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  • 1
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 33-33
    Abstract: Background: Mantle cell lymphoma (MCL) is an aggressive B-cell malignancy that is initially responsive but ultimately relapses after frontline therapy. Although the first-in-class Bruton's tyrosine kinase (BTK) inhibitor ibrutinib has achieved a 68% overall response rate in relapsed/refractory MCL patients, most experience disease progression after ibrutinib treatment. Furthermore, the diverse heterogeneity of molecular alterations in each patient makes improving patient outcome with a uniform regimen extremely challenging. Therefore, identification of effective drug therapies, especially personalized therapeutic strategies are urgently needed. In this study, clinical patient samples were submitted for molecular profiling analysis to identify the dysregulated pathways for each patient. Isolated tumor cells underwent an in vitro drug screen with a panel of clinic drug candidates. Final in vivo efficacy evaluation on the patient derived xenograft (PDX) mouse models could be utilized to predict and validate the clinical response. Methods: We collected fresh peripheral blood specimens, surgical biopsies, bone marrow aspirates and apheresis samples under established IRB-approved protocols. The extracted tumor RNA was subjected to a CLIA-validated nanoString nCounter analysis to interrogate the dysregulated signaling pathways, and whole-exome sequencing (WES) was conducted to reveal the somatic mutations and DNA copy number alterations. High throughput cell viability assays of 23 clinical drug agents targeting multiple pathways associated with MCL pathogenesis were tested per patient sample using the CellTiter-Glo luminescent assay (Promega). Meanwhile, subcutaneous, intravenous and subrenal injections of the purified patient tumor cells were performed on NSG-mice to create corresponding PDX mouse models and these models were used for in vivo validation of rational therapeutic treatment options for precision medicine. Results: We collected and submitted 21 clinical patient samples for molecular profiling analysis and screened them through the designed drug panel. We identified correlations between the WES and nanoString nCounter analysis to interrogate the dysregulated pathways for each patient. The PI3K/mTOR signaling, cell cycle regulation, and apoptosis pathways were among the three most markedly enriched pathways in the relapsed MCL samples based on the hallmark gene set analysis. For example, aberrant apoptosis pathway was identified as the predominant cancer hallmark in one of the patients, the Bcl-2 inhibitor venetoclax and MCL-1 inhibitor AZD5991 were chosen as rational therapeutic treatment options. Indeed, both venetoclax and AZD5991 dramatically induced cell death in both primary patient cells and isolated PDX tumor cells ex vivo. Furthermore, administration of venetoclax at 50mg/kg eradicated the tumor growth in the PDX mouse model established from this patient (p & lt;0.001). In another patient, dysregulated cell cycle pathway (E2F targets and G2M checkpoint) was the predominant cancer hallmark and treatment with CDK4/6 inhibitor abemaciclib (75mg/kg) significantly decreased the tumor size in the PDX model derived from this patient (p & lt;0.0001). Conclusions: Interrogation of dysregulated pathways could be achieved by molecular profiling analysis, and suggest rational treatment options. Follow-up in vitro & in vivo drug efficacy determination facilitates the identification of potential therapeutic options for precision medicine in MCL patient to ultimately improve patient survival outcome. Disclosures Wang: AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Molecular Templates: Research Funding; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; OncLive: Honoraria; Nobel Insights: Consultancy; InnoCare: Consultancy; Lu Daopei Medical Group: Honoraria; Beijing Medical Award Foundation: Honoraria; Guidepoint Global: Consultancy; Pulse Biosciences: Consultancy; Oncternal: Consultancy, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; MoreHealth: Consultancy; VelosBio: Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; Acerta Pharma: Research Funding; Verastem: Research Funding; Loxo Oncology: Consultancy, Research Funding; Targeted Oncology: Honoraria; Dava Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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  • 2
