bluuebunny/crossref_metadata_2025 huggingface dataset:
Safety and Efficacy of Purine Analogs for Treatment of Waldenstrom Macroglobulinemia
Authors: Dar Abdul Jabbar , Khurshid Qasim , Ahmad Muhaddis Ejaz , Mirza Muhammad Ali , Khalid Farhan , Tayyeb Muhammad , Abdullah Syed Maaz , Farooqi Muhammad Saad , Khan Sana Irfan , Kashyap Richi , Javed Saad , Faizan Unaiza , Anwer Faiz
Published: November 2020

Introduction:

There are about 1500 cases every year in the United States of America and while the disease is incurable but it is treatable. Purine analogs are anti-metabolites that mimic the structure of metabolic purines and are used for the treatment of Waldenstrom macroglobulinemia (WM).

Methods:

We performed a comprehensive literature search on articles following PRISMA guidelines. Beginning with articles published after 1995, we used databases like PubMed, Embase, Clinicaltrials.gov, Cochrane Library and Web of Science. Total 580 articles were identified initially and after detailed screening, we finalized 16 studies involving patients with Waldenstrom macroglobulinemia.

Results:

The total number of patients in the studies involving regimens based on purine analogs were 1211. The doses of Fludarabine ranged from 25-30 mg/m2 and that of Cladribine ranged from 0.1-0.5 mg/kg. The complete response (CR) observed ranged from 2-15% and the partial response (PR) ranged from 11-67%. The overall response rate (ORR) ranged from 38-95%.

Fludarabine:

In the study Dhodapkar et al., N=231, the highest CR and ORR was observed, 4% and 66% respectively. In the study Zinzani et al., the PR was 41%.

Fludarabine and Cyclophasphamide:

In the study Dimopoulos et al., the PR was 55% and the progression free survival (PFS) was 24 months.

Fludarabine, Cyclophosphamide and ofatumumab:

In the study Gavriatopoulou et al., the PR was 67% and very good partial response (VGPR) was 17% and the PFS was 23 months.

Fludarabine, rituximab and cyclophosphamide:

In the study Tedeschi et al., the CR was 11.60%, ORR was 79% and the PR was 41.8%.

Fludarabine and Rituximab:

In the study Treon et al., the CR was 4.6%, VGPR was 32.5%, PR was 48%, and ORR was 95.3% with PFS of 51.2 months.

Cladribine:

In the study Liu et al., the CR was 5% and PR was 50%. In the studies Dimopoulos et al., 1994 the highest CR was observed, 11.5% with an ORR of 85%. The PR was also the highest, 73%.

Conclusion:

There is limited literature on regimens containing both Fludarabine and Cladribine, which are used for the treatment of WM. Despite heterogenicity in WM patients and various regimens used in literature. Purine analogs containing regimens are a remarkably effective treatment with overall response rates reaching up to 79%. Neutropenia and thrombocytopenia were the main side effects. There is a paucity of phase 3 randomized trials demonstrating a clinical benefit of anyone regimen over another. We recommend future randomized prospective trials better to understand the efficacy and safety profile of regimens containing purine analogs.

Disclosures

Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.
Clinical Characterization and Risk Factors Associated with Cytokine Release Syndrome Induced By COVID-19 and Chimeric Antigen Receptor T-Cell Therapy
Authors: Hong Ruimin , Zhao Houli , Wang Yiyun , Chen Yu , Cai Hongliu , Hu Yongxian , Wei Guoqing , Huang He
Published: November 2020

Background: An excessive immune response during coronavirus disease (COVID-19) can induce cytokine release syndrome (CRS), which is associated with life-threatening complications and disease progression.

Methods: This study was aimed to investigate the differences and similarities between CRS induced by COVID-19 and CAR-T therapy, then provide valuable experiences for early identification and controlling CRS progression in COVID-19. We retrospectively evaluated the clinical characteristics of severe CRS (sCRS, grade 3-4) induced by COVID-19 (40 patients) or chimeric antigen receptor T-cell (CAR-T) therapy as a comparator (41 patients).

