scholarly journals Treatment of Bone Marrow Cancer Based on Model Predictive Control

2021 ◽  
Vol 1 (4) ◽  
pp. 463-476
Author(s):  
Ehsan Salajegheh ◽  
Sepide Mojalal ◽  
Ali Mojarrad Ghahfarokhi
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Model Predictive Control ◽  
Predictive Control ◽  
Blood Cells ◽  
The Body ◽  
Spongy Tissue ◽  
Osteoblast Cells ◽  
Femur Bone ◽  
Tumor Growth Model

Bone marrow is a spongy tissue that contains stem cells that are found inside some bones, including the hip and femur. Bone marrow cancer is a type of cancer that is caused by stem cells that make up the blood cells in the bone marrow. Sometimes these cells grow too fast or abnormally, which is called bone marrow cancer. Bone tissue cells are mainly composed of osteoblasts and osteoclasts. Osteoblast cells constantly build new bone throughout the life of each bone, and other cells called osteoclasts constantly absorb pieces of bone, so the bone is constantly being renewed. In this paper, mathematical models of tumors, the effect of the body on the drug, and the drug on the body are introduced, and then the appropriate dose of the drug to reduce tumor density is calculated using the model predictive control (MPC) algorithm. To obtain an adaptive MPC strategy, the extended least squares (ELS) method developed to learn the parameters of the tumor growth model is used. Finally, the simulation in MATLAB, assuming the model is correct, shows that the tumor is gone, and the bone mass improves over a period of time. The results demonstrate that the proposed method is effective for the treatment of bone marrow cancer.

A comparison of murine T-cell–depleted adult bone marrow and full-term fetal blood cells in hematopoietic engraftment and immune reconstitution

Blood ◽  
2002 ◽  
Vol 99 (1) ◽  
pp. 364-371 ◽  
Author(s):  
Benny J. Chen ◽  
Xiuyu Cui ◽  
Gregory D. Sempowski ◽  
Maria E. Gooding ◽  
Congxiao Liu ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
Cord Blood ◽  
Blood Cells ◽  
Immune Reconstitution ◽  
Full Term ◽  
Fetal Blood ◽  
Adult Bone

Umbilical cord blood has been increasingly used as a source of hematopoietic stem cells. A major area of concern for the use of cord blood transplantation is the delay in myeloid and lymphoid recovery. To directly compare myeloid and lymphoid recovery using an animal model of bone marrow and cord blood as sources of stem cells, hematopoietic engraftment and immune recovery were studied following infusion of T-cell–depleted adult bone marrow or full-term fetal blood cells, as a model of cord blood in a murine allogeneic transplantation model (C57BL/6 [H-2b] → BALB/c [H-2d]). Allogeneic full-term fetal blood has poorer radioprotective capacity but greater long-term engraftment potential on a cell-to-cell basis compared with T-cell–depleted bone marrow. Allogeneic full-term fetal blood recipients had decreased absolute numbers of T, B, and dendritic cells compared with bone marrow recipients. Splenic T cells in allogeneic full-term fetal blood recipients proliferated poorly, were unable to generate cytotoxic effectors against third-party alloantigens in vitro, and failed to generate alloantigen-specific cytotoxic antibodies in vivo. In addition, reconstituting T cells in fetal blood recipients had decreased mouse T-cell receptorδ single-joint excision circles compared with bone marrow recipients. At a per-cell level, B cells from fetal blood recipients did not proliferate as well as those found in bone marrow recipients. These results suggest that full-term fetal blood can engraft allogeneic hosts across the major histocompatibility barrier with slower hematopoietic engraftment and impaired immune reconstitution.

scholarly journals Direct evidence that natural killer cells in nonimmune spleen cell populations prevent tumor growth in vivo

1979 ◽  
Vol 149 (5) ◽  
pp. 1260-1264 ◽  
Author(s):  
M Kasai ◽  
JC Leclerc ◽  
L McVay-Boudreau ◽  
FW Shen ◽  
H Cantor
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Tumor Growth ◽  
Nk Cells ◽  
Spleen Cell ◽  
Cell Population ◽  
The Body ◽  
Nk Activity

