bluuebunny/crossref_metadata_2025_split huggingface dataset:
CD38-Directed CAR-T Cell Therapy: A Novel Immunotherapy Strategy for Relapsed Acute Myeloid Leukemia after Allogeneic Hematopoietic Stem Cell Transplantation
Authors: Tang Xiaowen , Wu Depei , Cui Qingya , Qian Chongsheng , Xu Nan , Kang Liqing , Dai Haiping , Song Baoquan , Cui Wei , Yin Jia , Li Zheng , Yu Lei 
Published: November 2020

There are few effective therapies for relapsed acute myeloid leukemia (AML) after allogeneic hematopoietic stem cell transplantation (allo-HSCT), which has a poor prognosis. Although CD19-targeted chimeric antigen receptor T cell (CAR-T-19) therapy has achieved remarkable success for B-cell malignancies, few successful CAR-T cell therapies in AML have been reported. In this prospective study, we explored the therapeutic effect and clinical safety of the application of CAR-T-38 in 6 AML patients with relapsed post allo-HSCT and CD38 expression. The decitabine (DAC) + HAAG regimen was used to reduce tumor burden, followed by the fludarabine and cyclophosphamide (FC) regimen for lymphodepletion chemotherapy before CAR-T cell infusion. In total, 8.05 (6.1-10) x 106/kg CAR-T-38 were infused by dose escalation over a 3- to 4-day period. At 1, 2 and 4 weeks after CAR-T infusion, two (33.3%), four (66.7%) and four (66.7%) of six patients achieved complete remission (CR) or CR with incomplete count recovery (CRi), respectively. Five of six (83.3%) patients experienced mild (grade I-II) cytokine release syndrome (CRS), and only one patient presented grade III hepatotoxicity. No neurological toxicities were observed, but all six patients had grade III/IV hematological toxicities. The 6-month overall survival (OS) and leukemia-free survival (LFS) rates were 50% and 50%, respectively, and the median OS and LFS were 12.3 and 10.3 months, respectively. The cumulative relapse rates at 3 and 6 months were 25% and 50%, respectively. Multiparameter flow cytometry (FCM) showed that the percentage of CD38-positive blasts remarkably decreased at day 7 and remained at low levels on day 28 after CAR-T cell infusion, but CD38-positive monocytes and lymphocytes were not depleted. This study is the first to indicate that CAR-T-38 therapy is a promising effective and safe approach for patients with relapsed AML after allo-HSCT. (NCT04351022)

Disclosures
No relevant conflicts of interest to declare.
Relationship between CD45 Expression and Outcomes in B Lymphoblastic Leukemia/Lymphoma
Authors: Espinoza-Gutarra Manuel Ricardo , Agarwal Pooja , Ferrer Lina , Czader Magdalena , Dave Utpal 
Published: November 2020

Introduction :
B lymphoblastic leukemia/lymphoma (B-ALL) constitutes the most common type of lymphoblastic leukemia, with about two thirds of the cases being of B-cell lineage. It represents a significant cause of cancer related morbidity and mortality in both pediatric and adult populations. B-ALL immunophenotype has been extensively studied and used for diagnosis. Recent data underscores the importance of the CD45 transmembrane phosphatase in the modulation of signal transduction pathways in leukemic cells. In fact, the gene encoding CD45, PTPRC, has been identified as a tumor suppressor that is deleted in 10% of cases of T-ALL. Based on the impact of CD45 on leukemic cell biology, we hypothesized a relationship between CD45 protein expression and clinical parameters.
Methods :
This is a retrospective, single center analysis of patients diagnosed with B-ALL at Indiana University Simon Comprehensive Cancer Center from December 2003 until December 2018. Patients were followed until July 2020. Variables included patient demographics, and clinical and treatment characteristics. B-ALL diagnosis, molecular profiles, and clinical outcomes were abstracted by chart review. Descriptive statistics were used to summarize baseline characteristics and outcomes. Flow cytometry analysis was performed using 4- and 10-color leukemia screening panel. Median and geometric mean of CD45 antigen intensity was analyzed using FCS Express V6 software. Statistical analysis was performed using SPSS statistical package.
Results:
A total of 148 BALL patients were included in the analysis. 19 (12.8%) were adults (&gt;18 years old) and 13 (8.7%) were Philadelphia chromosome positive. Average Median CD45 expression and CD45 Geometric Mean were 22.9 and 21.9 respectively for the entire cohort. Relevant clinical outcomes collected included complete remission (CR) at days 14 and 29, presence of minimal residual disease (MRD) at days 7 and 29, relapse of disease and death. Mann-Whitney Test was used to establish association between CD45 levels and clinical outcomes. A significant association was found between achieving CR at 29 days and lower levels of CD45 expression (as defined by median and geometric mean, p=0.03 for both). The association was was maintained when excluding Philadelphia positive cases (p=0.05 for both) and excluding patients over 30 years old (p=0.05 for both). There were no significant correlations between CD45 expression and other clinical variables.
Conclusions:
Lower CD45 expression as determined by flow cytometry is associated with higher rates of CR at 29 days. This finding is significant across different age groups and Philadelphia negative cohorts. This finding needs to be explored in further studies. CD45 protein expression levels could be an important biomarker for adjusting induction chemotherapy to achieve complete remission.

