Bone Marrow Transplantation Generates Immature Oocytes and Rescues Long-Term Fertility in a Preclinical Mouse Model of Chemotherapy-Induced Premature Ovarian Failure

2007 ◽  
Vol 25 (22) ◽  
pp. 3198-3204 ◽  
Author(s):  
Ho-Joon Lee ◽  
Kaisa Selesniemi ◽  
Yuichi Niikura ◽  
Teruko Niikura ◽  
Rachael Klein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mouse Model ◽  
Cancer Patients ◽  
Immune Cells ◽  
Cell Tracking ◽  
Ovarian Function ◽  
Coat Color ◽  
Female Cancer Patients ◽  
The Impact

Purpose Although early menopause frequently occurs in female cancer patients after chemotherapy (CTx), bone marrow (BM) transplantation (BMT) has been linked to an unexplained return of ovarian function and fertility in some survivors. Studies modeling this in mice have shown that BMT generates donor-derived oocytes in CTx-treated recipients. However, a subsequent report claimed that ovulated eggs are not derived from BM and that BM-derived oocytes reported previously are misidentified immune cells. This study was conducted to further clarify the impact of BMT on female reproductive function after CTx using a preclinical mouse model. Methods Female mice were administered CTx followed by BMT using coat color-mismatched female donors. After housing with males, the number of pregnancies and offspring genotype were recorded. For cell tracking, BM from germline-specific green fluorescent protein-transgenic mice was transplanted into CTx-treated wild-type recipients. Immune cells were sorted from blood and analyzed for germline markers. Results BMT rescued long-term fertility in CTx-treated females, but all offspring were derived from the recipient germline. Cell tracking showed that donor-derived oocytes were generated in ovaries of recipients after BMT, and two lines of evidence dispelled the claim that these oocytes are misidentified immune cells. Conclusion These data from a preclinical mouse model validate a testable clinical strategy for preserving or resurrecting ovarian function and fertility in female cancer patients after CTx, thus aligning with recommendations of the 2005 National Cancer Institute Breast Cancer Progress Review Group and President's Cancer Panel to prioritize research efforts aimed at improving the quality of life in cancer survivors.

scholarly journals The impact of socio-demographic factors on the survival of cancer patients in Zimbabwe

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Idika E. Okorie ◽  
Ricardo Moyo ◽  
Saralees Nadarajah
Keyword(s):  
Risk Factors ◽  
Survival Analysis ◽  
Marital Status ◽  
Cancer Patients ◽  
Hazard Rate ◽  
Significant Risk ◽  
Demographic Factors ◽  
Female Cancer Patients ◽  
Socio Demographic Factors ◽  
The Impact

AbstractWe provide a survival analysis of cancer patients in Zimbabwe. Our results show that young cancer patients have lower but not significant hazard rate compared to old cancer patients. Male cancer patients have lower but not significant hazard rate compared to female cancer patients. Race and marital status are significant risk factors for cancer patients in Zimbabwe.

The Impact of Age and Gender on Hematopoietic Stem Cells and Immune Contexture of the Bone Marrow Microenvironment

2020 ◽  
pp. 1-6
Author(s):  
Rebar N. Mohammed
Keyword(s):  
Stem Cells ◽  
Bone Marrow ◽  
Hematopoietic Stem Cells ◽  
Immune Cells ◽  
Absolute Number ◽  
Cell Number ◽  
Hematopoietic Stem ◽  
The Absolute ◽  
And Gender ◽  
The Impact

Hematopoietic stem cells (HSCs) are a rare population of cells that reside mainly in the bone marrow and are capable of generating and fulfilling the entire hematopoietic system upon differentiation. Thirty-six healthy donors, attending the HSCT center to donate their bone marrow, were categorized according to their age into child (0–12 years), adolescence (13–18 years), and adult (19–59 years) groups, and gender into male and female groups. Then, the absolute number of HSCs and mature immune cells in their harvested bone marrow was investigated. Here, we report that the absolute cell number can vary considerably based on the age of the healthy donor, and the number of both HSCs and immune cells declines with advancing age. The gender of the donor (male or female) did not have any impact on the number of the HSCs and immune cells in the bone marrow. In conclusion, since the number of HSCs plays a pivotal role in the clinical outcome of allogeneic HSC transplantations, identifying a younger donor regardless the gender is critical.

