bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting B-cell receptor and PI3K signaling in diffuse large B-cell lymphoma
Authors: Xu Wendan , Berning Philipp , Lenz Georg 
Published: July 2021

AbstractDiffuse large B-cell lymphoma (DLBCL) is a heterogeneous diagnostic category comprising distinct molecular subtypes characterized by diverse genetic aberrations that dictate patient outcome. As roughly one-third of patients with DLBCL are not cured by current standard chemoimmunotherapy, a better understanding of the molecular pathogenesis is warranted to improve outcome. B-cell receptor (BCR) signaling is crucial for the development, growth, and survival of normal B cells and a substantial fraction of malignant B cells. Various analyses revealed genetic alterations of central components of the BCR or its downstream signaling effectors in some subtypes of DLBCL. Thus, BCR signaling and the downstream NF-κB and phosphatidylinositol 3-kinase (PI3K) cascades have been proposed as potential targets for the treatment of patients with DLBCL. As one of the main effectors of BCR activation, PI3K-mediated signals play a crucial role in the pathogenesis and survival of DLBCL. In this review, we summarize our current understanding of BCR signaling with a special focus on the PI3K pathway in DLBCL and how to use this knowledge therapeutically.
BCL2 and MCL1 inhibitors for hematologic malignancies
Authors: Roberts Andrew W. , Wei Andrew H. , Huang David C. S. 
Published: July 2021

AbstractBCL2 and MCL1 are commonly expressed prosurvival (antiapoptotic) proteins in hematologic cancers and play important roles in their biology either through dysregulation or by virtue of intrinsic importance to the cell-of-origin of the malignancy. A new class of small-molecule anticancer drugs, BH3 mimetics, now enable specific targeting of these proteins in patients. BH3 mimetics act by inhibiting the prosurvival BCL2 proteins to enable the activation of BAX and BAK, apoptosis effectors that permeabilize the outer mitochondrial membrane, triggering apoptosis directly in many cells and sensitizing others to cell death when combined with other antineoplastic drugs. Venetoclax, a specific inhibitor of BCL2, is the first approved in class, demonstrating striking single agent activity in chronic lymphocytic leukemia and in other lymphoid neoplasms, as well as activity against acute myeloid leukemia (AML), especially when used in combination. Key insights from the venetoclax experience include that responses occur rapidly, with major activity as monotherapy proving to be the best indicator for success in combination regimens. This emphasizes the importance of adequate single-agent studies for drugs in this class. Furthermore, secondary resistance is common with long-term exposure and often mediated by genetic or adaptive changes in the apoptotic pathway, suggesting that BH3 mimetics are better suited to limited duration, rather than continuous, therapy. The success of venetoclax has inspired development of BH3 mimetics targeting MCL1. Despite promising preclinical activity against MYC-driven lymphomas, myeloma, and AML, their success may particularly depend on their tolerability profile given physiological roles for MCL1 in several nonhematologic tissues.
A STAT5B–CD9 axis determines self-renewal in hematopoietic and leukemic stem cells
Authors: Kollmann Sebastian , Grausenburger Reinhard , Klampfl Thorsten , Prchal-Murphy Michaela , Bastl Klavdija , Pisa Hanja , Knab Vanessa M. , Brandstoetter Tania , Doma Eszter , Sperr Wolfgang R. , Lagger Sabine , Farlik Matthias , Moriggl Richard , Valent Peter , Halbritter Florian , Kollmann Karoline , Heller Gerwin , Maurer Barbara , Sexl Veronika 
Published: July 2021

