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George S Laszlo, Mary E Beddoe, Colin D Godwin, Olivia M Bates, Chelsea J Gudgeon, Kimberly H Harrington, Roland B Walter
No abstract text is available yet for this article.
August 16, 2018: Haematologica
Noriko Otsuki, Reiko Arakawa, Kaori Kaneko, Ryoko Aoki, Masayuki Arakawa, Kayoko Saito
Spinal muscular atrophy (SMA) is a severe genetic neuromuscular disorder caused by insufficiency of functional survival motor neuron (SMN) protein. Several clinical trials have been conducted with the aim of upregulating the expression of the SMN protein in SMA patients. In order to evaluate the efficiency of these SMN-targeted approaches, it has become necessary to verify SMN protein levels in the cells of SMA patients. Accordingly, we have developed a method allowing the evaluation of the functional SMN protein with < 1...
2018: PloS One
Gunilla Enblad, Hannah Karlsson, Gustav Gammelgard, Jessica Wenthe, Tanja Lovgren, Rose-Marie Amini, Kristina I Wikstrom, Magnus Essand, Barbara Savoldo, Helene Hallbook, Martin Höglund, Gianpietro Dotti, Malcolm K Brenner, Hans Hagberg, Angelica Loskog
PURPOSE: CAR T cell therapy has been effective for patients with CD19+ B cell malignancies. Most studies have investigated second generation CARs with either CD28 or 4-1BB co-stimulatory domains in the CAR receptor. Here we describe the first clinical phase I/IIa trial using third generation CAR T cells targeting CD19 to evaluate safety and efficacy. EXPERIMENTAL DESIGN: Fifteen patients with B cell lymphoma or leukemia were treated with CAR T cells. The lymphoma patients received chemotherapy during CAR manufacture and eleven of fifteen were given low dose cyclophosphamide and fludarabine conditioning prior to CAR infusion...
August 10, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Naghmeh Niktoreh, Beate Lerius, Martin Zimmermann, Bernd Gruhn, Gabriele Escherich, Jean-Pierre Bourquin, Michael Dworzak, Lucie Sramkova, Claudia Rossig, Ursula Creutzig, Dirk Reinhardt, Mareike Rasche
Despite intensified salvage treatments, children with relapsed/refractory acute myeloid leukemia have poor survival. We evaluated Gemtuzumab Ozogamicin (CD33-targeted drug) used on compassionate basis in patients diagnosed from 1995 until 2014 within Acute Myeloid Leukemia-Berlin-Frankfurt-Munster studies and identified 76 patients (<18 years) with highly-advanced and pretreated acute myeloid leukemia [refractory de novo acute myeloid leukemia (n=10), de novo acute myeloid leukemia refractory to relapse (1st early: n=41; 1st late: n=10; 2nd or more: n=10), and secondary acute myeloid leukemia (n=5)]...
August 9, 2018: Haematologica
Markus Bauswein, Anurag Singh, Anjali Ralhan, Davide Neri, Katharina Fuchs, Kelly Daryll Blanz, Iris Schäfer, Andreas Hector, Rupert Handgretinger, Dominik Hartl, Nikolaus Rieber
Myeloid-derived suppressor cells (MDSC) represent an innate immune cell subset capable of suppressing T-cell responses in cancer and chronic inflammation. While the effect of MDSC on T cells has been defined thoroughly, the reciprocal impact of T cells on MDSC homeostasis remains poorly understood. Therefore, we comprehensively analyzed the effect of different T-cell subsets on the generation and survival of human MDSC. Using an in vitro MDSC generation assay, we demonstrate that unstimulated CD4+ , but not CD8+ T cells, induce polymorphonuclear MDSC (PMN-MDSC) from CD33+ myeloid cells...