Disclosures
No relevant conflicts of interest to declare.
Humoral Dysfunction in Patients with Chronic Lymphocytic Leukemia on Ibrutinib As Evidenced By Suboptimal Vaccine Responses
Authors: Ammad Ud Din Mohammad , Hassan Hamza , Mustafa Shahzad , Jamshed Saad 
Published: November 2020

Background:
Humoral and cell-mediated immune dysregulation is a hallmark of chronic lymphocytic leukemia (CLL) and predisposes these patients to recurrent infections, which remain the leading cause of mortality. Ibrutinib is widely used in both treatment-naive and relapsed CLL, and these patientshave a 48% cumulative rate of ≥grade 3 infections over a 5-year follow up (O'Brien et al.; Blood, April 2018). Our study evaluated humoral immunity in patients with CLL treated with ibrutinib by checking immunoglobulin (Ig) levels and vaccine responses.
Methods:
We measured serum IgG, IgM, IgA, and pre/post-vaccine IgG titers to diphtheria, tetanus, and Streptococcus pneumoniae in patients with CLL on treatment with ibrutinib. Patients were vaccinated with tetanus/diphtheria (Td) and the pneumococcal polysaccharide (PPV23) vaccines, with post-vaccination titers measured at four weeks. Descriptive statistics are reported with medians and interquartile ranges (IQR). Response to Td was defined as a two-fold increase in specific IgG into the protective range. Response to PPV23 was defined as a two-fold increase from baseline if pre-vaccination specific IgG ≥1.3 microgram per milliliter (mcg/ml), or if titers increased by four-fold from baseline if pre-vaccination specific IgG &lt; 1.3 mcg/ml, for &gt; 70% of the serotypes.
Results:
Ten patients were enrolled. The median age was 65 (IQR: 60-68) years; seven were male. The median time since diagnosis was 4.7 (IQR: 4-9.1) years. Patients were on ibrutinib for a median time of 1.3 (IQR: 0.4-2.8) years at the time of enrollment. Three patients had previously received treatment with rituximab monotherapy, while two patients had received prior combination therapy with fludarabine-rituximab-lenalidomide and fludarabine-cyclophosphamide-rituximab. Nine patients had received at least one course of antibiotics (ABx) in the year before enrollment; the median number of ABx courses was 2 (IQR 2-3). Four patients were on prophylactic antibiotics, and three had previously received immunoglobulin replacement therapy. The median serum IgG titer was 650 (IQR: 544-820) mg/dl. 40% (4/10) of patients responded to vaccination with diphtheria, 30% (3/10) of patients responded to vaccination with tetanus, and none of the patients responded to PPV23 (see Table 1).
Conclusion:
Patients with CLL treated with ibrutinib demonstrate a high prevalence of humoral dysfunction, as evidenced by suboptimal vaccine responses to both peptide and polysaccharide antigens despite adequate Ig levels. Clinicians should consider checking vaccine responses in conjunction with Ig levels for comprehensive evaluation of humoral dysfunction.

Disclosures
Mustafa: Genentech: Speakers Bureau; AstraZeneca: Speakers Bureau; Regeneron: Speakers Bureau; CSL Behring: Speakers Bureau. Jamshed:Takeda, Amgen and Celgene: Honoraria.
Siglec-15 Is a Novel Immunomodulatory Protein and Therapeutic Target in Childhood Leukemia
Authors: Pillsbury Claire E. , Fonseca Jairo A. , Dougan Jodi , Abukharma Hasan , Liu Linda N. , Porter Christopher C. 
Published: November 2020

