Статті в журналах з теми "Seminal interleukin 8"

ABSTRACTAnin vitromodel of bacterial biofilms on rigid gas-permeable contact lenses (RGPLs) was developed to challenge oral epithelial cells. This novel model provided seminal data on oral biofilm-host cell interactions, and with selected bacteria, the biofilms were more effective than their planktonic counterparts at stimulating host cell responses.

Objective: to estimate the effect of ejaculate consistency on the levels of interleukin-6 and interleukin-8 in human seminal plasma. Material and methods. The concentration of interleukin-6 and interleukin-8 was determined by ELISA using the kit manufactured by «Vector-Best» (Russia). The study included 64 men: the main group (n = 30) presents patients with high semen viscosity, the comparison group (n = 34) presents men with normal semen viscosity. Results. In average, interleukin-6 level in the semen was 13.45 pg/ml, the median was 13.79 pg/ml; the data ranged from 8.24 pg/ml to 19.34 pg/ml. In average, level of interleukin-8 was 28.9 pg/ml, the median – 13.96 pg/ml; there is a large range of values from 0.202 pg/ml to 174.5 pg/ml. There are no significant differences in the values of interleukin-6 and interleukin-8 of the main group from the comparison group: for interleukin-6, U = 377.0 (p = 0.074655); for interleukin-8, U = 407.0 (p = 0.863852). The data obtained did not correlate neither between groups nor with the fertility markers of the human semen.<br>Conclusion. Interleukin-6 and interleukin-8 levels in the human seminal plasma do not depend on semen viscosity.

Exposure to semen at intercourse in women elicits an inflammation-like response characterised by recruitment of inflammatory cells and expression of pro-inflammatory cytokines including GM-CSF, interleukin-6 (IL-6) and IL-8 (1). Studies in animal models have implicated TGFβ as the major active moiety in seminal plasma, and we have shown previously that TGFβ1 and TGFβ3 are present in high concentrations in human seminal plasma (>100 ng/mL), while TGFβ2 is less abundant. To investigate the physiological significance of each of the three TGFβ isoforms as pro-inflammatory agents in human seminal plasma, we have established in vitro model systems to measure human cervical cell cytokine synthesis. Primary cervical epithelial cells prepared from ectocervix of hysterectomy tissues or transformed Ect1 cells were incubated for 12 h with human recombinant TGFβ (isoforms 1, 2 or 3) or with seminal plasma in the presence or absence of isoform-specific TGFβ neutralising antibodies. Epithelial cell supernatants were recovered 24 h later and supernatants were analysed by commercial ELISA to quantify GM-CSF, IL-6 and IL-8 production. Each of the three TGFβ isoforms mimicked seminal plasma and were comparable in their capacity to stimulate >10-fold increases in both GM-CSF and IL-6 expression in a dose-responsive manner. In contrast, unlike seminal plasma none of the TGFβ isoforms induced IL-8 expression. Addition of neutralising antibodies to TFGβ1, TGFβ2 and TGFβ3 each effected >50% reduction in the ability of seminal plasma to induce GM-CSF and IL-6, but did not impair seminal plasma-stimulated IL-8 production. Together these data show that TGFβ1, TGFβ2 and TGFβ3 are major active constituents of seminal plasma, acting to elicit GM-CSF and IL-6 production in cervical epithelial cells. However, TGFβ does not fully account for the pro-inflammatory effects of human seminal plasma, and other active constituents remain to be identified. (1) D. J. Sharkey et al. (2003) Proc. SRB.