Results: Grade 4 CRS was significantly more common in the COVID-19 group (15/40 [35.7%] vs. 5/41 [12.2%], P=0.008). CAR-T group had more more dramatic increase in cytokine than COVID-19 group (Figure1), including IL-2 (7.3pg/mL [IQR: 2.0-12.7] vs.1.7 [0.7-2.7], P<0.001), IL-6 (7120.6 pg/mL [1066.8-15 136.4] vs. 110.3 [41.7-728.1], P<0.001), IL-10 (174.5pg/mL [61.7, 434.6] vs. 10.1 [6.3-20.6], P<0.001) and IFN-γ (1308.5pg/mL [296.6, 3108.2] vs .35.0 [16.9-60.8], P<0.001). Interestingly, COVID-19 group had significantly higher levels for TNF-α (31.1 pg/ml [16.1-70.0] vs. 3.3 [1.8-9.6], P<0.001).The correlations between viral load/ tumor burden and various cytokine levels were shown in Figure 2. Lg viral loads were correlated with lg IL-6 (R2=0.101; P<0.001) and lg IL-10 (R2=0.105; P<0.001) .In CAR-T group, LDH was a common indicator related to tumor burden among patients with ALL, NHL, and MM. The lg LDH concentration was correlated with the lg serum concentration of IL-6 (R2=0.161; P=0.01). The independent risk factors for COVID-19-related sCRS were hypertension history (OR: 7.167, 95% CI: 2.345-21.903; P=0.001) and minimum platelets <100×109 /L during disease course (OR: 9.237, 95% CI: 2.544-33.546; P=0.001).

Conclusion: Our study demonstrated that there were similar processes but different intensity of inflammatory responses of sCRS in COVID-19 and CAR-T group. The diagnose and management of COVID-19 related sCRS can learn lessons from treatment of sCRS induced by CAR-T therapy.

Keywords: Cytokine release syndrome, COVID-19, Chimeric antigen receptor T-cell therapy

Figure 1

Disclosures

No relevant conflicts of interest to declare.
Risk Mitigation Strategy for Concizumab Clinical Trials after Pause Due to Non-Fatal Thrombotic Events
Authors: Seremetis Stephanie Valer , Cepo Katarina , Skovgaard Rasmussen Josephine , Høyer Rose Trine , Tamer Søren , Porstmann Thomas , Haaning Jesper
Published: November 2020

Introduction Concizumab, a humanized recombinant monoclonal antibody directed against the tissue factor pathway inhibitor, is under investigation as a subcutaneous prophylactic treatment for patients with hemophilia A or B (HA/HB) with and without inhibitors. In the concizumab phase 2 trials, treatment was well tolerated and a favorable safety profile was shown, with no deaths or thromboembolic events and no adverse events (AEs) leading to withdrawal. We describe the non-fatal thrombotic serious AEs (SAEs) that occurred during the pivotal phase 3 explorer7 (NCT04083781) and explorer8 (NCT04082429) concizumab trials and the risk mitigations incorporated in the explorer clinical trials.

Methods The explorer7 and explorer8 trials were initiated in late 2019 to evaluate the efficacy and safety of concizumab prophylaxis in HA/HB patients with/without inhibitors, respectively. Concizumab was administered subcutaneously with a 1.0 mg/kg loading dose (concizumab-naïve patients only) and a maintenance dose of 0.25 mg/kg daily from the second day onwards.

Results In March 2020, explorer7 and explorer8 were paused due to the occurrence of two arterial and three venous thrombotic SAEs in three patients with HA or HB with inhibitors. All three patients had thrombotic risk factors present at baseline and had used concomitant hemostatic medication on the day of, and in two cases in the days up to, event onset. Two of the patients were among those with the highest concizumab exposure measured during phase 3. Laboratory parameters in all three patients were as expected. Based on these analyses, risk mitigation plans were developed, including guidelines for the concomitant use of hemostatic agents in the management of bleeding episodes while on concizumab prophylaxis and updates to the concizumab dosing regimen.

Conclusion Novo Nordisk has assessed all available data and defined risk mitigation strategies and changes to the explorer trial protocols.