August 1, 2018: Immunology Letters
Jennifer Hibma, Beverly Knight
BACKGROUND AND OBJECTIVE: Gemtuzumab ozogamicin is an antibody-drug conjugate composed of the anti-CD33 monoclonal antibody hP67.6 covalently linked to N-acetyl-gamma-calicheamicin dimethylhydrazide, a potent cytotoxic antibiotic. The aim of this study was to characterize the population pharmacokinetics of gemtuzumab ozogamicin, represented by total hP67.6 antibody and unconjugated calicheamicin, in adult patients with acute myeloid leukemia to support drug dosing strategies and explore intrinsic and extrinsic factors that may influence exposure...
July 30, 2018: Clinical Pharmacokinetics
Amir T Fathi, Harry P Erba, Jeffrey E Lancet, Eytan M Stein, Farhad Ravandi, Stefan Faderl, Roland B Walter, Anjali S Advani, Daniel J DeAngelo, Tibor J Kovacsovics, Anand Jillella, Dale Bixby, Moshe Y Levy, Megan M O'Meara, Phoenix A Ho, Jenna Voellinger, Anthony S Stein
Treatment of acute myeloid leukemia (AML) among the elderly is challenging due to intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33 directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMA followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMA...
July 25, 2018: Blood
Mohammed Gbadamosi, Soheil Meshinchi, Jatinder K Lamba
In September 2017, the US FDA announced re-approval of gemtuzumab ozogamicin (GO), a CD33-targeting immunoconjugate, for treatment of newly diagnosed and relapsed/refractory acute myeloid leukemia (AML). This is a very significant step toward defining new treatment regimens in AML, as the treatment has essentially stayed unchanged with the '7 + 3 induction regimen' (7 days cytarabine and 3 days of anthracycline) since 1973. GO is the first antibody-drug conjugate to receive FDA approval for treating cancer...
July 24, 2018: Future Oncology
Ying-Ping Jiang, Bob Y Liu, Quan Zheng, Swapna Panuganti, Ruoying Chen, Jianyu Zhu, Madhavi Mishra, Jianqing Huang, Trang Dao-Pick, Sharmili Roy, XiaoXian Zhao, Jeffrey Lin, Gautam Banik, Eric D Hsi, Ramkumar Mandalam, Jagath R Junutula
The current standard of care for acute myeloid leukemia (AML) is largely ineffective with very high relapse rates and low survival rates, mostly due to the inability to eliminate a rare population of leukemic stem cells (LSCs) that initiate tumor growth and are resistant to standard chemotherapy. RNA-sequencing analysis on isolated LSCs confirmed C-type lectin domain family 12 member A (CLL1, also known as CLEC12A) to be highly expressed on LSCs but not on normal hematopoietic stem cells (HSCs) or other healthy organ tissues...
July 24, 2018: Blood Advances
Xiaowen Tang, Lin Yang, Zheng Li, Ansel P Nalin, Haiping Dai, Ting Xu, Jia Yin, Fengtao You, Mingqing Zhu, Wenhong Shen, Guanghua Chen, Xiaming Zhu, Depei Wu, Jianhua Yu
CAR T cells have shown clinical efficacy for acute lymphoblastic leukemia, but this therapy has not been effective for acute myeloid leukemia (AML), and other treatment options are needed. Theoretically, CAR-NK cells have a more favorable toxicity profile compared to CAR T cells, especially in avoiding adverse effects such as cytokine release syndrome. However, the clinical evidence for this has not yet been reported. In the current study, we tested the safety of CD33-CAR NK cells in patients with relapsed and refractory AML...
2018: American Journal of Cancer Research
Stephan Fuhrmann, Richard Schabath, Anja Möricke, Martin Zimmermann, Joachim B Kunz, Andreas E Kulozik, Wolf-Dieter Ludwig, Martin Schrappe, Leonid Karawajew, Richard Ratei
This study reports the prognostic impact of the expression of the natural killer cell marker CD56 in a large series of risk-adapted paediatric patients with T cell acute lymphoblastic leukaemia (T-ALL; n = 493) treated within the ALL-Berlin-Frankfurt-Münster (BFM) 2000 protocol. The immunophenotype was analysed centrally at diagnosis using flow cytometry and correlated with clinical parameters and outcome. CD56 expression was detected in 7·1% and early T-cell precursor (ETP) phenotype in 6·7% of all T-ALL patients...
