• mice treated with tamoxifen exhibit a dosage and frequency dependent lethality dieing by 16 months unlike in mice lacking cre expression

• all mice develop tumors in the juxta-articular region in the limbs with some evidence of calcification

• following tamoxifen treatment, all mice develop tumors in the juxta-articular region in the limbs with some evidence of calcification

• mice develop synovial sarcomas

• following tamoxifen treatment, mice develop synovial sarcomas

• hematopoietic stem and progenitor cells (HSPCs) of mice treated with tamoxifen do not exhibit a selective advantage over cells not expressing the modified cDNA (J:158953)

• the total number of HSPCs is normal in irradiated mice (J:158953)

• following irradiation, the proportion of GFP+ cells in the hematopoietic stem and progenitor cell compartment and myeloid and lymphoid lineages of tamoxifen-treated mice is increased compared to un-irradiated mice

• GFP+ cell accumulation occurs whether mice are treated with tamoxifen 2 or 7 days after irradiation

• however, no competitive advantage is observed when mice are treated with tamoxifen and 5-fluorouracil without DNA damage or over similarly treated Cdkn2a^tm2.1Rdp cells in irradiated chimera experiments

• all tamoxifen-treated mice develop sarcomas of the skin or muscle connective tissue after 10 to 19 weeks

• 2 tamoxifen-treated mice develop large intestinal tumors resembling undifferentiated fibrosarcomas

• tamoxifen-treated mice develop muscle fibrosis at 10 to 19 weeks of age

• tamoxifen-treated mice develop skin fibrosis at 10 to 19 weeks of age

• after 15 weeks, tamoxifen-treated mice exhibit intestinal fibrosis

• tamoxifen-treated mouse embryonic fibroblasts exhibit cell cycle arrest after 6 days in culture unlike wild-type cells

• in MEFs at later time points after OHT treatment and serum addition cells develop large aberrant nuclei with frequent micronuclei

• in MEFS after OHT treatment and serum addition increases in the population of cells with 4N and 8N DNA content are seen

• live cell imaging indicates a median 8 h delay in mitotic entry in MEFS after OHT treatment and serum addition compared to controls

• in MEFS after OHT treatment and serum addition more cells are in prophase and most of these show an early prophase phenotype

• in MEFS after OHT treatment and serum addition almost no cells in metaphase, anaphase, and telophase are detected

• in MEFS after OHT treatment and serum addition cells in prometaphase have a monopolar spindle with closely adjacent chromosomes, the presence of these monopolar spindles activates the spindle checkpoint

• in MEFS 28 h after OHT treatment and serum addition the percent of cells positive for PH3 is increased about 3 fold compared to controls

• however, the timing of the peak in PH3 positive cells is similar to controls

• growth defect in MEFs following OHT treatment and serum addition

• at E12.5, following tamoxifen treatment at E8.5, mice display an expansion of the cortical hem and a reduction in dorsal telencephalon

• at E12.5, following tamoxifen treatment at E8.5, mice display an expansion of the cortical hem and a reduction in dorsal telencephalon

• treatment with tamoxifen at E10.5 results in subtle to inapparent abnormalities in the cortical hem at E12.5

• naive CD4+ T cells release more interferon gamma than controls after cre-mediated deletion of Rnasen induced by tamoxifen treatment

• deficient CD4+ T cells are capable of differentiating into Th1 or Th2 cells

• tamoxifen-treated mouse embryonic fibroblasts exhibit decreased DNA-damage signaling via Trp53, Cdkn1a and Chek1 compared to wild-type cells

• after 3 to 4 days in culture tamoxifen-treated mouse embryonic fibroblasts (MEFs) arrest with 2N or 4N DNA content and exhibit reduced S and M phase unlike wild-type MEFs

• after 3 to 4 days in culture tamoxifen-treated mouse embryonic fibroblasts (MEFs) exhibit a flattened senescence-like morphology unlike wild-type MEFs

• tamoxifen-treated mouse embryonic fibroblasts exhibit decreased DNA-damage signaling via Trp53, Cdkn1a and Chek1 compared to wild-type cells