Relatively large numbers of nonimmune spleen cells do not protect against the local growth of two lymphomas. However, this heterogeneous population of splenic lymphocytes contains a subset of cells that efficiently protects against in vivo tumor growth. This cell population (cell-surface phenotype Thyl.2(-)Ig(-)Ly5.1(+)) represents less than 5 percent of the spleen cell population and is responsible for in vitro NK-mediated lysis. Although these studies clearly and directly demonstrate that Ly5(+) NK cells selected from a heterogeneous lymphoid population from nonimmune mice can protect syngeneic mice against local in vivo growth of two different types of tumor cells (in contrast to other lymphocyte sets within the spleen), they do not directly bear upon the role of NK cells in immunosurveillance. They do indicate that highly enriched Ig(-)Thyl(-)Ly5(+) cells, which account for virtually all in vitro NK activity, can retard tumor growth in vivo. It is difficult to ascribe all anti-tumor surveillance activity to NK cells, because they probably do not recirculate freely throughout the various organ systems of the body. Perhaps NK ceils may play a role in prevention of neoplastic growth within discrete anatomic compartments where there is rapid differentiation of stem cells to mature progeny (e.g., bone marrow, spleen, and portions of the gastrointestinal tract)and may normally act to regulate the growth and differentiation of non-neoplastic stem cells. Long-term observation of chimeric mice repopulated with bone marrow from congenic or mutant donors expressing very low or very high NK activity may help to answer these questions.

scholarly journals Quantification and three-dimensional microanatomical organization of the bone marrow

2017 ◽  
Vol 1 (6) ◽  
pp. 407-416 ◽  
Author(s):  
Cesar Nombela-Arrieta ◽  
Markus G. Manz
Keyword(s):  
Bone Marrow ◽  
Blood Cells ◽  
Structural Organization ◽  
Imaging Techniques ◽  
White Blood Cells ◽  
Three Dimensional ◽  
The Body ◽  
Cellular Composition ◽  
Spatial Logic ◽  
Health And Disease

Abstract Bone marrow (BM) constitutes one of the largest organs in mice and humans, continuously generating, in a highly regulated manner, red blood cells, platelets, and white blood cells that together form the majority of cells of the body. In this review, we provide a quantitative overview of BM cellular composition, we summarize emerging knowledge on its structural organization and cellular niches, and we argue for the need of multidimensional approaches such as recently developed imaging techniques to uncover the complex spatial logic that underlies BM function in health and disease.

scholarly journals A review of the treatment landscape in paroxysmal nocturnal haemoglobinuria: where are we now and where are we going?

2020 ◽  
Vol 1 ◽  
pp. 263300402095934
Author(s):  
Morag Griffin ◽  
Richard Kelly ◽  
Alexandra Pike
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Life Expectancy ◽  
Red Blood Cells ◽  
Blood Cells ◽  
Treatment Options ◽  
White Blood Cells ◽  
Paroxysmal Nocturnal Haemoglobinuria ◽  
Complement Cascade ◽  
Future Treatments