Abstract
The transcription factors signal transducer and activator of transcription 5A (STAT5A) and STAT5B are critical in hematopoiesis and leukemia. They are widely believed to have redundant functions, but we describe a unique role for STAT5B in driving the self-renewal of hematopoietic and leukemic stem cells (HSCs/LSCs). We find STAT5B to be specifically activated in HSCs and LSCs, where it induces many genes associated with quiescence and self-renewal, including the surface marker CD9. Levels of CD9 represent a prognostic marker for patients with STAT5-driven leukemia, and our findings suggest that anti-CD9 antibodies may be useful in their treatment to target and eliminate LSCs. We show that it is vital to consider STAT5A and STAT5B as distinct entities in normal and malignant hematopoiesis.
High-dose AraC is essential for the treatment of ML-DS independent of postinduction MRD: results of the COG AAML1531 trial
Authors: Hitzler Johann , Alonzo Todd , Gerbing Robert , Beckman Amy , Hirsch Betsy , Raimondi Susana , Chisholm Karen , Viola Shelton , Brodersen Lisa , Loken Michael , Tong Spencer , Druley Todd , O’Brien Maureen , Hijiya Nobuko , Heerema-McKenney Amy , Wang Yi-Chang , Shore Reuven , Taub Jeffrey , Gamis Alan , Kolb E. Anders , Berman Jason N. 
Published: July 2021

Abstract
Myeloid leukemia in children with Down syndrome (ML-DS) is associated with young age and somatic GATA1 mutations. Because of high event-free survival (EFS) and hypersensitivity of the leukemic blasts to chemotherapy, the prior Children’s Oncology Group protocol ML-DS protocol (AAML0431) reduced overall treatment intensity but lacking risk stratification, retained the high-dose cytarabine course (HD-AraC), which was highly associated with infectious morbidity. Despite high EFS of ML-DS, survival for those who relapse is rare. AAML1531 introduced therapeutic risk stratification based on the previously identified prognostic factor, measurable residual disease (MRD) at the end of the first induction course. Standard risk (SR) patients were identified by negative MRD using flow cytometry (&lt;0.05%) and did not receive the historically administered HD-AraC course. Interim analysis of 114 SR patients revealed a 2-year EFS of 85.6% (95% confidence interval [CI], 75.7-95.5), which was significantly lower than for MRD− patients treated with HD-AraC on AAML0431 (P = .0002). Overall survival at 2 years was 91.0% (95% CI, 83.8-95.0). Twelve SR patients relapsed, mostly within 1 year from study entry and had a 1-year OS of 16.7% (95% CI, 2.7-41.3). Complex karyotypes were more frequent in SR patients who relapsed compared with those who did not (36% vs 9%; P = .0248). MRD by error-corrected sequencing of GATA1 mutations was piloted in 18 SR patients and detectable in 60% who relapsed vs 23% who did not (P = .2682). Patients with SR ML-DS had worse outcomes without HD-AraC after risk classification based on flow cytometric MRD.
CoFe2O4-Quantum Dots for Synergistic Photothermal/Photodynamic Therapy of Non-small-Cell Lung Cancer Via Triggering Apoptosis by Regulating PI3K/AKT Pathway
Authors: Liu Jingfeng , Shi Xiaoying , Zhang Rongjun , Zhang Miaomiao , He Juan , Chen Jian , Wang Zheng , Wang Qingwen 
Published: July 2021

AbstractNon-small-cell lung cancer (NSCLC) has become the second most diagnosed malignant tumors worldwide. As our long-term interests in seeking nanomaterials to develop strategies of cancer therapies, we herein constructed novel CoFe2O4-quantum dots (QDs) with outstanding synergistic photothermal/photodynamic property which suppressed NSCLC efficiently without apparent toxicity. We showed that the combination of CoFe2O4-QDs + NIR treatment induces apoptosis of NSCLC cells. In addition, the CoFe2O4-QDs + NIR treatment also promotes reactive oxygen species generation to trigger cell death through regulating PI3K/AKT pathway. Moreover, the CoFe2O4-QDs + NIR treatment successfully eliminates tumor xenografts in vivo without apparent toxic effects. Taken together, we reported that the novel nanomaterials CoFe2O4-QDs could exhibit enhanced synergistic photothermal therapy and photodynamic therapy effect on killing NSCLC without toxicity, which could be a promising photosensitizer for NSCLC therapy.
Targeted immune epitope prediction to HHLA2 and MAGEB5 protein variants as therapeutic approach to related viral diseases
Authors: Achinko Daniel A. , Dormer Anton , Narayanan Mahesh , Norman Elton F. 
Published: July 2021