The present study evaluates the efficacy of a combination of soyabean extracts associated with Curcuma Longa, Boswellia, Pinus pinaster and Urtica dioica (PROSTAFLOG®) in patients affected by CP/CPPS, through the evaluation of interleukin-8 (IL-8) plasma seminal levels. All patients diagnosed with CP/CPPS, attending the same urologic center, were enrolled in this randomized, controlled phase III study. Participants were randomized to receive oral capsules of PROSTAFLOG® (two capsules at bedtime every 24 h) or Ibuprofen 600 mg (1 tablet daily), lasting for a period of four weeks. NIH-CPSI and SF-36 questionnaires, as urological evaluations with a transrectal ultrasound (TRUS), the Meares–Stamey test, and IL-8 dosage in seminal plasma were performed at baseline and at 3 months follow-up. A total of 77 patients (mean age of 34.5 ± 6.1) were enrolled (PROSTAFLOG® (n = 39); ibuprofen (n = 38)) in the study. At 3 months, in the PROSTAFLOG® series, 69.2% of patients showed a significant reduction in the NIH-CPSI score, compared with 34.2% in the ibuprofen group (p < 0001). The mean IL-8 levels were significantly lower in the PROSTAFLOG® cohort compared with the ibuprofen series (p < 0.0001), while a significant reduction in the IL-8 level between the enrolment and last follow-up evaluation was also observed in this group (p < 0.0001). Additionally, a significant reduction in the volume of the seminal vesicles assessed by TRUS was also found in the PROSTAFLOG® series during the observational timeframe (18.3 ± 7.1 mL vs. 11.2 ± 2.4 mL (p < 0.0001). In conclusion, PROSTAFLOG® significantly improves the QoL in patients affected by CP/CPPS and it provides a significant reduction in IL-8 seminal levels as the overall seminal vesicles volume.

This randomized controlled trial was conducted to examine the effects of 24 weeks of combined aerobic and resistance exercise training on seminal markers of inflammation and oxidative stress as well as markers of male reproductive function and reproductive performance in infertile patients. Of a total of 1296 infertile patients (aged 25–40 years) who were screened, 556 were randomly assigned to exercise (n = 278) and nonexercise (n = 278) groups. Semen samples were taken before and at 12 and 24 weeks as well as 7 and 30 days post-intervention. The training program reduced seminal proinflammatory cytokines (interleukin (IL)-1β, IL-6, IL-8, and tumor necrosis factor alpha) and markers of oxidative stress (reactive oxygen species, malondialdehyde, and 8-isoprostane) (P < 0.05). Additional improvements were also achieved in seminal antioxidant defense system (superoxide dismutase, catalase, and total antioxidant capacity) (P < 0.05). Training-induced changes in inflammation and oxidative stress status correlated with favorable improvements in semen parameters, sperm DNA integrity, and pregnancy rate (P < 0.05). In conclusion, these results support the evidence for the favorable effects of combined aerobic and resistance exercise training in male factor infertility.

The aim of the study was to evaluate the parameters of oxidative stress and antioxidant defense in relation to the levels of proinflammatory cytokines and chemokines in patients diagnosed with oligozoospermia and asthenozoospermia. Based on the basic parameters of the spermogram, the examined group (n=243) was divided into three groups: oligospermic group (sperm count less than 15 × 106/ml) consisting of 152 men, astenozoospermic group (less than 40% of progressively moving sperm cells) consisting of 142 men, and oligoastenozoospermic group (both criteria met) consisting of 90 men. The control group consisted of 103 males with normal semen profile according to the WHO criteria. Total superoxide dismutase (SOD) activity in seminal plasma and spermatozoa lysate was significantly lower by 12% and 22%, respectively, in males with oligospermia than in the control group. Analogically, Mn-SOD activity in spermatozoa lysate was significantly lower in males with oligospermia, asthenospermia, and oligoasthenospermia by 44%, 32%, and 45%, respectively. By contrast, CuZn-SOD activity in spermatozoa lysate was significantly higher in males with oligospermia by 60%. The activity of glutathione peroxidase (GPx) in seminal plasma was also significantly higher in males with oligospermia and oligoasthenospermia by 56% and 78%, respectively. The level of malondialdehyde (MDA) in seminal plasma was significantly higher in males with asthenospermia than in the control group by 12%. By contrast, the level of MDA in spermatozoa lysate was significantly lower in males with oligospermia, asthenospermia, and oligoasthenospermia by 26%, 20%, and 26%, respectively. The level of interleukin- (IL-) 8 in seminal plasma was significantly higher in males with asthenospermia and oligoasthenospermia by 64% and 67%, respectively. Abnormalities in spermogram, such as oligospermia, asthenospermia, and oligoasthenospermia, may be related to a decreased activity of Mn-SOD in spermatozoa and increased levels of chemokines in seminal plasma.