Paroxysmal nocturnal haemoglobinuria (PNH) is an ultra-orphan disease, which until 15 years ago had limited treatment options. Eculizumab, a monoclonal antibody that inhibits C5 in the terminal complement cascade, has revolutionised treatment for this disease, near normalising life expectancy and improving quality of life for patients. The treatment landscape of PNH is now evolving, with ravulizumab a second longer acting intravenous C5 inhibitor now licenced by the FDA and EMA. With different therapeutic targets in the complement cascade and difference modalities of treatment, including subcutaneous, oral and intravenous therapies being developed, increasing independence for patients and reducing healthcare requirements. This review discusses the current and future therapies for PNH. Lay summary Review of current and future treatments for patients with Paroxysmal Nocturnal Haemoglobinuria What is Paroxysmal Nocturnal Haemoglobinuria? Paroxysmal nocturnal haemoglobinuria (PNH) is a very rare disease. It arises from PNH stem cells in the bone marrow. In a normal bone marrow these are inactive; however, if there has been a problem in the bone marrow, the PNH stem cells can expand and make PNH red blood cells, white blood cells and platelets. The problem with these cells is that they lack the cell surface markers that usually protect them. Red blood cells are broken down in the circulation rather than the spleen, which gives rise to PNH symptoms such as abdominal pain, difficulty swallowing, erectile dysfunction and red or black urine (known as haemoglobinuria). The white blood cells and platelets are ‘stickier’ increasing the risk of blood clots. Previously life expectancy was reduced as there were limited treatment options available. What was the aim of this review? To provide an overview of current and future treatment options for PNH Which treatments are available? • Eculizumab is an treatment given through a vein (intravenous) every week for 5 weeks then every 2 weeks after this, and has been available for 13 years, improving life expectancy to near normal. • Ravulizumab is a newer intravenous treatment similar to eculizumab but is given every 8 weeks instead of every 2 weeks. In clinical studies it was comparable with eculizumab. • Future Treatments - There is new research looking at different methods of treatment delivery, including injections under the skin (subcutaneous) that patients can give themselves, treatments taken by mouth (oral) or a combination of an intravenous and oral treatment for those patients who are not optimally controlled on eculizumab or ravulizumab. What does this mean? PNH is now treatable. For years, the only drug available was eculizumab, but now different targets and drug trials are available. Ravulizumab is currently the only second licenced product available, in USA and Europe, there are other medications active in clinical trials. Why is this important? The benefit for patients, from treatment every 2 weeks to every 8 weeks is likely to be improved further with the development of these new treatments, providing patients with improved disease control and independence. As we move into an era of more patient-friendly treatment options, the PNH community both physicians and patients look forward to new developments as discussed in this article.

Mesenchymal Stem Cells from the Wharton’s Jelly of Umbilical Cord Segments Support the Maintenance of Long Term Culture-Initiating Cells from Cord Blood.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3650-3650
Author(s):  
Kent W. Christopherson ◽  
Tiki Bakhshi ◽  
Shamanique Bodie ◽  
Shannon Kidd ◽  
Ryan Zabriskie ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Mesenchymal Stem Cells ◽  
Hematopoietic Stem Cells ◽  
Cord Blood ◽  
Umbilical Cord ◽  
Blood Cells ◽  
Hematopoietic Stem ◽  
Cord Blood Cells

Abstract Hematopoietic Stem Cells (HSC) are routinely obtained from bone marrow, mobilized peripheral blood, and umbilical Cord Blood. Traditionally, adult bone marrow has been utilized as a source of Mesenchymal Stem Cells (MSC). Bone marrow derived MSC (BM-MSC) have previously been shown to maintain the growth of HSC obtained from cord blood and have been utilized for cord blood expansion purposes. However, the use of a mismatched BM-MSC feeder stromal layer to support the long term culture of cord blood HSC is not ideal for transplant purposes. The isolation of MSC from a novel source, the Wharton’s Jelly of Umbilical Cord segments, was recently reported (Romanov Y, et al. Stem Cells.2003; 21: 105–110) (Lee O, et al. Blood.2004; 103: 1669–1675). We therefore hypothesized that Umbilical Cord derived MSC (UC-MSC) have the ability to support the long term growth of cord blood derived HSC similar to that previously reported for BM-MSC. To test this hypothesis, MSC were isolated from the Wharton’s Jelly of Umbilical Cord segments and defined morphologically and by cell surface markers. UC-MSC were then tested for their ability to support the growth of pooled CD34+ cord blood cells in long term culture - initiating cell (LTC-IC) assays as compared to BM-MSC. We observed that like BM-MSC, CB-MSC express a defined set of cell surface markers. By flow cytometry we determined that that both UC-MSC and BM-MSC are positive for CD29, CD44, CD73, CD90, CD105, CD166, HLA-A and negative for CD45, CD34, CD38, CD117, HLA-DR expression. Utilizing Mitomycin C treated (200 μM, 15 min.) UC-MSC from multiple donors as a feeder layer we observed that UC-MSC have the ability to support the maintenance of long term hematopoiesis during the LTC-IC assay. Specifically, UC-MSC isolated from separate umbilical cord donors support the growth of 69.6±11.9 (1A), 31.7±3.9 (2B), 67.0±13.5 (3A), and 38.5±13.7 (3B) colony forming cells (CFC) per 1×104 CD34+ cord blood cells as compared to 64.0±4.2 CFC per 1×104 CD34+ cord blood cells supported by BM-MSC (Mean±SEM, N=4 separate segments from three different donors). Thus, Umbilical Cord derived Mesenchymal Stem Cells, a recently described novel source of MSC, have the ability to support long term maintenance of Hematopoietic Stem Cells, as defined by the LTC-IC assay. These results may have potential therapeutic application with respect to ex vivo stem cell expansion of Cord Blood Hematopoietic Stem Cells utilizing a Mesenchymal Stem Cell stromal layer. In addition, these data suggest the possibility of co-transplantation of matched Mesenchymal and Hematopoietic Stem Cells from the same umbilical cord and cord blood donor respectively. Lastly, these results describe a novel model system for the future study of the interaction between Cord Blood Hematopoietic Stem Cells and the appropriate supportive microenvironment represented by the Umbilical Cord - Mesenchymal Stem Cells.