    In: Blood, American Society of Hematology, Vol. 136, No. Supplement 1 ( 2020-11-5), p. 35-35
    Abstract: Mantle cell lymphoma (MCL) is a rare but aggressive B-cell non-Hodgkin's lymphoma that represents 6% of all lymphomas in the United States. Recent therapies including anti-CD20 antibody rituximab, BTK inhibitors, and BCL-2 inhibitors alone or in combination have shown great anti-MCL efficacy. However, primary and acquired resistance to one or multiple therapies commonly occurs, resulting in poor clinical outcome. Therefore, resistance to such therapies is currently an unmet clinical challenge in MCL patients. Therapeutic strategies to overcome this resistance holds promise to significantly improve survival of refractory/relapsed MCL patients. Recent studies showed Fc gamma receptors (FcγRs) play important roles in enhancing the efficacy of antibody-based immunotherapy. In particular, FcgRIIB (CD32B), an inhibitory member of the FcγR family, is implicated in the immune cell desensitization and tumor cell resistance through the internalization of therapeutic antibodies such as rituximab. Based on our flow cytometry analysis, we demonstrated that FcgRIIB is highly expressed on the cell surface of MCL cell lines (n=10) and primary MCL patient samples (n=22). This indicates that FcgRIIB may play an important role in MCL malignancy and identifies FcgRIIB is a potential therapeutic target for the treatment of MCL. To address this, we tested the in vivo efficacy of BI-1206, a fully humanized monoclonal antibody targeting FcgRIIB, alone, or in combination with clinically approved or investigational drugs including rituximab, ibrutinib and venetoclax. In the first in vivo cohort, BI-1206, as a single agent, dramatically inhibited the tumor growth of ibrutinib-venetoclax dual-resistant PDX tumor models, suggesting that targeting FcgRIIB by BI-1206 alone has high anti-MCL activity in vivo. Next, we assessed whether BI-1206 can boost anti-MCL activity of antibody-based therapy such as rituximab in combination with ibrutinib or venetoclax using additional mice cohorts of cell line-derived xenograft and patient-derived xenograft models. BI-1206 significantly enhanced the in vivo efficacy of ibrutinib plus rituximab, and venetoclax plus rituximab, on tumor growth inhibition, including the JeKo-1 derived xenograft models, previously proven to be partially resistant to ibrutinib and venetoclax in vivo. This tumor-sensitizaton effect was further confirmed in the ibrutinib and venetoclax dual-resistant PDX models of MCL where BI-1206 was combined with venetoclax and rituximab. More detailed mechanistic studies are currently ongoing to reveal the mechanism of action of BI-1206-based combinations or as single therapy with the possibility that BI-1206 itself may have a cytotoxic anti-tumor direct activity in MCL. In conclusion, BI-1206 as single agent showed potent efficacy in overcoming ibrutnib-venetoclax dual resistance. Moveover, BI-1206 enhanced the in vivo efficacy of ibrutinib plus rituximab and venetoclax plus rituximab and overcomes resistance to these treatments resulting in enhanced anti-tumor effects. Disclosures Karlsson: BioInvent International AB: Current Employment. Mårtensson:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Kovacek:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Teige:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Frendéus:BioInvent International AB: Current Employment, Current equity holder in publicly-traded company. Wang:Pulse Biosciences: Consultancy; Loxo Oncology: Consultancy, Research Funding; Kite Pharma: Consultancy, Other: Travel, accommodation, expenses, Research Funding; BioInvent: Research Funding; Juno: Consultancy, Research Funding; Beijing Medical Award Foundation: Honoraria; OncLive: Honoraria; Verastem: Research Funding; Molecular Templates: Research Funding; Dava Oncology: Honoraria; Guidepoint Global: Consultancy; Nobel Insights: Consultancy; Oncternal: Consultancy, Research Funding; InnoCare: Consultancy; Acerta Pharma: Research Funding; VelosBio: Research Funding; MoreHealth: Consultancy; Targeted Oncology: Honoraria; OMI: Honoraria, Other: Travel, accommodation, expenses; Celgene: Consultancy, Other: Travel, accommodation, expenses, Research Funding; AstraZeneca: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Pharmacyclics: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Janssen: Consultancy, Honoraria, Other: Travel, accommodation, expenses, Research Funding; Lu Daopei Medical Group: Honoraria.
