261. Resistance to GH signalling through stat5 is an early event in PGF2α induced luteolysis in the ewe

2005 ◽  
Vol 17 (9) ◽  
pp. 106
Author(s):  
S. T. Anderson ◽  
D. H. L. Kusters ◽  
J. L. Barclay ◽  
J. D. Curlewis
Keyword(s):  
Western Blot ◽  
Corpus Luteum ◽  
Intramuscular Injection ◽  
Jugular Vein ◽  
Prolactin Receptor ◽  
Early Event ◽  
Control Groups ◽  
Pregnant Rats ◽  
Gh Receptor ◽  
Receptor Signalling

Recently we have shown that prostaglandin-induced luteolysis in pregnant rats involves resistance to prolactin-receptor signalling through the JAK2/STAT5 pathway.1 In the present study, we investigate whether PGF2alpha acts similarly to inhibit GH signalling in the ovine corpus luteum. The oestrous cycle of ewes was synchronised using cloprostenol and CIDR-G devices with oestrus detected by testosterone treated wethers with raddles. Twelve days after the first recorded oestrous mark, ewes were given an intramuscular injection of either saline or cloprostenol (125 µg), followed 1 h later with an intravenous injection (jugular vein) of either vehicle or 1.5 mg recombinant bovine GH (rbGH, Monsanto). After a further 15 min ewes were killed by pentobarbitone overdose and the corpus luteum removed. Tyrosine phosphorylation of STAT5 (STAT-P) in the corpus luteum was determined by immunoprecipitation and Western blot (n = 4 ewes/treatment). STAT5-P levels were relatively low in all ewes that were not treated with rbGH. Treatment with rbGH significantly (P < 0.01) increased STAT5-P in the corpus luteum of ewes pretreated with saline, compared to both control groups. However the STAT5-P response to rbGH was significantly (P < 0.01) reduced by the pretreatment with cloprostenol, although the response remained significantly (P < 0.05) higher than both control groups. In summary we have shown that (1) as expected, the GH-receptor signals through STAT5 in the ovine corpus luteum and (2) cloprostenol induces resistance to this GH-receptor signalling pathway. (1)Curlewis et al. (2002). Endocrinology 143, 3984–3993.

scholarly journals Prostaglandin F2α (PGF2α) and Prolactin Signaling: PGF2α-Mediated Inhibition of Prolactin Receptor Expression in the Corpus Luteum

Endocrinology ◽  
2003 ◽  
Vol 144 (8) ◽  
pp. 3301-3305 ◽  
Author(s):  
Carlos Stocco ◽  
Jean Djiane ◽  
Geula Gibori
Keyword(s):  
Corpus Luteum ◽  
Time Course ◽  
Prolactin Receptor ◽  
Prostaglandin F2α ◽  
Receptor Expression ◽  
Luteal Cell ◽  
Pregnant Rats ◽  
Prolactin Signaling ◽  
Stimulation Of

Abstract It is well established that prolactin (PRL) sustains, whereas prostaglandin F2α (PGF2α) curtails, progesterone production by the rodent corpus luteum (CL). We have previously shown that PGF2α inhibits the expression of several luteal genes stimulated by PRL, whereas it stimulates other genes inhibited by this hormone. We have also found that PGF2α stimulation of 20α-hydroxysteroid dehydrogenase (20αHSD), an enzyme that catabolizes progesterone, at the end of pregnancy is accompanied by a dramatic decrease in PRL receptor (PRL-R) expression. These findings, and the fact that the factors that inhibit PRL-R are not known, led us to examine in vivo whether the decline in PRL-R at the end of pregnancy is due to PGF2α and to also find out whether PGF2α opposes PRL action by inhibiting PRL-R expression. Using the PGF2α receptor (PGF2α-R) knockout, we examined whether the absence of the PGF2α-R prevents the decline in the expression of both the short and long forms of the PRL-R in the CL. We found that, in sharp contrast to the wild-type mice, in which both forms of the PRL-R decline to low levels between d 18–20 of pregnancy, expression of these receptors remained elevated in the PGF2α-R null mice. Furthermore, administration of PGF2α to pregnant rats inhibited PRL-R expression. Time-course analysis revealed that PGF2α treatment decreases both isoforms of PRL-R within 1 h of treatment in vivo, whereas its stimulatory effect on 20αHSD expression was further delayed. Similar results were obtained with luteinized granulosa cells in culture. To examine whether the decline in PRL-R is involved/necessary for PGF2α action, cells were transfected with a constitutively active PRL-R. The expression of this receptor did not prevent PGF2α effect on PRL-R or 20αHSD expression. Taken together, these results demonstrate that PGF2α inhibits the expression of the PRL-R and that the decline in both forms of the PRL-R that occurs at the end of pregnancy in the CL is due to PGF2α. The results further suggest that PGF2α-mediated stimulation of 20αHSD is independent from PGF2α inhibition of PRL signaling in luteal cell.