Abstract Bull fertility is highly influential to profits of cow-calf production; however, bulls often experience various planes of nutrition throughout the year. These changes may influence the composition of the ejaculate and their ability to get females pregnant. We hypothesized that differing nutritional planes would affect the cytokines concentration in the seminal plasma of bulls. Mature angus bulls (n = 12) were individually housed and randomly assigned to one of two treatments: 1) over-fed (n = 6) or 2) restricted (n = 6). Bulls were fed the same ration (35% ground hay, 35% cracked corn, 20% distillers’ grain and 10% soybean meal) at differing volumes to achieve desired nutritional planes. Body weight and BCS were taken every two weeks to monitor nutritional planes. Blood and ejaculate were collected once a month to determine cytokine profiles within seminal plasma. Statistical analyses were conducted with GLIMMIX procedure of SAS with bull within treatment as a random effect and time as a repeated measure to determine if nutrition level, time and the interaction influenced seminal plasma cytokine concentration. There were no significant time or treatment×time interactions for any cytokine concentrations. Interferon-γ tended to be increased (P &lt; 0.10) in restricted bulls (3.21±0.95 pg/mL) compared with over-fed bulls (0.64±0.95 pg/mL). The concentrations of IL-8 also tended to be increased (P &lt; 0.10) in restricted (318.89±66.42 pg/mL) compared with over-fed bulls (158.02±66.42 pg/mL). Interleukin-1β in over-fed bulls (24.77±17.51 pg/mL) tended to be decreased (P &lt; 0.10) compared with restricted bulls (65.8±17.51 pg/mL). Interleukin-10 tended to be greater (P &lt; 0.10) in restricted (17.95±2.29 pg/mL) than in the over-fed bulls (12.41±2.29 pg/mL). The concentration of VEGF-A was greater (P &lt; 0.05) in restricted bulls (3,551.28±224.49 pg/mL) than over-fed bulls (2,715.72±224.49 pg/mL). In conclusion, cytokine concentrations were elevated by restricted nutritional levels which could impact the ability of the ejaculate to stimulate uterine gene expression and establish pregnancy.

Background. Cytokines are involved in almost every aspect of reproduction and recent studies suggested a relationship between cytokines and male/female infertility. In the present study, the levels of interleukin-8 (IL-8) and interleukin-1 receptor antagonist (IL-1Ra) were determined in the cervical mucus of fertile and infertile women. Methods. Groups of patients were formed according to the results of the standard procedure for infertility investigation, including postcoital test and the presence of antispermatozoid antibodies in the sera of both partners and in seminal plasma, by mixed antiglobulin reaction (MAR) test and Kibrick agglutination test. IL-8 and IL-1Ra levels were determined in solubilized (ultrasonographic sonicaton) cervical mucus sampled in the midcycle by commercial ELISA kits and expressed as pg/mg proteins. Results. The groups were designated as fertile (n=20) and infertile (n=48). The latter was divided into two subgroups, one consisting of infertile women with positive postcoital test and without antispermatozoid antibodies (n=30), and the other designated as infertile women with negative postcoital test (n=18). This subgroup was composed of women with negative postcoital test and without antibodies (n=10) and the women with negative postcoital test with antibodies (n=8). Similar levels of IL-8 and IL-1 Ra were noted in the cervical mucus of in fertile women and women with positive postcoital test and without antispermatozoid antibodies. A tendency of decrease (p=0,052) and significant decrease in IL-8 levels (p<0.05) was noted in negative postcoital test group and negative postcoital test group without antibodies respectively, compared to the levels in the fertile examinees. A significant rise in IL-1Ra levels (p<0,05) was detected in the mucus of negative postcoital test group with further increase in negative postcoital test group with antibodies (p<0.02). Conclusion. Changes in IL-8 and IL-1 Ra levels in the cervical mucus of infertile patients with negative postcoital test suggested the existence of the relatinship between cervical cytokines and infertility in these women.