    Type of Medium: Online Resource
    ISSN: 0006-4971 , 1528-0020
    RVK:
    RVK:
    Language: English
    Publisher: American Society of Hematology
    Publication Date: 2020
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    detail.hit.zdb_id: 80069-7
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  • 3
    In: JAMA, American Medical Association (AMA), Vol. 327, No. 19 ( 2022-05-17), p. 1888-
    Type of Medium: Online Resource
    ISSN: 0098-7484
    RVK:
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2022
    detail.hit.zdb_id: 2958-0
    detail.hit.zdb_id: 2018410-4
    SSG: 5,21
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  • 4
    In: Kidney International Reports, Elsevier BV, ( 2023-8)
    Type of Medium: Online Resource
    ISSN: 2468-0249
    Language: English
    Publisher: Elsevier BV
    Publication Date: 2023
    detail.hit.zdb_id: 2887223-X
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  • 5
    In: JAMA Network Open, American Medical Association (AMA), Vol. 6, No. 5 ( 2023-05-01), p. e2310909-
    Abstract: Baseline findings from the China Dialysis Calcification Study (CDCS) revealed a high prevalence of vascular calcification (VC) among patients with end-stage kidney disease; however, data on VC progression were limited. Objectives To understand the progression of VC at different anatomical sites, identify risk factors for VC progression, and assess the association of VC progression with the risk of cardiovascular events and death among patients receiving maintenance dialysis. Design, Setting, and Participants This cohort study was a 4-year follow-up assessment of participants in the CDCS, a nationwide multicenter prospective cohort study involving patients aged 18 to 74 years who were undergoing hemodialysis or peritoneal dialysis. Participants were recruited from 24 centers across China between May 1, 2014, and April 30, 2015, and followed up for 4 years. A total of 1489 patients receiving maintenance dialysis were included in the current analysis. Data were analyzed from September 1 to December 31, 2021. Exposures Patient demographic characteristics and medical history; high-sensitivity C-reactive protein laboratory values; serum calcium, phosphorus, and intact parathyroid hormone (iPTH) values; and previous or concomitant use of medications. Main Outcomes and Measures The primary outcome was progression of VC at 3 different anatomical sites (coronary artery, abdominal aorta, and cardiac valves) and identification of risk factors for VC progression. Participants received assessments of coronary artery calcification (CAC), abdominal aortic calcification (AAC), and cardiac valve calcification (CVC) at baseline, 24 months, 36 months, and 48 months. Secondary outcomes included (1) the association between VC progression and the risk of all-cause death, cardiovascular (CV)–related death, and a composite of all-cause death and nonfatal CV events and (2) the association between achievement of serum calcium, phosphorus, and iPTH target levels and the risk of VC progression. Results Among 1489 patients, the median (IQR) age was 51.0 (41.0-60.0) years; 59.5% of patients were male. By the end of 4-year follow-up, progression of total VC was observed in 86.5% of patients; 69.6% of patients had CAC progression, 72.4% had AAC progression, and 33.4% had CVC progression. Common risk factors for VC progression at the 3 different anatomical sites were older age and higher fibroblast growth factor 23 levels. Progression of CAC was associated with a higher risk of all-cause death (model 1 [adjusted for age, sex, and body mass index]: hazard ratio [HR] , 1.97 [95% CI, 1.16-3.33]; model 2 [adjusted for all factors in model 1 plus smoking status, history of diabetes, and mean arterial pressure] : HR, 1.89 [95% CI, 1.11-3.21]; model 3 [adjusted for all factors in model 2 plus calcium, phosphorus, intact parathyroid hormone, and fibroblast growth factor 23 levels and calcium-based phosphate binder use] : HR, 1.92 [95% CI, 1.11-3.31]) and