• following injection of tamoxifen at E10.5 most embryonic cells appear to be in prometaphase

• following injection of tamoxifen at E10.5 embryos show a 4 fold increase in PH3 positive cells in the thymus and lungs compared to controls

• following injection of tamoxifen at E10.5 about a 3 fold increase in the percentage of apoptotic cells in the thymus and lungs is seen

• adult mice administered with tamoxifen die 9-21 days after a single injection

• tamoxifen treated females show a shorter survival span than males

• tamoxifen treated mutants show signs of illness such as slow movements, weight loss, pale paws, and low pO2 levels from 8-10 days after tamoxifen injection

• pulmonary arteries and veins are dilated

• high vascular permeability

• uterus shows signs of arteriovenous malformations in tamoxifen treated mutants

• mutants bearing excisional wounds on the dorsal skin and ear and treated with tamoxifen form arteriovenous shunts in the blood vessels near the wounds

• arteriovenous malformations in the GI tract of tamoxifen treated mutants are located in the Peyer's patches of small intestine and appendix

• in tamoxifen treated mutants

• in tamoxifen treated mutants

• tamoxifen treated mutants show signs of hemorrhages in the lungs

• arteriovenous malformations in the GI tract of tamoxifen treated mutants are located in the Peyer's patches of small intestine and appendix

• tamoxifen treated mutants exhibit darkened feces indicative of the presence of blood

• tamoxifen treated mutants exhibit reduced hematocrit

• in tamoxifen treated mutants

• pulmonary arteries and veins are dilated

• high vascular permeability

• tamoxifen treated mutants show signs of hemorrhages in the lungs

• hematopoietic stem and progenitor cells of irradiated mice treated with tamoxifen do not exhibit a selective advantage over cells not expressing the modified cDNA (J:158953)

• hematopoietic stem and progenitor cells of irradiated mice treated with tamoxifen do not exhibit a selective advantage over cells not expressing the modified cDNA (J:158953)

• most females that develop lymphomas die at about 9 weeks post-4OHT injection

• all mutants die from tumor burden by 45 weeks post-4OHT injection

• treatment of mice with 4OHT at 6 weeks of age to induce cre-mediated recombination results in tumor formation with a mean latency of 17 weeks

• multiple tumors are seen in 27.3% of 4OHT-treated mice

• 46.1% of females develop endometrial cancer after 4OHT treatment

• 40% incidence of lymphomas in males after 4OHT treatment

• lymphomas mainly arise from the thymus and mesenteric lymph nodes

• 76.9% incidence of lymphomas in females after 4OHT treatment

• all lymphomas are derived from CD3+ T-cells with either a mature appearance of small lymphocytes or large lymphoblasts

• about 50% of males and females exhibit malignant tumors at 21 weeks and 10-11 weeks after 4OHT treatment, respectively

• 10% of males and 15.4% of females develop squamous cell carcinoma of the epidermis after 4OHT treatment

• 35% of males develop intestinal cancer after 4OHT treatment, arising from the colorectum and small intestine

• 20% of males develop prostate cancer after 4OHT treatment (J:130367)

• prostate intraepithelial neoplasm (PIN) is observed at 4-6 weeks post 4-OHT treatment (J:130367)

• males develop small or large intestinal polyps at more than 35 weeks post 4OHT treatment

• prostate hyperplasia is observed at 4-6 weeks post 4-OHT treatment (J:130367)

• prostate hyperplasia is observed at 4-6 weeks post 4-OHT treatment (J:130367)

• most females develop endometrial hyperplasia at between 7 and 9 weeks post 4-OHT treatment (J:130367)

• 10% of males and 15.4% of females develop squamous cell carcinoma of the epidermis after 4OHT treatment

• in the small intestine and colon following tamoxifen treatment

• following tamoxifen treatment, enterocyte proliferation in the small intestine and colon is decreased compared to in wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells unlike in wild-type mice

• 24 hours following tamoxifen treatment, the Paneth cell compartment is expanded compared to in wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells compared to in wild-type mice

• tamoxifen-treated mice lack normal goblet cells unlike wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells compared to in wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells compared to in wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells compared to in wild-type mice