Disclosures

Seremetis: Novo Nordisk Ins: Current Employment, Current equity holder in private company. Cepo:Novo Nordisk: Current Employment. Skovgaard Rasmussen:Novo Nordisk: Current Employment. Høyer Rose:Novo Nordisk A/S: Current Employment, Divested equity in a private or publicly-traded company in the past 24 months. Tamer:Novo Nordisk: Current Employment, Current equity holder in private company, Divested equity in a private or publicly-traded company in the past 24 months. Porstmann:Novo Nordisk Health Care A/G: Current Employment. Haaning:Novo Nordisk: Current Employment, Current equity holder in publicly-traded company.
ANGPTL2-Containing Exosomes from Vascular Endothelial Cells Promote Leukemia Development
Authors: Sun Guohuan , Huang Dan , Hao Xiaoxin , He Xiaoxiao , Zheng Zhaofeng , Chen Chiqi , Yu Zhuo , Xie Li , Ma Shihui , Liu Ligen , Zhou Bo , Cheng Hui , Zheng Junke , Cheng Tao
Published: November 2020

Exosomes are functional messengers of certain cellular niches to permit non-contact cell communications. Whether niche-specific exosomes fulfill this role in cancer is unclear. Here, we show that blocking exosome secretion from endothelial cells (ECs), but not perivascular cells, megakaryocytes or spleen stromal cells, markedly delayed the progression of acute myeloid leukemia (AML). Notably, reducing exosome production from ECs had no effect on normal hematopoiesis. EC-derived exosomes contained a high level of ANGPTL2, which supported AML development via binding to LILRB2 receptor. Moreover, ANGPTL2 exosome released from ECs was governed by VPS33B. These findings demonstrate a role of niche-specific exosomes in cancer development and suggest that targeting ANGPTL2 exosomes from ECs might be a potential strategy to interfere AML.

Disclosures

No relevant conflicts of interest to declare.
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 (>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 < 1.3 mcg/ml, for > 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<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>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

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

Wood-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

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

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

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.
Relationship between patient activation measurement and self-rated health in patients with chronic diseases
Authors: Tusa Nina , Kautiainen Hannu , Elfving Pia , Sinikallio Sanna , Mäntyselkä Pekka
Published: November 2020

Background

In the aging population, chronic diseases and multimorbidity are common. Therefore, it is important to engage patients in their self-care. The aim of this study was to analyze the relationship between activity in self-care and self-rated health among primary care patients with chronic diseases.

Methods

The data of the present study were derived from a research project on the Participatory Patient Care Planning in Primary Care (4PHC). A total of 605 patients were recruited in the Siilinjärvi Health Center from those patients who were being monitored due to the treatment of hypertension, ischemic heart disease or diabetes.

We evaluated the level of patient’s activity in self-care with the Patient Activation Measurement (PAM). Self-rated health (SRH) was measured with the 5-item Likert scale. An adjusted hypothesis of linearity across categories of PAM and self-rated health was estimated using analysis of covariance (ANCOVA).

Results

It was found that 76 patients had low activity, 185 had moderate while 336 patients had high activity as measured with PAM. Patients with the highest activity were younger, less depressed, had a lower body mass index and a higher level of physical activity than those with the lower activity. Correspondingly, good SRH was perceived by 29, 45 and 67% of the patients in these three PAM groups adjusted with sex, age, depressive symptoms (BDI) and number of diseases. There was a significant linear trend (adjusted with age, number of diseases and depressive symptoms) between SRH and PAM, p < 0.001.

Conclusions

Activity in self-care had an independent, linear relationship with the self-rated health. The present findings suggest that Patient Activation Measurement has the potential to categorize the patients according to their perceived health and their needs related to their disease management and self-care. The present results warrant longitudinal studies on the impact of promoting patient activation levels.

Trial registration

ClinicalTrials.gov Identifier: NCT02992431. Registered 14 December 2016 https://clinicaltrials.gov/ct2/show/NCT02992431
Myasthenia gravis exacerbation after melatonin administration: case series from a tertiary referral centre
Authors: Nedkova-Hristova Velina , Vélez-Santamaría Valentina , Casasnovas Carlos
Published: November 2020

Background

Myasthenia gravis is an autoimmune disease mediated by antibodies against proteins associated with the postsynaptic membrane of the neuromuscular junction. Several drugs may trigger an exacerbation of the disease. Melatonin supplements are widely used for the treatment of insomnia as they are well tolerated with few side effects. The role of melatonin in the immune system and its effects in autoimmune disorders remain uncertain.

Case presentation

We identified three patients in our referral centre from 2014 to 2019 who presented a worsening within days or weeks of starting melatonin. Two of them stopped the treatment without clinical improvement in the next week. Increasing dose of corticosteroids did not lead to clinical improvement in the next month and one of the patients was finally administered intravenous immunoglobulins.