AbstractBackgroundTargeted immunotherapy is mostly associated with cancer treatment wherein designed molecules engage signaling pathways and mutant proteins critical to the survival of the cell. One of several genetic approaches is the use of in silico methods to develop immune epitopes targeting specific antigenic regions on related mutant proteins. In a recent study we showed a functional association between the gamma retrovirus HERV-H Long Terminal Associating (HHLA1, HHLA2 and HHLA3) proteins and melanoma associated antigen of the B class proteins (MAGEB5), with a resultant decrease in expression of HLA class I and II immune variants. HLA-C and HLA-DRB5 were the main HLA class I and II Immune variants, respectively, that showed expression changes across viral samples of interest. Specific immune variants for HLA-C and HLA-DRB5 were filtered for the top ten based on their relative frequency of counts across the samples.ResultsProtein variants for HHLA1, HHLA2, HHLA3 and MAGEB5 were used to predict antigenic epitope peptides to immune peptide-MHC class I and II binding using artificial neural networks. For IC50 peptide scores (PS) ≥ 0.5 with a transformed binding ability between 0 and 1, the top 5 epitopes identified for all targeted genes HHLA1,2 & 3 and MAGEB5 were qualified as strong or weak binders according to the threshold. Domain analysis using NCBI Conserved Domain Database (CDD) identified HHLA2 with immunoglobulin-like domains (Ig_C1-set) and MAGEB5 with the MAGE Homology Domain (MHD). Linear regression showed a statistical correlation (P < 0.001) for HHLA2 and MAGEB5 predicted epitope peptides to HLA-C but not HLA-DRB5. The prediction model identified HLA-C variant 9 (HLA-C9, BAA08825.1 HLA-B*1511) at 1.1% as the most valuable immune target for clinical considerations. Identification of the 9-mer epitope peptide within the domain showed for HHLA2: YANRTSLFY (PS = 0.5837) and VLAYYLSSSQNTIIN (PS = 0.77) for HLA-C and HLA-DRB5, respectively and for MAGEB5, peptides: FVRLTYLEY (PS = 0.5293) and YPAHYQFLWGPRAYT (PS = 0.62) for HLA-C and HLA-DRB5, respectively.ConclusionSpecific immune responses to targeted epitope peptides and their prediction models, suggested co-expression and co-evolution for HHLA2 and MAGEB5 in viral related diseases. HHLA2 and MAGEB5 could be considered markers for virus related tumors and targeted therapy for oncogenic diseases.
Mid-term (up to 12 years) clinical and echocardiographic outcomes of percutaneous transvenous mitral commissurotomy in patients with rheumatic mitral stenosis
Authors: Dadjo Yahya , Moshkani Farahani Maryam , Nowshad Reza , Sadeghi Ghahrodi Mohsen , Moaref Alireza , Kojuri Javad 
Published: July 2021

Abstract
Background
Rheumatic heart disease (RHD) is still a concerning issue in developing countries. Among delayed RHD presentations, rheumatic mitral valve stenosis (MS) remains a prevalent finding. Percutaneous transvenous mitral commissurotomy (PTMC) is the intervention of choice for severe mitral stenosis (MS). We aimed to assess the mid-term outcome of PTMC in patients with immediate success.