the composite of all-cause death and nonfatal CV events (model 1: HR, 1.98 [95% CI, 1.19-3.31] ; model 2: HR, 1.91 [95% CI, 1.14-3.21]; model 3: HR, 1.95 [95% CI, 1.14-3.33] ) after adjusting for all confounding factors except the presence of baseline calcification. Among the 3 targets of calcium, phosphorus, and iPTH, patients who achieved no target levels (model 1: odds ratio [OR], 4.75 [95% CI, 2.65-8.52] ; model 2: OR, 4.81 [95% CI, 2.67-8.66]; model 3 [for this analysis, adjusted for all factors in model 2 plus fibroblast growth factor 23 level and calcium-based phosphate binder use] : OR, 2.76 [95% CI, 1.48-5.16]), 1 target level (model 1: OR, 3.71 [95% CI, 2.35-5.88] ; model 2: OR, 3.62 [95% CI, 2.26-5.78]; model 3: OR, 2.19 [95% CI, 1.33-3.61] ), or 2 target levels (model 1: OR, 2.73 [95% CI, 1.74-4.26]; model 2: OR, 2.69 [95% CI, 1.71-4.25] ; model 3: OR, 1.72 [95% CI, 1.06-2.79]) had higher odds of CAC progression compared with patients who achieved all 3 target levels. Conclusions and Relevance In this study, VC progressed rapidly in patients undergoing dialysis, with different VC types associated with different rates of prevalence and progression. Consistent achievement of serum calcium, phosphorus, and iPTH target levels was associated with a lower risk of CAC progression. These results may be useful for increasing patient awareness and developing appropriate strategies to improve the management of chronic kidney disease–mineral and bone disorder among patients undergoing dialysis.
    Type of Medium: Online Resource
    ISSN: 2574-3805
    Language: English
    Publisher: American Medical Association (AMA)
    Publication Date: 2023
    detail.hit.zdb_id: 2931249-8
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  • 6
    In: Nephrology Dialysis Transplantation, Oxford University Press (OUP), ( 2018-10-09)
    Type of Medium: Online Resource
    ISSN: 0931-0509 , 1460-2385
    Language: English
    Publisher: Oxford University Press (OUP)
    Publication Date: 2018
    detail.hit.zdb_id: 1465709-0
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  • 7
    Online Resource
    Online Resource
    Editorial Committee of Japanese Journal of Infectious Diseases, National Institute of Infectious Dis ; 2014
    In:  Japanese Journal of Infectious Diseases Vol. 67, No. 5 ( 2014), p. 349-355
    In: Japanese Journal of Infectious Diseases, Editorial Committee of Japanese Journal of Infectious Diseases, National Institute of Infectious Dis, Vol. 67, No. 5 ( 2014), p. 349-355
    Type of Medium: Online Resource
    ISSN: 1344-6304
    Language: English
    Publisher: Editorial Committee of Japanese Journal of Infectious Diseases, National Institute of Infectious Dis
    Publication Date: 2014
    detail.hit.zdb_id: 2128836-7
    SSG: 12
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  • 8
    Online Resource
    Online Resource
    American Chemical Society (ACS) ; 2022
    In:  ACS Applied Materials & Interfaces Vol. 14, No. 1 ( 2022-01-12), p. 225-235
    In: ACS Applied Materials & Interfaces, American Chemical Society (ACS), Vol. 14, No. 1 ( 2022-01-12), p. 225-235
    Type of Medium: Online Resource
    ISSN: 1944-8244 , 1944-8252
    Language: English
    Publisher: American Chemical Society (ACS)
    Publication Date: 2022
    detail.hit.zdb_id: 2467494-1
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  • 9
    Online Resource
    Online Resource
    MDPI AG ; 2023
    In:  International Journal of Molecular Sciences Vol. 24, No. 7 ( 2023-04-06), p. 6864-
    In: International Journal of Molecular Sciences, MDPI AG, Vol. 24, No. 7 ( 2023-04-06), p. 6864-