162 FERTILITY OF BEEF RECIPIENTS FOLLOWING A FIXED-TIME EMBRYO TRANSFER PROTOCOL WHICH INCLUDED FOLLICLE STIMULATING HORMONE DILUTED IN HYALURONAN

2013 ◽  
Vol 25 (1) ◽  
pp. 229
Author(s):  
J. W. Thorne ◽  
C. R. Looney ◽  
J. F. Hasler ◽  
D. K. Hockley ◽  
D. W. Forrest
Keyword(s):  
Corpus Luteum ◽  
Pregnancy Rate ◽  
Embryo Transfer ◽  
Transfer Rate ◽  
Animal Health ◽  
Fixed Time ◽  
Control Groups ◽  
Pfizer Animal Health ◽  
And Control ◽  
Estradiol 17Β

This study was performed to test the viability of administering Folltropin-V® (FSH, Bioniche Animal Health) diluted in hyaluronan (MAP-5 50 mg, sodium hyaluronate, Bioniche Animal Health) to beef cows enrolled in a recipient synchronization protocol to evaluate its effect on recipient fertility. All recipients were administered an estradiol 17β (2.5 mg, IM) and progesterone (50 mg, IM) combination injection on Day 0, a CIDR® (progesterone 1.34 g, Pfizer Animal Health, Groton, CT, USA) was inserted for 7 days. Lutalyse® (dinoprost tromethamine, Pfizer Animal Health, 25 mg, IM) was administered at the time of CIDR removal on Day 7, and estradiol 17β (1 mg, IM) was administered on Day 8. On Day 16, the presence of at least one corpus luteum, detected via ultrasound, resulted in the recipient receiving an embryo (both fresh and frozen–thawed embryos were used). Embryos were not transferred into cows that did not show ultrasonic evidence of a CL. Dependent variables for which data were collected included circulating progesterone levels at the time of transfer and CL diameter, area, and circumference; measured in millimeters. The total study (n = 274) consisted of both wet (n = 85) and dry (n = 189) cows and included both Bos indicus (Brahman-influenced) crossbred (n = 93) and Bos taurus (Angus-based) cows (n = 181). The experiment consisted of cows being placed in either the treated or control groups, with treated cows receiving a single 40 mg (1 mL) IM injection of Folltropin-V in hyaluronan on Day 5 and control cows receiving no additional injections. Results are shown in Table 1. Transfer rate, conception rate, and pregnancy rate were tested for significance with chi-square analysis and remaining statistics were analyzed with a t-test: two-sample assuming equal variances. There were no significant differences found between the treated and control groups for transfer rate, conception rate, or pregnancy rate. Corpus luteum diameter was shown to be larger in control cows (P < 0.05); however, CL area and circumference did not differ significantly. Folltropin-V given with hyaluronan at a 40-mg dose on Day 5 did not improve fertility, induce a larger CL, or increase circulating progesterone levels in synchronized beef recipients as hypothesized. Further work is needed with Folltropin-V in hyaluronan to determine if an alternative dose or timing of administration would be more appropriate for improving fertility in recipients. Table 1.Fertility data in beef recipients following synchronization for fixed-time embryo transfer with a protocol that included (Treated) or did not include (Control) FSH in hyaluronan

scholarly journals Can the Presence of Ovarian Corpus Luteum Modify the Hormonal Composition of Follicular Fluid in Mares?