Methods
In this retrospective cohort study, out of 220 patients who had undergone successful PTMC between 2006 and 2018, the clinical course of 186 patients could be successfully followed. Cardiac-related death, undergoing a second PTMC or mitral valve replacement (MVR) were considered adverse cardiac events for the purpose of this study. In order to find significant factors related to adverse cardiac outcomes, peri-procedural data for the studied patients were collected.The patients were also contacted to find out their current clinical status and whether they had continued secondary antibiotic prophylaxis regimen or not. Those who had not suffered from the adverse cardiac events were additionally asked to undergo echocardiographic imaging, in order to assess the prevalence of mitral valve restenosis, defined as mitral valve area (MVA) < 1.5 cm2 and loss of ≥ 50% of initial area gain.

Results
During the mean follow-up time of 5.69 ± 3.24 years, 31 patients (16.6% of patients) had suffered from adverse cardiac events. Atrial fibrillation rhythm (p = 0.003, HR = 3.659), Wilkins echocardiographic score > 8 (p = 0.028, HR = 2.320) and higher pre-procedural systolic pulmonary arterial pressure (p = 0.021, HR = 1.031) were three independent predictors of adverse events and immediate post-PTMC mitral valve area (IMVA) ≥ 2 cm2 (p < 0.001, HR = 0.06) was the significant predictor of event-free outcome. Additionally, follow-up echocardiographic imaging detected mitral restenosis in 44 patients (23.6% of all patients). The only statistically significant protective factor against restenosis was again IMVA ≥ 2 cm2 (p = 0.001, OR = 0.240).

Conclusion
The mid-term results of PTMC are multifactorial and may be influenced by heterogeneous peri-procedural determinants. IMVA had a great impact on the long-term success of this procedure. Continuing secondary antibiotic prophylaxis was not a protective factor against adverse cardiac events in this study. (clinicaltrial.gov registration: NCT04112108).
Preoperative stereotactic radiosurgery for brain metastases: the STEP study protocol for a multicentre, prospective, phase-II trial
Authors: Ginzac Angeline , Dupic Guillaume , Brun Lucie , Molnar Ioana , Casile Mélanie , Durando Xavier , Verrelle Pierre , Lemaire Jean-Jacques , Khalil Toufic , Biau Julian 
Published: July 2021

Abstract
Background
Surgery is an important therapeutic option for brain metastases. Currently, postoperative stereotactic radiosurgery (SRT) leads to 6-month and 1-year local control estimated at 70 and 62% respectively. However, there is an increased risk of radio-necrosis and leptomeningeal relapse. Preoperative SRT might be an alternative, providing local control remains at least equivalent. It is an innovative concept that could enable the stereotactic benefits to be retained with advantages over post-operative SRT.

Methods
STEP has been designed as a national, multicentre, open-label, prospective, non-randomized, phase-II trial. Seventeen patients are expected to be recruited in the study from 7 sites and they will be followed for 12 months. Patients with more than 4 distinct brain metastases, including one with a surgical indication, and an indication for SRT and surgery, are eligible for enrolment. The primary objective of the trial is to assess 6-month local control after preoperative SRT. The secondary objectives include the assessment of local control, radio-necrosis, overall survival, toxicities, leptomeningeal relapse, distant control, cognitive function, and quality of life. The experimental design is based on a Flemming plan.

Discussion
There is very little data available in the literature on preoperative SRT: there have only been 3 American single or two-centre retrospective studies. STEP is the first prospective trial on preoperative SRT in Europe. Compared to postoperative stereotactic radiotherapy, preoperative stereotactic radiotherapy will enable reduction in the irradiated volume, leptomeningeal relapse and the total duration of the combined treatment (from 4 to 6 weeks to a few days).

Trial registration number
Clinicaltrials.gov: NCT04503772, registered on August 07, 2020. Identifier with the French National Agency for the Safety of Medicines and Health Products (ANSM): N°ID RCB 2020-A00403–36, registered in February 2020. Protocol: version 4, 07 December 2020.
Myopic foveal detachment associated with pachychoroid characteristics
Authors: Shin Yong Kyun , Han Sun Hyup , Kang Se Woong , Kim Sang Jin , Kim A Young 
Published: July 2021

Abstract
Purpose
To describe myopic nontractional foveal detachment associated with pachychoroid diseases.