Despite advances that have greatly improved the overall survival of pediatric B cell acute lymphoblastic leukemia (B-ALL), it remains one of the leading causes of cancer-related death in children. Immunotherapy has shown efficacy in treatment of refractory disease, highlighting the need for greater understanding of the immune evasion mechanisms underlying this disease so that additional immune modulating therapeutic strategies can be developed.
Siglec-15 (Sig15) was recently reported to have immune modulatory functions in the context of solid tumors. We have found that SIGLEC15 is overexpressed at the RNA level in primary B cell acute lymphoblastic leukemia (B-ALL), acute myelogenous leukemia (AML), and diffuse large B cell lymphoma as compared to healthy donor controls. As compared to healthy donor PBMCs, we have confirmed higher expression of Sig15 at the RNA and protein levels through RT-qPCR, immunoblotting, and flow cytometry across a panel of human B-ALL, AML, DLBCL, and T cell acute lymphoblastic leukemia (T-ALL) cell lines. Knockout of Sig15 expression in a BCR-ABL1+ murine model of B-ALL engrafted in immunocompetent and Rag1-/- immunodeficient recipients resulted in leukemia clearance in immunocompetent, but not immunodeficient, recipients and 100% survival (Figure 1). These data suggest a prominent role for Sig15 in the suppression of adaptive immune response to B-ALL as well as other hematological malignancies.
Additional studies suggest that SIGLEC15 expression is positively regulated by NFκB signaling, which is known to be constitutively activated in certain B-ALL subsets. Importantly, we have observed release of a soluble form of Sig15 (sSig15) from B-ALL cells, which is regulated by PKC and calcineurin-mediated signaling. To discover translational application, we measured sSig15 in the plasma of both healthy and pediatric leukemia patients and found significantly higher levels of sSig15 as compared to healthy individuals (Figure 2; LLD = 5 pg/ml; **P&lt;0.01).
Together, these results suggest Siglec-15 is a novel and potent immunosuppressive molecule active in leukemia that may be targeted therapeutically to activate lymphocytes against leukemia cells.

Disclosures
Abukharma: NextCure, Inc.: Current Employment. Liu:NextCure, Inc.: Current Employment.
MyD88 L265P Mutation-Specific TCR Gene Therapy for Treatment of B-Cell Lymphoma and Leukemia
Authors: Çinar Özcan , Kloetzel Peter Michael , Peuker Caroline Anna , Keller Ulrich , Pezzutto Antonio , Busse Antonia 
Published: November 2020

Adoptive transfer of engineered T cells has shown remarkable success in hematopoietic malignancies. However, the current most common strategy of targeting lineage-specific antigens often leads to undesirable side effects and a high relapse rate. Therefore, novel treatment approaches are still needed. Oncogenic somatic mutations represent ideal targets because of tumor specificity: such (neo)antigens can be recognized by T cell receptors (TCR) in the context of MHC-peptide presentation. Here we have generated T cell lines from multiple healthy donors targeting one of the most common driver mutations found in B-cell lymphomas; a missense mutation on adaptor protein MyD88 changing leucine at position 265 to proline (L265P). T cell lines generated by autologous in vitro priming were reactive selectively against the predicted mutant epitope restricted to HLA-B7, but not against the corresponding wild-type peptide. Cloned TCRs from these lines led to mutation-specific and HLA-restricted reactivity with varying functional avidity. T cells engineered with mutation-specific TCR (TCR-T cells) recognized and killed cell lines of diffuse large B-cell lymphoma characterized by intrinsic MyD88 L265P. Furthermore, TCR-T cells showed promising therapeutic efficacy in xenograft mouse models, while initial safety screening did not indicate any sign of cross- or allo-reactivity risk. Taken together, our data suggest that mutation-specific TCRs can be used to target MyD88 L265P mutation, and hold promise for precision therapy for a significant subgroup of B-cell malignancies.

Disclosures
Keller: Bristol Myers Squibb: Honoraria, Other: Travel support, Speakers Bureau. Busse:Daiichi Sankyo: Other: Travel Support; Hexal: Honoraria, Research Funding; Roche: Honoraria; BMS: Honoraria; Novartis: Research Funding.
Utility of Procalcitonin in Differentiating Acute Chest Syndrome from Vaso-Occlusive Crisis in Sickle Cell Disease
Authors: Maharaj Satish , Chang Simone , Seegobin Karan , Shaikh Marwan , Cisak Kamila I. 
Published: November 2020