Aim. To asses an effectiveness of assisted reproductive technologies (ART) program given characteristics of the cytokine profile of seminal plasma (SP) entering the female reproductive tract during sexual intercourse. Outcomes and methods. 33 married couples who applied for a treatment of infertility by means of in vitro fertilization /ICSI (Intracytoplasmic Sperm Injection) were included in the prospective study. Patients were recommended to have sexual intercourse with no restrictions during treatment and to have the last sexual intercourse 3 days before an intended transvaginal puncture (ITP). Testing of cytokines (transforming growth factor (TGF)-b1, interferon (IFN)-g, interleukin (IL)-33, IL-6, IL-8, IL-23, IL-10, tumor necrosis factor (TNF)-a, IL-18, IL- 17A, IFN-a, IL-12, monocyte chemotactic protein-1) levels in samples of partners’ SP obtained on the day having ITP were carried out using multiplex analysis with LegendPlex kits (BioLegend, USA). Results. When comparing a cytokine profile of SP in couples who did not become pregnant (n=25) and couples who become pregnant (n=8) increased IL-18 and reduced IL-10 levels (p=0,017 and p=0, 01 respectively) were revealed in the group which got pregnant. To assess a clinical relevance of cytokine content in SP ROC (Receiver Operating Characteristics) curve was used. It was established that determining of IL-18 concentration in SP has the greatest diagnostic significance (the area under a curve was 0.792±0.107, test sensitivity - 62.5%, test specificity - 95.24% at threshold concentration>210.43 pg/ml). Incidence of pregnancy at IL-18 concentration above threshold levels was 83,3% while at lower concentrations of IL-18 pregnancy occurred only in 13.0% of women. Conclusions. Elevated IL-18 levels and decreased IL-10 levels in SP of female patients’ partners who don’t have restriction of sexual life when treating infertility with ART are favorable factors for a pregnancy to occur.

Abstract Introduction CMML is a clonal hematopoietic stem cell disorder with overlapping features of myelodysplastic syndromes (MDS) and myeloproliferative neoplasms (MPN). Current therapeutic options for patients (pts) with CMML are limited, leaving a significant unmet medical need. Pts classified to have the MPN subtype, compared with the MDS subtype, and those with high-risk genetic features tend to have a higher rate of transformation to acute myeloid leukemia (AML) and median survival of 2-3 years. The seminal observation of increased expression of CD123 (interleukin-3Rα) on leukemia stem cells and clonal plasmacytoid dendritic cells led to the clinical investigation of a novel CD123-targeted agent, tagraxofusp (TAG, SL-401), in CD123-positive hematologic malignancies, including blastic plasmacytoid dendritic cell neoplasm (BPDCN), CMML, AML, and myelofibrosis. TAG demonstrated robust clinical activity in pts with BPDCN and is now approved in the US and EU for this indication. Data from an ongoing phase 1/2 study of TAG monotherapy for pts with relapsed/refractory (R/R) CMML (NCT02268253) also demonstrated clinical activity (Patnaik et al. J Clin Oncol 2019;37: abstr 7059). Herein, we present updated safety and efficacy results of this study in first-line (1L) high-risk and R/R pts. Methods A multicenter, multistage, phase 1/2 trial was designed initially to assess the safety and efficacy of TAG monotherapy in adult pts with R/R CMML (Stages 1 and 2), and subsequently expanded to include 1L high-risk and R/R pts (Stage 3A). Clinical responses were initially assessed by the International Working Group/MDS 2006 criteria, and subsequently amended to the MDS/MPN 2015 criteria. Splenomegaly was assessed by palpation in Stages 1 and 2, and by palpation and imaging in Stage 3A. TAG was administered as a daily IV infusion at 7, 9, or 12 mcg/kg on days (d)1-3 every 21 d (cycles [C]1-4), 28 d (C5-7), and 42 d (C8 and beyond) in Stage 1, and at 12 mcg/kg (recommended phase 2 dose defined in Stage 1) every 21 d (C1-4) and 28 d (C5 and beyond) in Stages 2-3A. Results As of July 2021, 36 pts have been enrolled, comprising 20 pts with CMML-1 and 16 with CMML-2; median age is 69 years (range 42-81); 75% are male. Twenty-three (64%) pts had either high- or intermediate-risk genetics based on CPSS, GFM, MMM, or ELN risk-stratification systems. Prior therapies included HMA in 