Animals ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 646
Author(s):  
Katiuska Satué ◽  
Esterina Fazio ◽  
Pietro Medica
Keyword(s):  
Corpus Luteum ◽  
Follicular Fluid ◽  
Jugular Vein ◽  
Blood Samples ◽  
Follicle Diameter ◽  
New Knowledge ◽  
Hormonal Content ◽  
Follicle Size ◽  
Small Follicle

The hypothesis of this study was to investigate if the presence of corpus luteum (CL) in one ovary could modify the hormonal content of follicular fluid (FF) in the follicles. Sixty ovaries were taken after the slaughter of 30 clinically healthy mares. In relation to the sizes, the follicles were classified into three different categories, as small (20–30 mm), medium (31–40 mm) and large (≥41 mm). Blood samples were collected from the jugular vein of mares before their slaughter, and then the FF samplings were extracted from each single follicle. The ovaries that were collected were classified into two groups, according to the presence (CL-bearing) or absence (non-CL-bearing) of CL. The serum and FF samples were analysed for progesterone (P4), oestradiol-17β (E2), testosterone (T), androstenedione (A4) and dehydroepiandrosterone (DHEA). Intrafollicular P4 concentrations in large follicles of CL-bearing groups were lower than for non-CL-bearing ones. Intrafollicular E2 concentrations increased with the increase of the follicle diameter in both groups, CL-bearing and non-CL-bearing. However, in the FF with a large and medium follicle size, E2 concentrations were significantly higher in non-CL-bearing groups than in CL-bearing groups. T and A4 significantly increased in the large and medium follicle sizes when compared to the small follicle sizes in both groups, but higher concentrations in the non-CL-bearing group were obtained. Intrafollicular DHEA significantly decreased with the increase of the follicular diameter in both groups. Steroid hormones in FF dynamically changed, according to the presence or not of CL in the ovary. This study brings new knowledge on the role of the CL in the follicular hormonal composition in mares.

scholarly journals Participation of intraluteal progesterone and prostaglandin F2 alpha in LH-induced luteolysis in pregnant rat

1998 ◽  
Vol 156 (2) ◽  
pp. 253-259 ◽  
Author(s):  
CO Stocco ◽  
RP Deis
Keyword(s):  
Corpus Luteum ◽  
Dehydrogenase Activity ◽  
Subcutaneous Administration ◽  
Hydroxysteroid Dehydrogenase ◽  
Good Evidence ◽  
Pregnant Rats ◽  
Pregnant Rat ◽  
Prostaglandin F2 Alpha

We examined the participation of the intraluteal levels of progesterone (P4) and prostaglandin F2 alpha (PGF2 alpha) in the induction of luteolysis by LH and its relationship with the induction of the 20 alpha-hydroxysteroid dehydrogenase activity (20 alpha-HSD). Subcutaneous administration of four doses of 10 microgram ovine LH (oLH) at 0800, 0900, 1000 and 1100 h on day 19 of pregnancy induced a decrease in the activity of the enzyme 3 beta-HSD 24 and 48 h after treatment and an increase in luteal 20 alpha-HSD activity 48 h after oLH treatment when compared with control rats. Intraluteal and serum P4 levels were lower than control values 24 and 48 h after oLH treatment, with a significant increase in luteal PGF2 alpha content and a decrease in corpus luteum (CL) weight 48 h after oLH treatment. Intrabursal ovarian (i.b.) treatment with an inhibitor of PG's biosynthesis (diclofenac) (70 microgram/ovary) or P4 (3 microgram/ovary) on day 20 of pregnancy, prevented the increase in 20 alpha-HSD activity observed 48 h after oLH treatment, without any effect on 3 beta-HSD activity. The i.b. administration of P4 prevented the increase in intraluteal PGF2 alpha content induced by oLH treatment and the increases in 20 alpha-HSD activity and intraluteal PGF2 alpha content observed in control animals on day 21 of pregnancy. The inhibition of PG biosynthesis also prevents the decrease in intraluteal and serum P4 level induced by oLH. These results provide good evidence of the important participation of intraluteal P4 and PGF2 alpha on the oLH-induced luteolysis in pregnant rats. We also found the P4 produced by the CL is involved, in part, in the regulation of luteal PG synthesis. Thus, the early decline in 3 beta-HSD activity and the consequent fall in intraluteal P4 content, may trigger the synthesis of PGs and thereafter the increase in luteal 20 alpha-HSD activity to establish luteolysis.

scholarly journals Evidence that non-covalent forces, thiol and disulphide groups affect the structure and binding properties of the prolactin receptor on hepatocytes from pregnant rats