• 24 hours following tamoxifen treatment, the Paneth cell compartment is expanded compared to in wild-type mice

• 3 days following tamoxifen treatment, mice show loss of normal goblet cells, acute inflammatory infiltrates in the lamina propria, and further expansion of the Paneth cells compared to in wild-type mice

• in the small intestine and colon following tamoxifen treatment

• following tamoxifen treatment, enterocyte proliferation in the small intestine and colon is decreased compared to in wild-type mice

• after tamoxifen treatment, the external granule cell layer is much thinner than that of control littermates

• after tamoxifen treatment, the layer is depleted of cycling immature precursors

• no cycling granule neuron precursor cells are detected in the external granule cell layer 10 days after tamoxifen treatment

• 10 days after tamoxifen treatment

• 10 days after tamoxifen treatment most mice have atrophic cerebella

• no cycling granule neuron precursor cells are detected in the external granule cell layer 10 days after tamoxifen treatment

• ectopic masses show numerous mitotic granule neuron precursors 10 days after tamoxifen treatment

• 10 days after tamoxifen treatment, neoplastic and preneoplastic lesions in which the external granule layer lacks the normal layered structure develop in the external layer of the cerebellum

• hypertrophic 10 days after tamoxifen treatment

• 10 days after tamoxifen treatment, neoplastic and preneoplastic lesions in which the external granule layer lacks the normal layered structure develop in the external layer of the cerebellum

• ectopic masses show numerous mitotic granule neuron precursors 10 days after tamoxifen treatment

• GFP+ hematopoietic stem and progenitor cells (HSPC) from irradiated mice transplanted into irradiated mice reconstitute the HSPC population exhibit a competitive advantage over HSPC from untreated mice compared with cells from similarly irradiated wild-type mice

• 6 months after tamoxifen treatment, mice develop intestinal disease and eventually die or are sacrificed

• tamoxifen-treated mice exhibit partial or complete fibrosis of the small intestine and cecum unlike in wild-type mice with increased submucosal connective tissue and proportional increase in fibroblast-like cells and collagenous matrix

• tamoxifen-treated mice exhibit partial or complete fibrosis of the small intestine and cecum unlike in wild-type mice with increased submucosal connective tissue and proportional increase in fibroblast-like cells and collagenous matrix

• tamoxifen-treated mice exhibit partial or complete fibrosis of the small intestine and cecum unlike in wild-type mice with increased submucosal connective tissue and proportional increase in fibroblast-like cells and collagenous matrix

• in tamoxifen-treated mice

• in tamoxifen-treated mice

• sclerotic glomeruli in tamoxifen-treated mice

• in tamoxifen-treated mice

• enlarged glomeruli in tamoxifen-treated mice

• in tamoxifen-treated mice

• at between 44 and 76 weeks of age, 5 of 29 tamoxifen-treated mice develop sarcomas arising from dermis or muscle connective tissue

• in tamoxifen-treated mice

• around the bronchioles in tamoxifen-treated mice

• in tamoxifen-treated mice

• following treatment with tamoxifen, cultured tracheal ciliated epithelium exhibits no ciliary activity likely due to a lack of outer dynein arms unlike similarly treated wild-type samples

• however, epithelium morphology and number of ciliated cells are normal following treatment with tamoxifen

• tamoxifen-treated mice exhibit chronic rhinosinusitis unlike wild-type mice

• however, no lung inflammation develops in tamoxifen-treated mice

• after 3 months, tamoxifen-treated mice exhibit absent mucociliary clearance in the nasopharynx and a 50% decreased in the trachea compared with wild-type mice

• after 6 months, 3 of 4 tamoxifen-treated mice exhibit no mucociliary clearance in the trachea while 1 of 4 mice exhibit a substantial reduction in clearance compared with similarly treated wild-type mice

• after 7.5 months, tamoxifen-treated mice exhibit no mucociliary clearance in the trachea compared with similarly treated wild-type mice

• tamoxifen-treated mice exhibit chronic rhinosinusitis unlike wild-type mice

• however, no lung inflammation develops in tamoxifen-treated mice

• despite ciliary defects, tamoxifen-treated mice exhibit no evidence hydroencephaly (J:155730)