    Abstract: Microbial fatty acids are synthesized by Type II fatty acid synthase and could be tailored by acyl-ACP thioesterase. With the prospects of medium-chain fatty-acid-derivative biofuels, the selectivity of thioesterase has been studied to control the fatty acid product chain length. Here, we report an alternative approach by manipulating the acyl carrier protein portion of acyl-ACP to switch the chain length propensity of the thioesterase. It was demonstrated that ChFatB2 from Cuphea hookeriana preferred C10-ACP to C8-ACP with ACP from E. coli, while converting preference to C8-ACP with ACP from Cuphea lanceolate. Circular dichroism (CD) results indicated that the C8-EcACP encountered a 34.4% α-helix increment compared to C10-EcACP, which resulted in an approximate binding affinity decrease in ChFatB2 compared to C10-EcACP. Similarly, the C10-ClACP2 suffered a 45% decrease in helix content compared to C8–ClACP2, and the conformational changes resulted in an 18% binding affinity decline with ChFatB2 compared with C10-ClACP2. In brief, the study demonstrates that the ACP portion of acyl-ACP contributes to the selectivity of acyl-ACP thioesterase, and the conformational changes of EcACP and ClACP2 switch the chain length preference of ChFatB2 between C8 and C10. The result provides fundamentals for the directed synthesis of medium-chain fatty acids based on regulating the conformational changes of ACPs.
    Type of Medium: Online Resource
    ISSN: 1422-0067
    Language: English
    Publisher: MDPI AG
    Publication Date: 2023
    detail.hit.zdb_id: 2019364-6
    SSG: 12
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  • 10
    In: mSystems, American Society for Microbiology, Vol. 5, No. 4 ( 2020-08-25)
    Abstract: Perturbation of vaginal microbiome of reproductive-age women influences all the phases of a woman's reproductive life. Although studies have shown that dynamic changes in vaginal microbiome can affect pregnancy, its role in secondary infertility (i.e., inability to become pregnant or to carry a pregnancy successfully after previous success in delivering a child) and i n v itro f ertilization (IVF) remains to be unraveled. To determine the vaginal microbiome in women undergoing i n v itro f ertilization and e mbryo t ransfer (IVF-ET) and investigate its potential correlations with hormone stimulation, we recruited 30 patients with secondary infertility and receiving IVF and 92 matched healthy women and analyzed their vaginal microbiome composition using 16S rRNA gene sequencing. Our results show that women suffering from infertility (infertile women) exhibit a significant decrease in microbiome diversity and richness compared with healthy women during the nonovulation period (follicular phase) ( P  〈   0.01), whereas vaginal microbiome of healthy women reveals dramatic fluctuations during ovulation ( P  〈   0.05). Interestingly, infertility patients show no change of the vaginal microbiome under conditions of g o n adotropin- r eleasing h ormone (GnRH) agonist and r ecombinant h uman c horionic g onadotropin (r-hCG) induction ( P  〉   0.05). Moreover, our results indicate that infertile women show characteristic variations in vaginal microbiome, such as increased abundance of Atopobium, Aerococcus , and Bifidobacterium and decreased abundance of Lactobacillus and Leuconostoc . IMPORTANCE The microbiome had been hypothesized to be involved in the physiology and pathophysiology of assisted reproduction before the first success in IVF, while the data supporting or refuting this hypothesis were less than conclusive. Thanks to sequencing data from the 16S rRNA subunit, we characterized the microbiome in the reproductive tract of infertile women, and we found that changes in the vaginal microbiome are related to female infertility. We also found that the characteristic microbiome bacteria are mainly members of several genera and that the vaginal microbiome of infertile women is not sensitive to hormonal changes during IVF. In conclusion, our report provides data that can be used for discovering the role of the vaginal microbiome in patients suffering from secondary infertility.
    Type of Medium: Online Resource
    ISSN: 2379-5077
    Language: English
    Publisher: American Society for Microbiology
    Publication Date: 2020
    detail.hit.zdb_id: 2844333-0
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