Conclusion

Melatonin may trigger exacerbations of myasthenia gravis, probably due to an upregulation of the adaptive immune system and an interaction with the corticosteroids and other immunosuppressant treatments. We consider that melatonin should be administered with caution in these patients.
RX-5902, a novel β-catenin modulator, potentiates the efficacy of immune checkpoint inhibitors in preclinical models of triple-negative breast Cancer
Authors: Tentler John J. , Lang Julie , Capasso Anna , Kim Deog Joong , Benaim Ely , Lee Young B. , Eisen Andrew , Bagby Stacey M. , Hartman Sarah J. , Yacob Betelehem W. , Gittleman Brian , Pitts Todd M. , Pelanda Roberta , Eckhardt S. Gail , Diamond Jennifer R.
Published: November 2020

Background

Triple-negative breast cancer (TNBC) is an aggressive breast cancer subtype with limited systemic treatment options. RX-5902 is a novel anti-cancer agent that inhibits phosphorylated-p68 and thus attenuates nuclear β-catenin signaling. The purpose of this study was to evaluate the ability of β-catenin signaling blockade to enhance the efficacy of anti-CTLA-4 and anti-PD-1 immune checkpoint blockade in immunocompetent, preclinical models of TNBC.

Methods

Treatment with RX-5902, anti-PD-1, anti-CTLA-4 or the combination was investigated in BALB/c mice injected with the 4 T1 TNBC cell line. Humanized BALB/c-Rag2nullIl2rγnullSIRPαNOD (hu-CB-BRGS) mice transplanted with a human immune system were implanted with MDA-MB-231 cells. Mice were randomized into treatment groups according to human hematopoietic chimerism and treated with RX-5902, anti-PD-1 or the combination. At sacrifice, bone marrow, lymph nodes, spleen and tumors were harvested for flow cytometry analysis of human immune cells.

Results

The addition of RX-5902 to CTLA-4 or PD-1 inhibitors resulted in decreased tumor growth in the 4 T1 and human immune system and MDA-MB-231 xenograft models. Immunologic analyses demonstrated a significant increase in the number of activated T cells in tumor infiltrating lymphocytes (TILs) with RX-5902 treatment compared to vehicle (p < 0.05). In the RX-5902/nivolumab combination group, there was a significant increase in the percentage of CD4+ T cells in TILs and increased systemic granzyme B production (p < 0.01).

Conclusions

Conclusions: RX-5902 enhanced the efficacy of nivolumab in a humanized, preclinical model of TNBC. Several changes in immunologic profiles were noted in mice treated with RX-5902 and the combination, including an increase in activated TILs and a decrease in human myeloid populations, that are often associated with immunosuppression in a tumor microenvironment. RX-5902 also was shown to potentiate the effects of checkpoint inhibitors of CTLA4 and the PD-1 inhibitor in the 4 T-1 murine TNBC model. These findings indicate that RX-5902 may have important immunomodulatory, as well as anti-tumor activity, in TNBC when combined with a checkpoint inhibitor.
Surgical treatment of 125 cases of congenital diaphragmatic eventration in a single institution
Authors: Zhao Shengliang , Pan Zhengxia , Li Yonggang , An Yong , Zhao Lu , Jin Xin , Fu Jian , Wu Chun
Published: November 2020

Background

This study sought to investigate the clinical characteristics of congenital diaphragmatic eventration (CDE) and to compare the efficacies of thoracoscopy and traditional open surgery in infants with CDE.

Methods

We retrospectively analyzed the clinical data of 125 children with CDE (90 boys, 35 girls; median age: 12.2 months, range: 1 h-7 years; body weight: 1.99–28.5 kg, median body weight: 7.87 ± 4.40 kg) admitted to our hospital in the previous 10 years, and we statistically analyzed their clinical manifestations and surgical methods.

Results

A total of 108 children in this group underwent surgery, of whom 67 underwent open surgery and 41 underwent thoracoscopic diaphragmatic plication. A total of 107 patients recovered well postoperatively, except for 1 patient who died due to respiratory distress after surgery. After 1–9.5 years of follow-up, 107 patients had significantly improved preoperative symptoms. During follow-up, the location of the diaphragm was normal, and no paradoxical movement was observed. Eleven of the 17 children who did not undergo surgical treatment did not have a decrease in diaphragm position after 1–6 years of follow-up. The index data on the operation time, intraoperative blood loss, chest drainage time, postoperative mechanical ventilation time, postoperative hospital stay and postoperative CCU admission time were better in the thoracoscopy group than in the open group. The difference between the two groups was statistically significant (P < 0.05).