16 (43%) pts, allogeneic stem cell transplantation (allo-SCT) in 3 (8%), and other in 12 (32%); 7 (19%) pts were high-risk and treatment naive. Overall, 16 (44%) pts had baseline palpable splenomegaly, of whom 12 pts' spleen size was ≥5 cm below left costal margin. The most common (in ≥20% of pts, n=34) treatment-related adverse events (TRAEs) were hypoalbuminemia (26%), thrombocytopenia (24%), nausea (24%), and capillary leak syndrome (CLS, 21%; grade 2, n=4; grade 3, n=3). Grade ≥3 TRAEs were thrombocytopenia (21%), CLS (9%), anemia (9%), and nausea (3%). Discontinuation rate due to TRAEs was low (n=1). Overall, 4 of 36 (11%) pts achieved bone marrow morphologic complete responses (BMCRs), of whom 1 pt was bridged to allo-SCT; all 4 pts had splenomegaly at baseline. Noteworthy, 2 of the 4 BMCRs were observed in pts with high-risk genetic features. Fifteen (42%) pts with baseline splenomegaly had spleen responses; 9 (60%) pts had a ≥50% reduction in spleen size, including 5 (42%) with splenomegaly ≥5 cm at baseline. Median follow-up was 11 weeks (range 1-163 weeks). In the Stage 3A cohort, 2 high-risk 1L pts had BM partial remissions, with 1 also having clinical benefit. Three pts had a spleen volume reduction by MRI scans following C1 (range 7%-36%) and 1 pt had a reduction of 57% after C4. While on study, none of the 7 pts (2 transfusion dependent at baseline) have required blood or platelet transfusions. Updated results on Stage 3A, including total symptom scores, will be presented. Conclusions Ongoing results in pts with CMML demonstrate TAG monotherapy has significant clinical activity in 1L pts with high-risk disease as well as those with R/R disease. The responses were particularly notable in those with baseline splenomegaly. As Stage 3A of the trial continues, mutational correlates and BM PDCs are being assessed. TAG treatment is well-tolerated, with a manageable and predictable safety profile. Overall, the data suggest that TAG may offer a novel targeted approach for pts with CMML. Stage 3A of the trial continues. Disclosures Patnaik: Kura Oncology: Research Funding; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Membership on an entity's Board of Directors or advisory committees. Ali: BMS: Speakers Bureau; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; CTI BioPharma: Membership on an entity's Board of Directors or advisory committees. Wang: Kite Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; Mana Therapeutics: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Other: Advisory Board; BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Stemline Therapeutics: Consultancy, Honoraria, Other: Advisory board, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; DAVA Oncology: Consultancy, Speakers Bureau; Takeda: Consultancy, Honoraria, Other: Advisory board; Kura Oncology: Consultancy, Honoraria, Other: Advisory board, steering committee, Speakers Bureau; Pfizer: Consultancy, Honoraria, Other: Advisory Board, Speakers Bureau; Jazz Pharmaceuticals: Consultancy, Honoraria, Other: Advisory Board; GlaxoSmithKline: Consultancy, Honoraria, Other: Advisory Board; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Rafael Pharmaceuticals: Other: Data safety monitoring committee; Gilead: Consultancy, Honoraria, Other: Advisory board; Daiichi Sankyo: Consultancy, Honoraria, Other: Advisory board; PTC Therapeutics: Consultancy, Honoraria, Other: Advisory board; Genentech: Consultancy; MacroGenics: Consultancy. Yacoub: Incyte: Consultancy, Honoraria, Speakers Bureau; CTI Biopharma: Membership on an entity's Board of Directors or advisory committees; ACCELERON PHARMA: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Dynavex: Current equity holder in publicly-traded company; Cara: Current equity holder in publicly-traded company; Ardelyx: Current equity holder in publicly-traded company; Seattle Genetics: Honoraria, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Hylapharm: Current equity holder in publicly-traded company. Gupta: Pfizer: Consultancy; BMS-Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AbbVie: Consultancy, Honoraria; Incyte: Honoraria, Research Funding; Sierra Oncology: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Constellation Pharma: Consultancy, Honoraria; Roche: Consultancy. Lee: AstraZeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Consultancy, Membership