Background: Acute chest syndrome (ACS) frequently complicates sickle cell disease (SCD) and is a leading cause of hospitalization and mortality. Many factors have been implicated in ACS, including infections, thrombosis, fat and pulmonary emboli. However, a clear etiology is not defined in 50% of the cases and ACS is considered a clinical endpoint for different pathogenic processes (Vichinsky et al 2000). The non-specific nature of ACS makes diagnostic tests challenging, and there are no serum tests clinical used to aid diagnosis. Procalcitonin (PCT) is a prohormone of calcitonin and serum PCT rises within hours of an inflammatory stimulus. PCT has clinical utility as a marker of severe systemic inflammation, infection, and sepsis (Becker et al. 2008). Few studies have evaluated PCT as a biomarker for ACS in patients presenting with vaso-occlusive crises (VOC). Two studies have reported no difference in PCT (Biemond et al. 2018 and Stankovic et al 2011), while one study reported higher PCT between ACS and VOC (Patel et al 2014).
Methods: We retrospectively reviewed 106 patients with SCD who presented to the emergency department with fever and painful crises during 2015-2019. The patients were divided into two categories based on discharge diagnoses - patients with VOC only (n=88) and patients with ACS (n=18). Inclusion criteria for both groups were patients with SCD, 17 years and older and PCT measurement on presentation. Exclusion criteria were defined as patients who had received empiric antibiotics prior to PCT testing. Data collected on presentation included genotype, age, gender, complete blood count, PCT, creatinine, total bilirubin and hydroxyurea use. Length of stay was recorded. Data was analyzed between the two groups using descriptive statistics and accounting for unequal variances, withp-value set at 0.05 for significance.
Results: Demographics and clinical characteristics are summarized in Table 1 (Figure). The sample included primarily adult males (77%), with about two-thirds on hydroxyurea. Genotype HbSS (73.6%) was most prevalent followed by HbSC (22.6%) and HbSβ (3.8%). The ACS group had a higher percentage of HbSS, lower use of hydroxyurea and higher mean bilirubin. Mean PCT for the ACS group was 0.52 ng/mL (range, 0.05-2.04), compared to 0.31 ng/mL (range, 0.02-6.82) in the VOC group; withp=0.084. ROC analysis showed a PCT&gt;0.5ng/mL had 39% sensitivity and 85% specificity for ACS in this sample.
Conclusion: In this sample, PCT on presentation was higher in those with ACS compared to VOC, but this difference did not achieve statistical significance. Further study in a larger population would be useful to evaluate this finding.

Disclosures
No relevant conflicts of interest to declare.
Controlled Synthesis and Properties of 3d–4f Metals Co-doped Polyoxometalates-Based Materials
Authors: Liu Ning , Guo Ningning , Sun Lin , Liu Shixian , Wang Guan , Zhao Yuan 
Published: November 2020

Abstract
It is challenging to explore and prepare polyoxometalates-based nanomaterials (PNMs) with controllable morphologies and diversiform components. Herein, 3d–4f metals are introduced into isopolyoxometalates and Anderson-type polyoxometalates, CeCdW12 nanoflower and EuCrMo6 microflaky have been fabricated respectively. A series of control experiments are carried out to identify the impact factors on the rare morphologies in PNMs. Furthermore, upon excitation at 396 nm, the emission spectrum of EuCrMo6 displays five prominent f − f emitting peaks at 674, 685, 690, 707, and 734 nm that are assigned to Eu3+ 5D0 → 7FJ (J = 0, 1, 2, 3, 4) transitions. Meanwhile, the VSM results show that the Cr+3 ions in EuCrMo6 display anti-ferromagnetic interactions when the temperature is lower than − 17.54 K. After rising temperature, this material exhibits paramagnetic property. This work opens up strategies toward the brand new morphologies and components of PNMs, endowing this kind of material with new functions.
Application of Nanotechnology in Wood-Based Products Industry: A Review
Authors: Jasmani Latifah , Rusli Rafeadah , Khadiran Tumirah , Jalil Rafidah , Adnan Sharmiza 
Published: November 2020

AbstractWood-based industry is one of the main drivers of economic growth in Malaysia. Forest being the source of various lignocellulosic materials has many untapped potentials that could be exploited to produce sustainable and biodegradable nanosized material that possesses very interesting features for use in wood-based industry itself or across many different application fields. Wood-based products sector could also utilise various readily available nanomaterials to enhance the performance of existing products or to create new value added products from the forest. This review highlights recent developments in nanotechnology application in the wood-based products industry.
The distribution of eukaryotic initiation factor 4E after bouts of resistance exercise is altered by shortening of recovery periods
Authors: Takegaki Junya , Ogasawara Riki , Kouzaki Karina , Fujita Satoshi , Nakazato Koichi , Ishii Naokata 
Published: November 2020