Conclusions

The clinical symptoms of congenital diaphragmatic eventration vary in severity. Patients with severe symptoms should undergo surgery. Both thoracoscopic diaphragmatic plication and traditional open surgery can effectively treat congenital diaphragmatic eventration, but compared with open surgery, thoracoscopic diaphragmatic plication has the advantages of a short operation time, less trauma, and a rapid recovery. Thus, thoracoscopic diaphragmatic plication should be the first choice for children with congenital diaphragmatic eventration.
The role of the nurse in the care and management of patients with atopic dermatitis
Authors: van Os-Medendorp Harmieke , Deprez Elfie , Maes Nele , Ryan Sheila , Jackson Karina , Winders Tonya , De Raeve Linda , De Cuyper Christa , Ersser Steven
Published: November 2020

Background

The purpose of this paper is to provide an overview of key aspects of specialised dermatology nursing practice in the management of patients with moderate to severe atopic dermatitis. The role of dermatology nurse specialists in supporting patients and promoting disease understanding, education and treatment adherence continues to evolve. As features of specialised nursing care can also inform other nursing staff in a wide range of care settings, an overview of key components is examined. Observations presented are from a pan-European perspective and represent the collected view of a group of dermatology nurse specialists, dermatologists and patient advocates following two round-table discussions.

Main body

Atopic dermatitis is a common, chronic, inflammatory disease characterised by erythematous/scaling skin lesions, with often intense pruritus. Disease course is cyclic with periodic disease flares of varying intensity, presenting management challenges to patients and families. Dermatology nurse specialists play a key role in providing education and substantial patient support to improve treatment outcomes and quality of life to patients and their family, delivered within a multidisciplinary team framework. Nurse-led education and 'eczema schools’ are of benefit in reducing disease severity and improving quality of life by enhancing self-management, adherence and patient engagement. eHealth tools, such as patient portals or online training platforms, can provide online learning, individualised education, and help to improve engagement. These and other initiatives, such as written action plans, are all essential to improve or maintain treatment adherence, self-management and quality of life.

Conclusions

Dermatology nurse specialists play a central role in the assessment and management of moderate to severe atopic dermatitis patients and families. This places them in an ideal position to build strong and often long-term relationships with patients and parents. Such engagement promotes trust, assists in setting realistic expectations of treatment and outcomes, and enhances self-management and engagement in their own care. Providing emotional support, as well as formal and systematic education (including individualised practical advice) all contribute to improved treatment adherence and can enhance the quality of life of patients and their families throughout the course of this long-term condition.
Construction and investigation of a combined hypoxia and stemness index lncRNA-associated ceRNA regulatory network in lung adenocarcinoma
Authors: Guo Lili , Li Hongxia , Li Weiying , Tang Junfang
Published: November 2020

Hypoxia and stemness are important factors in tumor progression. We aimed to explore the ncRNA classifier associated with hypoxia and stemness in lung adenocarcinoma (LUAD). We found that the prognosis of LUAD patients with high hypoxia and stemness index was worse than that of patients with low hypoxia and stemness index. RNA expression profiles of these two clusters were analyzed, and 6867 differentially expressed (DE) mRNAs were screened. Functional analysis showed that DE mRNAs were associated with cell cycle and DNA replication.
Protein–protein interaction network analysis revealed 20 hub genes, among which CENPF, BUB1, BUB1B, KIF23 and TTK had significant influence on prognosis. In addition, 807 DE lncRNAs and 243 DE miRNAs were identified. CeRNA network analysis indicated that AC079160.1-miR-539-5p-CENPF may be an important regulatory axis that potentially regulates the progression of LUAD. The expression of AC079160.1 and CENPF were positively correlated with hypoxia and stemness index, while miR-539-5p expression level was negatively correlated with hypoxia and stemness index. Overall, we identified CENPF, BUB1, BUB1B, KIF23 and TTK as potentially key genes involved in regulating hypoxia-induced tumor cell stemness, and found that AC079160.1-miR-539-5p-CENPF axis may be involved in regulating hypoxia induced tumor cell stemness in LUAD.