on an entity's Board of Directors or advisory committees; Innate: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pin Therapeutics: Consultancy, Membership on an entity's Board of Directors or advisory committees. Schiller: Kite/Gilead: Honoraria, Research Funding, Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; FujiFilm: Research Funding; PrECOG: Research Funding; Karyopharm: Research Funding; Actinium Pharmaceuticals, Inc: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Geron: Research Funding; Stemline Therapeutics, Inc.: Honoraria, Research Funding, Speakers Bureau; Takeda: Research Funding; Constellation Pharmaceuticals: Research Funding; Trovagene: Research Funding; Actuate: Research Funding; BMS/Celgene: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; Amgen: Consultancy, Current equity holder in publicly-traded company, Honoraria, Research Funding, Speakers Bureau; Regimmune: Research Funding; Delta-Fly: Research Funding; Genentech-Roche: Research Funding; Gamida Cell Ltd.: Research Funding; Astellas: Honoraria, Research Funding, Speakers Bureau; Celator: Research Funding; Daiichi-Sankyo: Research Funding; Arog: Research Funding; Forma: Research Funding; Samus: Research Funding; Deciphera: Research Funding; Jazz: Consultancy, Honoraria, Research Funding, Speakers Bureau; Elevate: Research Funding; Bio: Research Funding; Ono-UK: Consultancy, Research Funding; Abbvie: Research Funding; Mateon: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Onconova: Research Funding; Novartis: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding, Speakers Bureau; Pharma: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company; Biomed Valley Discoveries: Research Funding; Eli Lilly: Research Funding; ASH foundation: Other: Chair-unpaid; Sellas: Research Funding; Ono: Consultancy; Incyte: Consultancy; Ariad: Research Funding; AstraZeneca: Consultancy; Kaiser Permanente: Consultancy; Cyclacel: Research Funding; MedImmune: Research Funding; Ambit: Research Funding; Leukemia & Lymphoma Society: Research Funding; Bluebird Bio: Research Funding; Boehringer-Ingleheim: Research Funding; Cellerant: Research Funding; CTI Biopharma: Research Funding; Janssen: Research Funding; Kura Oncology: Research Funding; Pharmacyclics: Honoraria, Speakers Bureau; Millennium: Research Funding; National Marrow Donor Program: Research Funding; NIH: Research Funding; Onyx: Research Funding; Pharmamar: Research Funding; UC Davis: Research Funding; UCSD: Research Funding; Evidera: Consultancy; NCI: Consultancy; Novartis: Speakers Bureau. Foran: takeda: Research Funding; taiho: Honoraria; syros: Honoraria; boehringer ingelheim: Research Funding; trillium: Research Funding; abbvie: Research Funding; aptose: Research Funding; actinium: Research Funding; kura: Research Funding; sanofi aventis: Honoraria; gamida: Honoraria; certara: Honoraria; servier: Honoraria; revolution medicine: Honoraria; bms: Honoraria; pfizer: Honoraria; novartis: Honoraria; OncLive: Honoraria; h3bioscience: Research Funding; aprea: Research Funding; sellas: Research Funding; stemline: Research Funding. Brooks: Stemline Therapeutics: Current Employment. Mughal: Oxford University Press, Informa: Other: financial benefit and/or patents ; Stemline: Current Employment, Current holder of stock options in a privately-held company. Pemmaraju: Cellectis S.A. ADR: Other, Research Funding; Daiichi Sankyo, Inc.: Other, Research Funding; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; CareDx, Inc.: Consultancy; Aptitude Health: Consultancy; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Bristol-Myers Squibb Co.: Consultancy; Sager Strong Foundation: Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; ImmunoGen, Inc: Consultancy; Samus: Other, Research Funding; Plexxicon: Other, Research Funding; Blueprint Medicines: Consultancy; Clearview Healthcare Partners: Consultancy; DAVA Oncology: Consultancy; Roche Diagnostics: Consultancy; MustangBio: Consultancy, Other; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Celgene Corporation: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; LFB Biotechnologies: Consultancy; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Incyte: Consultancy; Affymetrix: Consultancy, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Pacylex Pharmaceuticals: Consultancy.