July 20, 2018: British Journal of Haematology
Kiyoyuki Ogata, Kazuma Sei, Leonie Saft, Naoya Kawahara, Matteo G Della Porta, Nicolas Chapuis, Yumi Yamamoto
Diagnosis of myelodysplastic syndromes (MDS) is not straightforward when objective data, such as blast excess and abnormal cytogenetics, are lacking. Expert laboratories use flow cytometry (FCM) to help diagnose MDS. However, most of FCM protocols for MDS are complex, requiring a high level of expertise and high cost. We have reported a FCM mini-panel consisting of four FCM parameters (so-called Ogata score), which is simple to conduct and inexpensive. In this paper, to refine this mini-panel, we have introduced a new FCM parameter, which quantifies CD33 expression on CD34+ cells (called Granulocyte/CD34 cell CD33 ratio)...
August 2018: Leukemia Research
Joanna C Masters, Elly Barry, Beverly Knight
BACKGROUND AND OBJECTIVE: To date, the population pharmacokinetics (popPK) of gemtuzumab ozogamicin (GO), a CD33-directed antibody-drug conjugate consisting of hP67.6 antibody linked to N-acetyl gamma calicheamicin used in the treatment of acute myeloid leukemia (AML), has not been characterized in pediatric patients. This report describes the popPK of GO following intravenous administration in 29 pediatric patients aged ≤ 17 years with relapsed or refractory AML who were enrolled in the 0903A1-102-US phase I/II study...
July 19, 2018: Clinical Pharmacokinetics
Daiju Sakurai, Ryosuke Uchida, Fumie Ihara, Naoki Kunii, Takuya Nakagawa, Hideaki Chazono, Toyoyuki Hanazawa, Shinichiro Motohashi, Yoshitaka Okamoto
OBJECTIVE: Different sensitizations and immune responses are thought to be induced in response to antigens at different mucosal sites between the oral floor and nose. The aim of this study was to investigate differences in the distributions of lymphocyte subsets in the submandibular (SM) and upper jugular (UJ) lymph nodes (LNs), which are supposed to be regional LNs of the oral floor and nasal mucosa, respectively. SMLNs and UJLNs were collected from patients with head and neck tumors who underwent surgical resection...
July 16, 2018: BMC Research Notes
Sakaorat Lertjuthaporn, Ladawan Khowawisetsut, Rassamon Keawvichit, Korakot Polsrila, Ampaiwan Chuansumrit, Kulkanya Chokephaibulkit, Premrutai Thitilertdecha, Nattawat Onlamoon, Aftab A Ansari, Kovit Pattanapanyasat
Dengue virus (DENV) is the most prevalent arthropod-borne viral disease in humans. DENV causes a spectrum of illness ranging from mild to potentially severe complications. Dendritic cells (DCs) play a critical role in initiating and regulating highly effective antiviral immune response that include linking innate and adaptive immune responses. This study was conducted to comparatively characterize in detail the relative proportion, phenotypic changes, and maturation profile of subsets of both myeloid DCs (mDCs) and plasmacytoid DCs (pDCs) in children with dengue fever (DF), dengue hemorrhagic fever (DHF) and for purposes of control healthy individuals...
2018: PloS One
Jessica Corean, K David Li
Anaplastic lymphoma kinase-positive large B-cell lymphoma (ALK+ LBCL) is a very rare and aggressive subtype of diffuse large B-cell lymphoma characterized by ALK rearrangement. Immunophenotypically, the tumor cells are typically negative for common B-cell markers, T-cell markers, and CD30; however, they express markers of terminally differentiated B cells/plasma cells such as CD38, CD138, and MUM-1/IRF4. The diagnosis of ALK+ LBCL can be challenging, and often a large panel of immunostains is required to exclude other hematopoietic and nonhematopoietic neoplasms...