Abstract
Insufficient duration of recovery between resistance exercise bouts reduces the effects of exercise training, but the influence on muscle anabolic responses is not fully understood. Here, we investigated the changes in the distribution of eukaryotic initiation factor (eIF) 4E, a key regulator of translation initiation, and related factors in mouse skeletal muscle after three successive bouts of resistance exercise with three durations of recovery periods (72 h: conventional, 24 h: shorter, and 8 h: excessively shorter). Bouts of resistance exercise dissociated eIF4E from eIF4E binding protein 1, with the magnitude increasing with shorter recovery. Whereas bouts of resistance exercise with 72 h recovery increased the association of eIF4E and eIF4G, those with shorter recovery did not. Similar results were observed in muscle protein synthesis. These results suggest that insufficient recovery inhibited the association of eIF4E and eIF4G, which might cause attenuation of protein synthesis activation after bouts of resistance exercise.
Polymerization of Bacillus subtilis MreB on a lipid membrane reveals lateral co-polymerization of MreB paralogs and strong effects of cations on filament formation
Authors: Dersch Simon , Reimold Christian , Stoll Joshua , Breddermann Hannes , Heimerl Thomas , Defeu Soufo Hervé Joel , Graumann Peter L. 
Published: November 2020

Abstract

Background
MreB is a bacterial ortholog of actin and forms mobile filaments underneath the cell membrane, perpendicular to the long axis of the cell, which play a crucial role for cell shape maintenance. We wished to visualize Bacillus subtilis MreB in vitro and therefore established a protocol to obtain monomeric protein, which could be polymerized on a planar membrane system, or associated with large membrane vesicles.

Results
Using a planar membrane system and electron microscopy, we show that Bacillus subtilis MreB forms bundles of filaments, which can branch and fuse, with an average width of 70 nm. Fluorescence microscopy of non-polymerized YFP-MreB, CFP-Mbl and mCherry-MreBH proteins showed uniform binding to the membrane, suggesting that 2D diffusion along the membrane could facilitate filament formation. After addition of divalent magnesium and calcium ions, all three proteins formed highly disordered sheets of filaments that could split up or merge, such that at high protein concentration, MreB and its paralogs generated a network of filaments extending away from the membrane. Filament formation was positively affected by divalent ions and negatively by monovalent ions. YFP-MreB or CFP-Mbl also formed filaments between two adjacent membranes, which frequently has a curved appearance. New MreB, Mbl or MreBH monomers could add to the lateral side of preexisting filaments, and MreB paralogs co-polymerized, indicating direct lateral interaction between MreB paralogs.

Conclusions
Our data show that B. subtilis MreB paralogs do not easily form ordered filaments in vitro, possibly due to extensive lateral contacts, but can co-polymerise. Monomeric MreB, Mbl and MreBH uniformly bind to a membrane, and form irregular and frequently split up filamentous structures, facilitated by the addition of divalent ions, and counteracted by monovalent ions, suggesting that intracellular potassium levels may be one important factor to counteract extensive filament formation and filament splitting in vivo.
Scl-Ab reverts pro-osteoclastogenic signalling and resorption in estrogen deficient osteocytes
Authors: Allison H. , Holdsworth G. , McNamara L. M. 
Published: November 2020

Abstract

Background
Neutralising antibodies to sclerostin (Scl-Ab) have shown significant potential to induce bone formation and decrease bone resorption, increase strength and substantially reduce fracture risk in animal studies and clinical trials. Mechanical loading negatively regulates sclerostin expression, and sclerostin has been shown to induce RANKL synthesis in osteocytes. However, how Scl-Ab governs osteocyte regulation of osteoclast differentiation and function is not fully understood. We have recently discovered that osteoblasts and osteocytes alter osteoclastogenic signalling (RANKL/OPG) during estrogen-deficiency, and that osteoblast-induced osteoclastogenesis and resorption are exacerbated. However, it is not known whether estrogen deficient osteocytes exacerbate osteoclastogenesis. The aims of this study were to (1) establish whether osteocytes induce osteoclastogenesis and bone resorption during estrogen deficiency in vitro (2) investigate whether the sclerostin antibody can revert osteocyte-mediated osteoclastogenesis and resorption by attenuating RANKL/OPG expression.

Results
Using conditioned media and co-culture experiments we found increased osteocyte-induced osteoclastogenesis and bone resorption in estrogen deficient conditions. This is the first study to report that administration of Scl-Ab has the ability to revert osteocyte-mediated osteoclastogenesis and resorption by decreasing RANKL/OPG ratio expression and increasing WISP1 expression in estrogen deficient osteocytes.

Conclusions
This study provides an enhanced understanding of the biological changes underpinning decreases in bone resorption following Scl-Ab treatment observed in vivo by revealing that Scl-Ab can reduce pro-osteoclastogenic cell signalling between osteocytes and osteoclasts.