1985 ◽  
Vol 228 (2) ◽  
pp. 383-390 ◽  
Author(s):  
K Yamada ◽  
D B Donner
Keyword(s):  
Growth Hormone ◽  
Binding Capacity ◽  
Prolactin Receptor ◽  
Sodium Dodecyl ◽  
Specific Effect ◽  
Scatchard Analysis ◽  
Pregnant Rats ◽  
Receptor Complexes ◽  
Affinity Labelling ◽  
Triton X

Incubation of hepatocytes from pregnant rats with dithiothreitol decreased specific 125I-prolactin (125I-prl) binding to such cells by about 20% relative to control. This was not due to a non-specific effect of dithiothreitol on the cell membrane, since reduction also altered the binding of prl to solubilized partially purified receptor. Exposure of hepatocytes to N-ethylmaleimide (6 mM) for periods as brief as 1 min decreased the subsequent specific binding of 125I-prl by more than 50%. N-Ethylmaleimide was less effective as an inhibitor of binding when applied after hepatocytes had been exposed to 125I-prl, binding being decreased by about 15%. Scatchard analysis demonstrated that the effect of N-ethylmaleimide resulted from loss of receptor-binding capacity without any substantial effect on the affinity of the prl receptor for hormone. Dithiothreitol diminished the affinity of lactogenic sites for prolactin without altering cellular binding capacity. These observations suggest that thiol and disulphide groups are present in the prl receptor and that these functional moieties regulate the formation and properties of prl receptor complexes. The species to which 125I-prl had bound were identified by affinity labelling. 125I-prl was covalently coupled into saturable complexes of Mr 65000 and 50000. 125I-human growth hormone (125I-hGH) was covalently incorporated into complexes of Mr 300 000, 220 000, 130 000, 65 000 and 50 000. Bovine growth hormone (bGH), but not prl, competed for 125I-hGH uptake into the 300 000-, 220 000- and 130 000-Mr complexes, indicating that these species were somatogenic. Prl, but not bGH, inhibited 125I-hGH uptake into 65 000- and 50 000-Mr complexes. This demonstrated that 125I-hGH in the presence of bGH could affinity-label lactogenic receptors. 125I-prl aggregates in Triton X-100, whereas 125I-hGH does not. Therefore lactogenic complexes to which 125I-hGH was bound in the presence of excess bGH were solubilized in Triton X-100 and characterized sequentially by gel filtration and affinity labelling. Prl receptors were eluted from columns of Sepharose 6B as a species of Mr380 000. Fractionation of the 380 000-Mr species on sodium dodecyl sulphate polyacrylamide gels resulted in the isolation of complexes of Mr 65 000 and 50 000. Thus non-covalent forces stabilize aggregates of the monomeric prolactin receptor.

scholarly journals Anticancer Activity of Modified Tongyou Decoction on Eca109 Esophageal Cancer Cell Invasion and Metastasis through Regulation of the Epithelial-Mesenchymal Transition Mediated by the HIF-1α-Snail Axis

2020 ◽  
Vol 2020 ◽  
pp. 1-10
Author(s):  
Yongsen Jia ◽  
Xin Yan ◽  
Ying Cao ◽  
Wei Song ◽  
Guangji Zhang ◽  
...  
Keyword(s):  
Esophageal Cancer ◽  
Western Blot ◽  
Cell Invasion ◽  
Epithelial Mesenchymal Transition ◽  
Invasion And Metastasis ◽  
Control Groups ◽  
Transwell Assay ◽  
Scratch Assay ◽  
Mesenchymal Transition ◽  
Related Proteins