Modeling CML Development and Drug Resistance Using iPSC Technology,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3767-3767
Author(s):  
Kran Suknuntha ◽  
Yuki Ishii ◽  
Kejin Hu ◽  
Jean YJ Wang ◽  
Igor Slukvin
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Drug Resistance ◽  
Stem Cell ◽  
Blood Cells ◽  
Kinase Activity ◽  
Hematopoietic Cells ◽  
Patient Specific ◽  
Hematopoietic Progenitors ◽  
Abl Kinase

Abstract Abstract 3767 Reprogramming of neoplastic cells to pluripotency provides a unique tool to personalize the exploration of tumor pathogenic mechanisms and drug resistance using iPSCs with patient-specific chromosomal abnormalities. We have developed a technology to generate transgene-free iPSCs from bone marrow and cord blood cells employing episomal vectors. Using this approach we created transgene-free iPSCs from a patient with CML in the chronic phase. CMLiPSCs showed a unique complex chromosomal translocation identified in the patinet's marrow sample while displaying typical embryonic stem cell phenotype and pluripotent differentiation potential. Importantly, these CMLiPSCs are devoid of genomic integration and expression of reprogramming factors, which are incompatible for modeling tumor development and drug response (Hu et al. Blood 117:e109). We have also shown that these CMLiPSCs contain the BCR-ABL oncogene without any detectable mutations in its kinase domain. By coculture with OP9, we generated APLNR+ mesodermal cells, MSCs, and lin-CD34+CD45+ hematopoietic progenitors from CMLiPSCs, and control BMiPSCs from a normal subject and analyzed the levels of BCR-ABL protein and tyrosine-phosphorylated (pTyr) cellular proteins in the different cell populations. The highest level of BCR-ABL protein expression was found in the in undifferentiated iPSCs, however, the overall cellular pTyr levels was lower than the control BMiPSCs, suggesting that BCR-ABL kinase activity was suppressed in the CMLiPScs. Consistent with these findings, imatinib does not inhibit the growth and survival of these CMLiPSCs. The levels of BCR-ABL protein decreased upon differentiation with a major reduction observed when cells became mesoderm. Following differentiation of CMLiPSC-derived mesoderm into the MSCs and lin-CD34+CD45+ hematopoietic progenitors, the levels of BCR-ABL protein did not change significantly, indicating that the major epigenetic regulation of BCR-ABL expression occurs during the transition to mesoderm. In spite of the decrease in BCR-ABL expression, the total pTyr levels significantly increased following transition of CMLiPSCs to mesoderm and blood cells, suggesting recovery of BCR-ABL kinase activity during differentiation. Interestingly, we found that imatinib had no effect on CFC potential of the most primitive lin-CD34+CD45+ hematopoietic progenitors derived from CMLiPSCs, while significant inhibition in hematopoietic CFC potential was observed when we used the patient's bone marrow cells. Following expansion of lin-CD34+CD45+ progenitors in serum-free medium with cytokines, we found that more differentiated hematopoietic cells became imatinib sensitive. The differential response of progenitors versus more differentiated cells to imatinib recapitulate the clinical observation that CML stem cells display innate resistance to imatinib but their differentiated progenies become sensitive to this BCR-ABL kinase inhibitor. The iPSC-based models provide several advantages for the study of CML pathogenesis. iPSCs can provide an unlimited supply of hematopoietic cells carrying patient-specific genetic abnormalities. Using well-defined temporal windows and surface markers, distinct cell subsets with tumor-initiating/tumor-propagating potential after transplantation in immunodeficient mice could be identified and used for drug screening. iPSC models make it possible to address CML stem-cell potential at various stages of differentiation for which it may be difficult to obtain samples from the patient, for example, at the hemangioblast stage. They also provide a unique opportunity to explore the interplays between epigenetics and oncogene function, as we have demonstrated using the CMLiPSCs. The major unsolved question is why CML stem cells are naturally resistant to imatinib, and this question can be addressed using the iPS system. Disclosures: Slukvin: CDI: Consultancy, Equity Ownership.