Long-term Follow-up of Bladder Cancer Patients with Disseminated Tumour Cells in Bone Marrow

2011 ◽  
Vol 60 (2) ◽  
pp. 231-238 ◽  
Author(s):  
Margitta Retz ◽  
Jens Rotering ◽  
Roman Nawroth ◽  
Alexander Buchner ◽  
Michael Stöckle ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bladder Cancer ◽  
Cancer Patients ◽  
Tumour Cells ◽  
Long Term Follow Up ◽  
Disseminated Tumour Cells

scholarly journals Clinical and Oncological Value of Preoperative BMI in Gastric Cancer Patients: A Single Center Experience

2015 ◽  
Vol 2015 ◽  
pp. 1-8 ◽  
Author(s):  
Costantino Voglino ◽  
Giulio Di Mare ◽  
Francesco Ferrara ◽  
Lorenzo De Franco ◽  
Franco Roviello ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Cancer Patients ◽  
Blood Proteins ◽  
Term Survival ◽  
Long Term Survival ◽  
Single Center Experience ◽  
Group B ◽  
Gastric Cancer Patients ◽  
The Impact

Introduction. The impact of preoperative BMI on surgical outcomes and long-term survival of gastric cancer patients was investigated in various reports with contrasting results.Materials & Methods. A total of 378 patients who underwent a surgical resection for primary gastric cancer between 1994 and 2011 were retrospectively studied. Patients were stratified according to BMI into a normal group (<25, group A), an overweight group (25–30, group B), and an obesity group (≥30, group C). These 3 groups were compared according to clinical-pathological characteristics, surgical treatment, and long-term survival.Results. No significant correlations between BMI and TNM (2010), UICC stage (2010), Lauren’s histological type, surgical results, lymph node dissection, and postoperative morbidity and mortality were observed. Factors related to higher BMI were male genderP<0.05, diabetesP<0.001, and serum blood proteinsP<0.01. A trend to fewer lymph nodes retrieved during gastrectomy with lymphadenectomy in overweight patients (B and C groups) was observed, although not statistically significant. There was no difference in overall survival or disease-specific survival between the three groups.Conclusion. According to our data, BMI should not be considered a significant predictor of postoperative complications or long-term result in gastric cancer patients.

scholarly journals The impact of the loco-regional treatment in elderly breast cancer patients: Hypo-fractionated exclusive radiotherapy, single institution long-term results

The Breast ◽  
2010 ◽  
Vol 19 (5) ◽  
pp. 413-416 ◽  
Author(s):  
Cyrus Chargari ◽  
Youlia M. Kirova ◽  
Fatima Laki ◽  
Alexia Savignoni ◽  
Thierry Dorval ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Cancer Patients ◽  
Long Term Results ◽  
Breast Cancer Patients ◽  
Single Institution ◽  
The Impact ◽  
Regional Treatment

Replicative Senescence-Associated Gene Expression Changes In Human MSPCs Independent of Genomic Variations

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4775-4775
Author(s):  
Katharina Schallmoser ◽  
Christina Bartmann ◽  
Eva Rohde ◽  
Simone Bork ◽  
Christian Guelly ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Culture ◽  
Bone Marrow ◽  
Large Scale ◽  
Replicative Senescence ◽  
Genomic Stability ◽  
The State ◽  
Efficient Treatment ◽  
The Impact

Abstract Abstract 4775 Background: Based on promising experimental studies with mesenchymal stem and progenitor cells (MSPCs) multiple clinical trials have been initiated. In previous studies we have observed genomic stability of MSPCs after efficient short-term expansion in a humanized GMP compliant system with pooled human platelet lysate (pHPL) replacing fetal bovine serum (FBS) as the cell culture supplement (Schallmoser K. and Strunk D., Journal of Visualized Experiments (32) DOI: 10.3791/1523, 2009). Notably, depending on culture protocols, an extensive propagation with highly variable cell culture duration may be necessary to yield enough MSPCs for therapy. The decline in proliferation rates of MSPCs in the course of the different long-term expansion procedures may indicate a propensity for replicative senescence which may hamper long term functionality in vivo. We have therefore initiated a molecular profiling of senescence-associated regulated genes to determine the state of senescence before MSPC transplantation. Methods: Human bone marrow-derived MSPCs were cultured following a highly efficient two-passage protocol (primary culture of unseparated bone marrow and subsequent large scale expansion; Schallmoser K. et al., Tissue Engineering 14:185-196, 2008) compared to conventional serial passaging in three different growth conditions with regularly more then four passages to obtain comparable final cell numbers. Culture media were either supplemented with FBS in different concentrations or pHPL. Gene expression changes were tested by microarray analysis and selected targets were reanalyzed by quantitative real-time PCR. The genomic stability of MSPCs after long-term culture was determined by array comparative genomic hybridization (CGH). Results: Despite high proliferation rate large scale expanded MSPCs showed genomic stability in array CGH. Long-term MSPC growth induced similar gene expression changes in MSPCs irrespective of isolation and expansion conditions. In particular, genes involved in cell differentiation, apoptosis and cell death were up-regulated, whereas genes involved in mitosis and proliferation were down-regulated. Furthermore, overlapping senescence-associated gene expression changes were found in all MSPC preparations. The genomic copy number variations detected in MSPCs of early and late passages in all culture conditions did not coincide with differentially expressed genes. Conclusion: Our data indicate that MSPC expansion can induce gene expression changes independent of isolation and FBS-supplemented as well as FBS-free expansion conditions. A panel of genes will be presented that might offer a practicable approach to assess MSPC quality with regard to the state of replicative senescence in advance of therapeutic application. Determining the impact of senescence acquired during cell expansion on the therapeutic potential of MSCPs for both immune modulation and organ regeneration may help to develop more efficient treatment strategies. Disclosures: No relevant conflicts of interest to declare.