2018: Case Reports in Hematology
Fang-Yuan Mao, Yong-Liang Zhao, Yi-Pin Lv, Yong-Sheng Teng, Hui Kong, Yu-Gang Liu, Xiao-Long Wu, Chuan-Jie Hao, Weisan Chen, Mu-Bing Duan, Bin Han, Qiang Ma, Ting-Ting Wang, Liu-Sheng Peng, Jin-Yu Zhang, Ping Cheng, Chong-Yu Su, Xiao-Long Fu, Quan-Ming Zou, Gang Guo, Xiao-Lan Guo, Yuan Zhuang
Myeloid-derived suppressor cells (MDSCs) are a prominent component of the pro-tumoral response. The phenotype of and mechanisms used by MDSCs is heterogeneous and requires more precise characterization in gastric cancer (GC) patients. Here, we have identified a novel subset of CD45+ CD33low CD11bdim MDSCs in the peripheral blood of GC patients compared to healthy individuals. CD45+ CD33low CD11bdim MDSCs morphologically resembled neutrophils and expressed high levels of the neutrophil marker CD66b. Circulating CD45+ CD33low CD11bdim MDSCs effectively suppressed CD8+ T cells activity through the inhibition of CD8+ T cell proliferation and interferon-γ (IFN-γ) and granzyme B (GrB) production...
July 9, 2018: Cell Death & Disease
Eun-Hye Seo, Ji Hyeon Namgung, Chung-Sik Oh, Seong-Hyop Kim, Seung Hyun Lee
Myeloid-derived suppressor cells (MDSCs) are highly immunosuppressive myeloid cells that show increased expression in cancer patients; however, the molecular mechanisms underlying their generation and function are unclear. Whereas granulocytic-MDSCs correlate with poor overall survival in breast cancer (BC), the presence and relevance of monocytic (Mo)-MDSCs are unknown. Here, we report for the first time increased chemokine and chemokine receptor production by Mo-MDSCs in BC patients. A clear population of Mo-MDSCs with the typical cell surface phenotype (human leukocyte antigen-antigen D related [HLA-DR]low/- CD11b+ CD33+ CD14+ ) increased significantly during disease progression...
June 2018: Immune Network
Martin Palus, Yahya Sohrabi, Karl W Broman, Hynek Strnad, Matyáš Šíma, Daniel Růžek, Valeriya Volkova, Martina Slapničková, Jarmila Vojtíšková, Lucie Mrázková, Jiří Salát, Marie Lipoldová
BACKGROUND: Tick-borne encephalitis (TBE) is the main tick-borne viral infection in Eurasia. Its manifestations range from inapparent infections and fevers with complete recovery to debilitating or fatal encephalitis. The basis of this heterogeneity is largely unknown, but part of this variation is likely due to host genetic. We have previously found that BALB/c mice exhibit intermediate susceptibility to the infection of TBE virus (TBEV), STS mice are highly resistant, whereas the recombinant congenic strain CcS-11, carrying 12...
July 6, 2018: BMC Neuroscience
Carsten Krieg, Malgorzata Nowicka, Silvia Guglietta, Sabrina Schindler, Felix J Hartmann, Lukas M Weber, Reinhard Dummer, Mark D Robinson, Mitchell P Levesque, Burkhard Becher
In the version of this article initially published, Figs. 5a,c and 6a were incorrect because of an error in a metadata spreadsheet that led to the healthy donor patient 2 (HD2) samples being used twice in the analysis of baseline samples and in the analysis at 12 weeks of anti-PD-1 therapy, while HD3 samples had not been used. Data from sets of both samples should have been used in the analyses. The influence of this error on population proportions, marker expression, P values and tSNE visualization (in Figs...
July 2, 2018: Nature Medicine
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