Sparc Is Dispensable for Murine Hematopoiesis, Despite Its Suspected Role in 5q- Myelodysplastic Syndrome

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4822-4822
Author(s):  
Kavitha Siva ◽  
Pekka Jaako ◽  
Kenichi Miharada ◽  
Emma Rörby ◽  
Mats Ehinger ◽  
...  
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Knockout Mice ◽  
Peripheral Blood ◽  
Blood Cells ◽  
Lethal Dose ◽  
Wild Type ◽  
Hematopoietic Stem ◽  
Normal Peripheral Blood ◽  
Expression Levels

Abstract Abstract 4822 Hematopoiesis is a complex process where a limited number of stem cells give rise to all mature blood cells. It involves interplay of several factors, many of which are yet to be identified. In a search for novel regulators of hematopoiesis, we chose to study SPARC (Secreted Protein Acidic and Rich in Cysteine, also known as Osteonection and BM40) because it is downregulated upon hematopoietic differentiation (Bruno et al., Mol Cell Biol, 2004) and might therefore play a role in the regulation of hematopoietic stem cells (HSC). SPARC is a matricellular protein that forms a major component of bone and is ubiquitously expressed in a variety of tissues. It is the founding member of a family of SPARC-like proteins. Several publications have indicated an important role for SPARC in hematopoiesis. In particular – knockdown of SPARC in zebrafish embryos resulted in an altered number of circulating blood cells, and a knockout mouse model showed thrombocytopenia and reduced erythroid colony formation. We carried out an in depth phenotypic and functional analysis of the hematopoietic system of SPARC knockout mice; using it as a model to gain insight into the role of SPARC in hematopoiesis. These mice are viable and fertile but show severe osteopenia and age-onset cataract at about six months of age. They also show an altered response to tumour growth and wound healing. We used mice (129SVJ background) (Gilmour et al. EMBO, 1998) that were less than six months old. These mice had normal peripheral blood counts and the bone marrow and spleen showed no alterations in morphology or cellularity. A detailed phenotypic analysis of precursors within the bone marrow showed no significant differences in myelo-erythroid precursors as compared to wild types (n=6). Though in vitro, the precursors showed lower ability to form BFU-E (n=5, p=0.048). In transplantations of lethally irradiated recipient mice, SPARC knockout cells gave rise to multi-lineage long-term reconstitution. Also, when competed with wild type cells, they provided reconstitution as well as their wild type counterparts. When SPARC knockout mice (n=8) were transplanted with wild type cells, there was normal reconstitution, indicating that a SPARC deficient niche can fully support normal hematopoiesis. We also tested if SPARC deficient mice respond differently to hematopoietic stress. We subjected mice (n=7) to sub lethal dose of irradiation and to experimentally induced anemia (n=7) and followed recovery by analyzing peripheral blood counts. In both SPARC knockouts and wild type mice, the blood counts recovered in a similar fashion. In conclusion, we find that SPARC is dispensable for murine hematopoiesis. It is possible that there are compensatory mechanisms involving other members of the SPARC family that ultimately lead to normal hematopoiesis in the murine model. In humans, SPARC maps to the deleted region in 5q MDS and has been reported to be 71 % down regulated in patient samples (Lehmann et al. Leukemia, 2007). It is the most prominent gene that is up regulated in response to lenalidomide, a drug that inhibits the malignant clone (Pellagatti et al. PNAS, 2007). SPARC is thus increasingly speculated to be involved in the pathophysiology of this hematopoetic disease. We analysed the expression levels of SPARC mRNA in the hematopoietic stem/progenitor cell compartment and found high expression levels in the CD34+ fraction of human cord blood cells. In contrast, there is very low level of SPARC expression in all compartments of murine HSCs. Therefore SPARC function may play a more important role in human hematopoiesis than in murine blood cell regulation. Disclosures: No relevant conflicts of interest to declare.