Conditioning Intensity and T Cell Dose Determine Efficacy of CD19-Targeted T Cell-Mediated Tumor Eradication in an Immunocompetent Mouse Model of B-ALL.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2613-2613
Author(s):  
Marco L Davila ◽  
Christopher Kloss ◽  
Renier J Brentjens ◽  
Michel Sadelain
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Mouse Model ◽  
B Cell ◽  
Immunocompetent Mouse ◽  
Cell Dose ◽  
Conditioning Intensity

Abstract Abstract 2613 Recent work by our group and others demonstrates the therapeutic potential of CD19-targeted T cells to treat patients with indolent B cell malignancies. These studies make use of T cells that are genetically engineered with chimeric antigen receptors (CARs) comprising an scFv fused to various T cell activating elements. Whereas firs-generation CARs only direct T cell activation, second-generation CARs include two signal elements, such as CD3z and CD28 signaling domains (19–28z). We and our colleagues at MSKCC are currently evaluating the safety of 19–28z-transduced T cells in patients with acute leukemia (B-ALL) in a Phase I protocol (NCT01044069). Pre-clinical studies performed to date have mostly relied on xenogeneic models utilizing immunodeficient animals, which enable the evaluation of human engineered T cells but do not recapitulate all the interactions that may affect tumor eradication by CAR-modified T cells. We have therefore developed a pre-clinical immunocompetent mouse model of B-ALL, and addressed therein the impact of conditioning and T cell dose on the eradication of leukemia by syngeneic, CAR-targeted T cells. To establish an immunocompetent mouse model of B cell leukemia, we generated a clone from the lymph node of an Eμ-myc B6 transgenic mouse. The immunophenotype and gene-expression profile of clone Eμ-ALL01 is consistent with a progenitor B cell origin. Syngeneic B6 mice inoculated with this clone develop florid acute leukemia and die approximately 2–4 weeks after injection from progressive bone marrow infiltration. We created an anti-mouse CD19 CAR comprising all murine elements, including the CD8 signal peptide, a CD19-specific single chain variable fragment, the CD8 transmembrane region, and the CD28 and CD3z signaling domains. Transduction of the murine 19–28z CAR into mouse T cells was robust and successfully retargeted the T cells to B cells. In vitro assays demonstrated that m19–28 z transduced T cells mediated effective killing of CD19-expressing target cells and the production of effector cytokines such as IFNγ and TNFα. Cyclophosphamide either alone or in combination with control syngeneic T cells is insufficient to eradicate established Eμ-ALL01 in B6 mice. However, treatment with cyclophosphamide and m19–28z-transduced T cells cured nearly all mice. Mice sacrificed six months after treatment exhibited a dramatic reduction of B cells in the bone marrow (BM), blood, and spleen. The few remaining B lineage cells found in the BM had a phenotype consistent with early pro-B cells, suggesting that endogenous reconstitution of the B cell compartment was thwarted by persisting, functional m19–28z+ T cells. Thus, T cells are retained at the site of antigen expression, which is maintained through regeneration of progenitor B cells. The persisting CD19-targeted T cells in the BM exhibited a cell surface phenotype consistent with effector and central memory cells. Using B cell aplasia as a surrogate endpoint for assessing in vivo T cell function and persistence, we evaluated how conditioning chemotherapy and T cell dose determine the level of B cell depletion induced by adoptively transferred CD19-targeted T cells. Overall, increasing the cyclophosphamide or T cell dose, increased the degree and duration of B cell depletion and the number of persisting CAR-modified T cells. Significantly, increasing the T cell dose at a set cyclophosphamide level had a lesser impact than increasing the conditioning intensity for a given T cell dose. In summary, the new Eμ-ALL01 syngeneic, immunocompetent B-ALL model we describe here is a valuable tool for modeling CD19 CAR therapies. Our results indicate that m19–28z transduced T cells are effective at eradicating B-ALL tumor cells and persist long-term, preferentially in bone marrow. Our findings further establish that conditioning intensity and T cell dose directly determine B cell elimination and long-term T cell persistence. These studies in mice will serve as an important framework to further model and perfect our studies in patients with B-ALL. Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document