Abstract Background Pure red cell aplasia (PRCA), Diamond-Blackfan anemia (DBA) and moderate aplastic anemia (MAA) are all bone marrow failure syndromes that are immune-mediated or may respond to immunosuppressive therapies (IST). Anti-thymocyte globulin, cyclosporine and corticosteroids have been used with some success but have significant toxicities. The humanized monoclonal antibody to the interleukin-2 receptor on T cells, daclizumab, showed efficacy in MAA and PRCA patients with some patients achieving transfusion independence (Sloand et al, Haematologica 2010). However, this agent has since been withdrawn from the market. It is increasing recognized that the anti-CD20 chimeric monoclonal antibody, rituximab, may modulate T cell immunity in addition to its known depletion of B cells (Staci, Seminars in Hematology 2010). There are anecdotal case reports of rituximab, showing benefit in PRCA. Here, we summarize our experience using rituximab in PRCA, DBA and MAA. Design and Methods We enrolled 11 patients with PRCA (n = 7), DBA (n = 1), and MAA (n = 3) who had failed at least one prior immunosuppressive regimen to receive rituximab 375 mg/m2intravenous infusions weekly times 4 doses (NCT00229619). Responses were evaluated at 3, 6 and 12 months. Patients with MAA, DBA or PRCA were eligible for trial participation. MAA was defined as a hypocellular marrow without evidence of an underlying disease process and depression of at least two of three cell lines (an absolute neutrophil count (ANC) ≤ 1200/µL, a platelet count ≤ 70,000/µL, and a hemoglobin ≤ 8.5 g/dL or absolute reticulocyte count (ARC) ≤ 60, 000/µL in transfusion-dependent patients) but who do not fulfill criteria for severe aplastic anemia (i.e. bone marrow cellularity < 30% and depression of two of the three peripheral counts: ANC < 500/µL, a platelet count < 20,000/µL and an ARC < 60,000/µL). DBA and PRCA were defined as anemia, reticulocytopenia (ARC ≤ 50, 000/µL) and absent or decreased marrow erythroid precursors. Patients with Fanconi’s anemia, other congenital bone marrow failure syndromes, cytologic abnormalities indicating myelodysplasia or recent/ongoing parvovirus infection were excluded. Complete response (CR) was defined as return of blood counts to normal. Partial response (PR) for MAA was defined as improvement in two of the three depressed blood counts that qualified patient for participation. PR for DBA/PRCA was defined as an increase in hemoglobin by 1.5 g/dl of blood and or ARC ≥ 50,000/µL but not meeting criteria for normal counts. Results Overall, 5/11 (45%) patients responded to rituximab, all achieving PR. At 3 months, one patient with PRCA had responded. At 6 months, two additional patients responded (one with PRCA, one with MAA). At 12 months, an additional two responses were confirmed (one PRCA, one MAA). One PRCA patient lost his response between the 6 and 12 month endpoint. Among the three responding PRCA patients, the mean reticulocyte count at study initiation was 4400/µL; this increased to 54,000/µL at 6 months and further increased to 61,000/µL at 12 months (including patient who lost his response). The study was terminated early for poor accrual; many eligible patients received alternate treatments at home. Due to early study termination, the duration of responses for majority of the patients is unknown. Given the reports of daclizumab efficacy in these diseases, 90% of our patients were previously treated with daclizumab. Notably, 3 of the patients responding to rituximab had previously not responded to daclizumab. Safety The most common toxicity of rituximab observed was an infusion related reaction affecting (8/11) 73% of patients with the first infusion of rituximab. One patient developed serum sickness after the third cycle which precluded the administration of the last dose. An expected decrease in quantitative immunoglobulin levels was observed; at the 6 month evaluation there was an 11% decrease in IgG and IgA; a greater decrease (48%) was observed in IgM. Conclusions Rituximab is a viable treatment option in the armamentarium for patients with PRCA and MAA. Rituximab is safe, effective, and easily administered. Responses can be delayed to beyond 6 months therefore we suggest observation for at least 6 months after rituximab administration. Disclosures: Off Label Use: Rituximab is not FDA approved for the treatment of Pure Red Cell Aplasia, Diamond-Blackfan Anemia or Moderate Aplastic Anemia.

Abstract Objective Insemination with spermatozoa, seminal plasma and extender, cause a rapid inflammatory response in pig endometrium, characterized by an influx of neutrophils into the uterus. The transient inflammatory response to semen involves cytokine induction. Potential functions for Interleukin-23 (IL-23) in the inflammatory response to different insemination treatments were examined by studying mRNA expression and immunostaining in gilt oviduct and endometrium 35–40 h after insemination. Insemination was performed with seminal plasma (SP), spermatozoa (SPZ) without SP in the extender Beltsville thawing solution (BTS), or BTS alone. In control gilts an insemination catheter was inserted without anything being inseminated. Results Results showed that IL-23 mRNA was expressed in oviduct and endometrium after insemination regardless of treatment. There was an approximate two- to fourfold increase in expression of IL-23 mRNA in catheter-insertion control compared with SPZ, SP and BTS treatment groups. IL-23 immunolabelling was detected in a small number of separate cells and in the sub-epithelial connective tissue of the endometrium, the endosalpinx of isthmus and infundibulum. Conclusion In conclusion, insemination with SP, SPZ in BTS, and BTS alone decreased the expression of IL-23 mRNA in the endometrium compared to catheter-insertion control, indicating a possible role for IL-23 in the inflammatory response after insemination in gilts.