Fetal Liver-Derived Stem Cells Ameliorate Immune Functions in Leptin Receptor-Deficient Mice

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5417-5417
Author(s):  
Ming Li ◽  
Yasushi Adachi ◽  
Susumu Ikehara
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Body Weight ◽  
Leptin Receptor ◽  
Conflicts Of Interest ◽  
Fetal Liver ◽  
The Body ◽  
Immune Functions ◽  
Glucose Levels ◽  
Blood Glucose Levels

Abstract Fetal liver (FL) contains hepatic stem cells, hematopietic stem cells, and mesenchymal stem cells, as well as pluripotent stem cells and very small embryonic-like stem cells. FL has thus been available as a source of stem cells for regenerative medicine. Our previous report suggested that combining FL cell transplantation with the transplantation of fetal thymus prevented tumor growth in tumor-bearing mice. Moreover, in animal models, intra bone marrow-bone marrow transplantation (IBM-BMT) has proven to be the best approach for allogenic BMT. We here propose that transplanting FL cells by IBM-BMT can improve immune functions in leptin receptor-deficient (db/db) mice. FL cells were collected from FLs of C57BL/6 mice at 16 days post coitum, and then transplanted by IBM-BMT to leptin receptor deficent mice, an animal model of type 2 diabetes with obesity. Our results showed that the body weight was significantly lowered in the treated db/db mice than in the sham-treated db/db mice. The plasma IL-6 level significantly decreased and adiponectin level significantly increased after the transplantation of FL cells. Blood glucose levels also significantly decreased although not to within the normal range. This is the first report that the transplantation of FL cells may improve immune function, resulting in increased adiponectin levels, and decreased body weight in db/db mice. Disclosures No relevant conflicts of interest to declare.

Model Predictive Control Application to Flexible-Bodied Railway Vehicles for Vibration Suppression

2013 ◽  
Vol 10 ◽  
pp. 25-35
Author(s):  
P.E. Orukpe
Keyword(s):  
Model Predictive Control ◽  
Predictive Control ◽  
High Speed ◽  
Ride Comfort ◽  
The Body ◽  
Ride Quality ◽  
Linear Matrix ◽  
Railway Vehicle ◽  
Railway Vehicles ◽  
Effective Manner

In this paper, we apply model predictive control (MPC) based on mixed H2/H to active vibration control of the flexibility of railway vehicle to improve ride quality. However, the flexibility in the body of high-speed railway vehicles creates difficulties which in practice may result in the body structure being heavier than what it is supposed to be. The use of active suspension helps to model the vehicle and its flexibility in an effective manner. Conventional control approaches are compared with linear matrix inequality MPC technique using flexible-bodied railway vehicle as an example. The result indicates that the MPC technique performs better in improving ride comfort compared to the passive and classical techniques when flexible modes are present.

Sign in / Sign up

Export Citation Format

Share Document