Background. To explore the activity of Modified Tongyou Decoction (MTD) against Eca109 esophageal cancer (EC) cell invasion and metastasis and to ascertain the mechanism of its anticancer activity during the epithelial-mesenchymal transition (EMT) as mediated by the HIF-1α-Snail axis. Methods. Herbal compounds were prepared by ethanol extraction, and 6 herbs composing into MTD were dipped in water-free ethanol and filtered. The filtrate was collected and centrifuged. The remains were concentrated into a paste which was adjusted to 5000mg/mL concentration with DMSO. PBS was used to dilute the herbal solution to the half maximal inhibitory concentration. A hypoxic microenvironment was induced with CoCl2 in RPMI 1640 medium, in which Eca109 cells were cultured. The cytotoxicity of MTD was determined with CCK-8 assay. The activity of MTD against cell invasion and metastasis was explored with scratch assay and transwell assay. Western blot analysis was conducted to analyze the anticancer effects of MTD on the expression of HIF-1α-Snail axis- and EMT-related proteins. Quantitative RT-PCR was used to assess the mRNA expression of Snail. Immunofluorescence labeling was performed to examine how MTD affected the coexpression of Snail and HIF-1α. Results. The fifty percent inhibitory dose of MTD was 1410 μg/mL in the normoxic environment and 1823 μg/mL in the hypoxic environment based on the CCK-8 assay. The scratch assay showed that MTD significantly inhibited cell migration in both the normoxic and hypoxic microenvironments compared with the control groups ( P  < 0.05). The transwell assay showed that MTD significantly inhibited cell invasion in both the normoxic and hypoxic environments compared with the control groups ( P  < 0.05). Western blot showed that MTD significantly inhibited the expression of the HIF-1α, Snail, Vimentin, MMP-2, MMP-9, and VE-cadherin proteins and significantly induced the expression of E-cadherin in both the normoxic and hypoxic microenvironments compared with the control groups ( P  < 0.05). qRT-PCR indicated that MTD significantly inhibited Snail mRNA expression compared with that in the control groups ( P  < 0.05). Immunofluorescence assay showed that MTD significantly inhibited the coexpression of HIF-1α and Snail in both the normoxic and hypoxic microenvironments compared with the control groups ( P  < 0.05). Conclusion. MTD downregulated HIF-1α-Snail axis- and EMT-related proteins to inhibit EC cell invasion and metastasis in both the normoxic and hypoxic environments.

scholarly journals Use of Carazolol at Pre-Synchronized Timed Artificial Insemination in Cows

2008 ◽  
Vol 77 (1) ◽  
pp. 59-64
Author(s):  
Ş. M. Pancarci ◽  
Y. Öztürkler ◽  
Ö. Güngör ◽  
C. Kaçar ◽  
S. Yildiz ◽  
...  
Keyword(s):  
Beneficial Effect ◽  
Corpus Luteum ◽  
Artificial Insemination ◽  
Adrenergic Receptor ◽  
Jugular Vein ◽  
Receptor Blocker ◽  
Transrectal Ultrasonography ◽  
Physiologic Saline ◽  
Timed Artificial Insemination ◽  
Rectal Palpation

Efficacy of the β-adrenergic receptor blocker (carazolol) at Timed Artificial Insemination (TAI) was investigated. Cows (n = 73) were pre-synchronized with two PGF2α injections given 14 d apart to initiate the Ovsynch protocol at early and middle luteal stages 14 d later, and received injections of GnRH and PGF2α seven d apart followed by GnRH 48 h later, and TAI 16 - 18 h later. Corpus luteum (CL) was detected via rectal palpation at the beginning of the Ovsynch protocol. Carazolol (Treatment I; n = 41) or physiologic saline (Treatment II; n = 32) were administered via jugular vein five min before TAI. Uterine tone was determined prior to infusion and at TAI via rectal palpation. Pregnancies were diagnosed with transrectal ultrasonography 40 ± 7 d after TAI. Uterine tone was 2.8 (1.4 - 5.3) times higher (P < 0.01) in Treatment I than that in Treatment II at TAI. Increase in uterine tone was affected by treatment × CL × parity (P < 0.05), and 66.7%, 75%, 52.6%, 100% and 16.7%, 33.3%, 25%, 28.6% in primiparous cows with CL and without CL, and in multiparous cows with CL and without CL in Treatments I and II, respectively. Pregnancy rates did not differ between treatments I (34.2%) and II (40.6%). In conclusion, no beneficial effect of carazolol administration prior to TAI was found except for the increased uterine tone.