• when cre expression is induced with a tamoxifen-containing diet (400 mg/kg of chow), mice die by day 9 post-introduction of tamoxifen

• during the initial 3 days after cre induction by tamoxifen, all mice show decrease in body weight due to decreased food intake, but whereas controls regain recover some weight, experimental mice do not

• mice show a cumulative loss of body weight compared to controls following cre induction, but energy intake (cumulative food intake) is similar to controls

• without induction of cre by tamoxifen treatment, animals are indistinguishable from controls (J:164406)

• increased fat oxidation after induction is basis for increased weight loss

• following cre induction, animals exhibit a decreased respiratory exchange ratio (RER) indicative of pure fat oxidation compared to controls by day 6

• inspection of animals dying after cre induction by tamoxifen shows loss of body fat in these mice

• analyses of carcasses show significant decreases in whole body fat mass, but not lean mass

• increased fat oxidation after induction is basis for increased weight loss

• energy intake on day 7 is significantly higher than on day 1 after cre induction

• during the initial 3 days after cre induction by tamoxifen, all mice show decrease in body weight due to decreased food intake, but whereas controls regain recover some weight, experimental mice do not

• following cre induction, animals exhibit a decreased respiratory exchange ratio (RER) indicative of pure fat oxidation compared to controls by day 6

• inspection of animals dying after cre induction by tamoxifen shows loss of body fat in these mice

• analyses of carcasses show significant decreases in whole body fat mass, but not lean mass

• following tamoxifen-treatment, mouse embryonic fibroblasts (MEFs) exhibit impaired chemotaxis in response to HMGB1 compared with wild-type cells

• however, chemotaxis in response to PDGF is normal and chemotaxis is rescued by over expression of Nfkb2

• following tamoxifen-treatment, MEFs exhibit random migration in response to an HMGB1 gradient unlike wild-type cells

• 30 to 60 minutes after exposure to HMGB1, tamoxifen-treated MEFs exhibit reduced migration velocity compared with wild-type mice

• mice treated with tamoxifen after neurogenesis (at E10.5) exhibit normal motor pool formation (J:178550)

• mice treated with tamoxifen at E8.5 exhibit delayed motor neuron formation compared with control mice

• at E12.5, mice treated with tamoxifen at E8.5 exhibit fewer Isl1/2+ and vasti, adductor longus and magnus, and posterior gracilis muscle motor neurons compared with control mice

• at E14.5, mice treated with tamoxifen at E8.5 exhibit fewer Isl1/2+ and vasti muscle motor neurons compared with control mice

• however, motor neurons in adductor longus and magnus and posterior gracilis muscles recover by E14.5

• mice treated with tamoxifen at E8.5 exhibit delayed motor neuron formation compared with control mice

• at E18.5 in mice treated with tamoxifen at E12.5 or E13.5

• PFN in adults displays nearly complete loss of alkaline phosphatase expressing Fzd5-null neurons by 10 days after 4HT injection and cre activation, but no loss is observed in Fzd5^tm2Nat/+, cre-positive control PFNs 8 days after 4HT treatment

• all mice die within 2 weeks of the 4th injection of tamoxifen (4 injections administered over an 8 day period)

• starting after 3 injections of tamoxifen in mice at 6 - 9 months of age

• becomes significant 1 week after the 4th injection of tamoxifen

• 1 week after the last tamoxifen injection

• enhanced lipid peroxidation and impaired electron transport chain activity and ATP production in mitochondria 1 week after the last tamoxifen injection

• seen in tamoxifen treated mice shortly before death

• elevated astrocyte activation in the hippocampal region 1 week after the last tamoxifen injection

• in the hippocampal region 1 week after the last tamoxifen injection

• 1 week after the last tamoxifen injection

• 4 of 9 tamoxifen-treated mice exhibit intestinal fibrosis

• in one tamoxifen-treated mouse

• sclerotic glomeruli in tamoxifen-treated mice

• enlarged glomeruli in tamoxifen-treated mice

• in tamoxifen-treated mice

• in tamoxifen-treated mice

• in some tamoxifen-treated mice