem/progenitor level, hematopoiesis may, in fact, be a continuum of transcriptional opportunity. The most primitive hematopoietic stem cells are either continually cycling at a slow rate or entering and exiting cell cycle. Associated with this cycle passage are changes in functional phenotype including reversible alterations in engraftment, adhesion protein expression, cytokine receptor expression, homing to marrow, and progenitor cell numbers. Global gene expression, as measured in one point in cycle, is also markedly altered. The differentiation potential of the marrow as it transits cell cycle in response to a set differentiation stimulus also shows marked variations. This cycle-related plasticity has been clearly established for hematopoiesis. It also holds for the ability of murine marrow stem cells to home to lung and to convert to pulmonary cells. These data indicate that bone marrow stem cells can probably not be defined as discrete entities but must rather be studied on a population basis. They also indicate that mathematical modeling will become progressively more important in this field.

Research paper thumbnail of Eosinophilia secondary to strongyloides in Rhode Island

Medicine and health, Rhode Island, 2010

Research paper thumbnail of The marrow cell continuum: stochastic determinism

Folia histochemica et cytobiologica / Polish Academy of Sciences, Polish Histochemical and Cytochemical Society, 2005

Traditional models of hematopoiesis have been hierarchical in nature. Over the past 10 years, we ... more Traditional models of hematopoiesis have been hierarchical in nature. Over the past 10 years, we have developed data indicating that hematopoiesis is regulated in a continuum with deterministic and stochastic components. We have shown that the most primitive stem cells, as represented by lineage negative rhodamine(low) Hoechst(low) murine marrow cells are continuously or intermittently cycling as determined by in vivo BrdU labeling. When marrow stem cells are induced to transit cell cycle by in vitro exposure to cytokines, either IL-3, IL-6, IL-11, and steel factor or thrombopoietin, FLT3 ligand, and steel factor, they progress through cycle in a highly synchronized fashion. We have determined that when the stem cells progress through a cytokine stimulated cell cycle the homing, engraftment, adhesion protein, global gene expression, and hematopoietic differentiation phenotypes all change in a reversible fashion. This has led to the continuum model, in which, with cycle transit, chro...

Research paper thumbnail of The latest treatment advances for acute myelogenous leukemia

Medicine and health, Rhode Island, 2003

The research into pathogenesis and mechanisms behind AML is advancing rapidly, but in general, tr... more The research into pathogenesis and mechanisms behind AML is advancing rapidly, but in general, translation into global application for the majority of patients is wanting. As more becomes known about the cytogenetic and molecular characteristics of leukemia cells and the pathways of leukemogenesis are further elucidated, it is hoped that future therapies will be directed more specifically toward the least toxic method to eradicate clonal malignant cells. HLA-haploidentical and alloBMT using KIR mismatch may dramatically improve survival for many more patients.

Research paper thumbnail of Targeted T cell Therapy in Stage IV Breast Cancer: A Phase I Clinical Trial

Clinical cancer research : an official journal of the American Association for Cancer Research, Jan 16, 2015

This study reports a phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer c... more This study reports a phase I immunotherapy (IT) trial in 23 women with metastatic breast cancer consisting of eight infusions of anti-CD3 x anti-HER2 bispecific antibody (HER2Bi) armed anti-CD3 activated T cells (ATC) in combination with low dose interleukin 2 (IL-2) and granulocyte-macrophage-colony stimulating factor to determine safety, maximum tolerated dose (MTD), technical feasibility, T cell trafficking, immune responses, time to progression, and overall survival (OS). ATC were expanded from leukapheresis product using IL-2 and anti-CD3 monoclonal antibody and armed with HER2Bi. In 3+3 dose escalation design, groups of 3 patients received 5, 10, 20, or 40 x 10(9) armed ATC (aATC) per infusion. There were no dose limiting toxicities and the MTD was not defined. It was technically feasible to grow 160 x 10(9) ATC from a single leukapheresis. aATC persisted in the blood for weeks and trafficked to tumors. Infusions of aATC induced anti-breast cancer responses and increases in im...