Targeting Autophagy As a Therapeutic Strategy in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3950-3950 ◽  
Author(s):  
Houman Nourkeyhani ◽  
Den Haese P Jason ◽  
Portwood Scott ◽  
Diana Hanekamp ◽  
Megan Johnson ◽  
...  
Keyword(s):  
Cell Death ◽  
Acute Myeloid Leukemia ◽  
Western Blot ◽  
Cell Viability ◽  
Myeloid Leukemia ◽  
Control Groups ◽  
Hel Cells ◽  
Autophagy Pathway ◽  
Acute Myeloid ◽  
Time Point

Abstract Introduction: Autophagy is a process whereby cells digest their own organelles in conditions of stress, such as low nutrient concentration, hypoxia or exposure to chemotherapy. It is well established that acute myeloid leukemia (AML) cells presiding within a hypoxic microenvironment are markedly less sensitive to cytarabine chemotherapy than normoxic cells. We hypothesized that AML cells survive and mediate chemoresistance by invoking autophagy mediators, specifically light chain 3B protein (LC3B). LC3B is a key regulator in the fusion of autophagosomes and lysosomes, giving rise to autophagolysosomes. Methods: Human AML cells (HEL, HL60) were grown under normoxic (21% O2) and hypoxic (1% O2) conditions for 24-72 hours. Cells were treated with cytarabine chemotherapy and/or the autophagy inhibitors, bafilomycin A1 (Baf) and chloroquine (CQ). Viability was determined using trypan blue cell counting and tetrazolium dye MTT. Apoptosis and cell death were measured by flow cytometry for annexin-FITC and propidium iodide. Autophagy was assessed by flow cytometry using Cyto-ID Green Dye (Enzo Life Sciences), fluorescent microscropy for acridine orange dye accumulation, and western blot analysis. HEL cells were also transfected with an anti-LC3B siRNA and non-target sequences or anti-GAPDH siRNA as negative and positive controls, respectively. Real-time PCR with LC3B-specific probes, along with Western blotting with a rabbit anti-LC3B primary antibody, were performed to assess for changes in LC3B mRNA and protein levels. Results: Autophagy in human AML cell lines was significantly increased following 24-72 hours of low oxygenation (1% O2) as compared with normoxia and was a predominantly late response to prolonged hypoxia (> 48 hours). We determined that AML cells exposed to chronic hypoxia were able to overcome an initial growth restriction with a corresponding increase in LC3B levels by Western blotting. Treatment of AML with ARA-C under hypoxia resulted in further dose-dependent increases in autophagic vesicles in AML cells consistent with enhanced autophagy induction. In contrast, exposure of hypoxic HEL cells to the autophagy inhibitors (Baf, CQ), led to arrest in autophagic flux (via higher levels of the LC3BII isoform expression as compared with LC3B I) and decreased autophagic vesicle density (as measured by fluorescent microscopy for acridine orange). Combination treatment with autophagy inhibitors (Baf, CQ) and ARA-C chemotherapy significantly enhanced apoptosis and cell death of AML cells under hypoxia as compared with single agent therapy. To further confirm these effects were LC3B dependent, we used anti-LC3B versus nonspecific siRNA to knockdown protein expression in HEL cells. HEL cells with anti-LC3B siRNA exhibited markedly decreased cell viability under prolonged hypoxia as compared to control siRNA transfected cells. Cells also demonstrated enhanced cell death following ARA-C treatment under hypoxia with the most pronounced effects ranging from 48h up to 72h from the start of treatment (Figure 1). Conclusions: Our experiments demonstrate that the autophagy pathway is upregulated in human AML cells under hypoxic conditions and likely confers a rescue pathway under such conditions to promote leukemia survival. Using pharmacological inhibitors of autophagy and anti-LC3B siRNA technology, we show that targeting the autophagy pathway can render hypoxic AML cells more susceptible to cell death and enhance sensitivity to cytarabine chemotherapy. These preclinical results show promise for further exploring autophagy as a therapeutic target in acute myeloid leukemia. Figure A: Graph showing decreased cell viability and increased chemosensitivity in the anti-LC3B siRNA-treated HEL-Luc cells. This effect is not as pronounced in the control groups, and is most pronounced after the 48h time point. B: Western blot showing LC3B protein knockdown compared to control groups Figure. A: Graph showing decreased cell viability and increased chemosensitivity in the anti-LC3B siRNA-treated HEL-Luc cells. This effect is not as pronounced in the control groups, and is most pronounced after the 48h time point. / B: Western blot showing LC3B protein knockdown compared to control groups Disclosures Scott: Immunogen: Research Funding. Wang:Immunogen: Research Funding; Incyte: Speakers Bureau.

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