Methods
This retrospective study included 15 myopic eyes which had nontractional serous foveal detachment. The eyes were divided into myopic central serous chorioretinopathy (CSC) group (n = 8) and a myopic pachychoroid neovascularization (PNV) group (n = 7) according to the presence of type 1 choroidal neovascularization on multimodal imaging. The findings of multimodal imaging and treatment response were described.

Results
In myopic CSC group, pachychoroid features such as pachyvessels, choroidal vascular hyperpermeability and punctate hyperfluorescent spots were noted in 8 eyes (100%), 8 eyes (100%), 5 eyes (62.5%) respectively. The above features were noted in 7 eyes (100%), 5 eyes (83.3%), 5 eyes (83.3%), respectively, in the myopic PNV group. Five of 8 eyes in myopic CSC and all 7 eyes received treatment including anti-vascular endothelial growth factor injection and/or photodynamic therapy. However, only five eyes had a complete response.

Conclusions
The pachychoroid phenotype may coexist with high myopia and lead to myopic nontractional serous foveal detachment. Our series suggest that the response to treatment for these conditions would be limited.
The health implications of distrust in the food system: findings from the dimensions of trust in food systems scale (DOTIFS scale)
Authors: Tonkin Emma , Webb Trevor , Henderson Julie , Ward Paul R. , Coveney John , Meyer Samantha B. , McCullum Dean , Wilson Annabelle M. 
Published: July 2021

Abstract
Background
Consumer trust in food systems is essential for consumers, food industry, policy makers and regulators. Yet no comprehensive tool for measuring consumer trust in food systems exists. Similarly, the impact that trust in the food system has on health-related food behaviours is yet to be empirically examined. The aim of this research was to develop a comprehensive instrument to measure trust in the food system (the Dimensions of Trust in Food Systems Scale (DOTIFS scale) and use it to explore whether trust in the food system impacts consumers’ health-related behaviours.

Methods
The DOTIFS scale was developed using sociological theories of trust and pre-existing instruments measuring aspects of trust. It was pilot tested and content validity was assessed with 85 participants. A mixed-methods exploration of the health-related behaviours of 18 conveniently sampled Australian consumers with differing trust scores determined by the DOTIFS scale was then conducted. During March–July 2019 shopping- and home-observations were used to assess participants’ food safety practices and exposure to public health fortification programs, while the CSIRO Healthy Diet Score determined their adherence to national dietary guidelines.

Results
The DOTIFS scale was found to have high comprehension, ease of use and content validity. Statistical analysis showed scale scores significantly trended as predicted by participants’ stated level of trust. Differences were found in the way individuals with more or less trust in the food system comply with national dietary guidelines, are exposed to public health fortification programs, and adhere to recommended food safety practices.

Conclusions
The DOTIFS scale is a comprehensive, sociologically- and empirically- informed assessment of consumer trust in food systems that can be self-administered online to large populations and used to measure changes in consumer trust over time. The differences in health-related behaviours between individuals with varying levels of trust warrant further investigation.
Determinants of multiple partner fertility among males in Uganda: a cross-sectional study
Authors: Candia Douglas Andabati , Kisangala Ephraim 
Published: July 2021

Abstract
Background
Multiple-partner fertility is a relatively new area of study, especially in Sub-Saharan Africa. This study focused on identifying determinants of multiple partner fertility among males in Uganda.

Method
The assessment was carried out using a logistic regression model and secondary data from the 2016 Uganda Demographic and Health Survey.

Results
Among the males, 42% had children with multiple partners. Older age, being Muslim, and being divorced or separated increased the likelihood of multiple partner fertility whereas residing in the Western region, reporting an age at first sex above 19 years and being married or cohabiting reduced the likelihood. Increase in number of wives or partners and lifetime sex partners resulted into a higher likelihood of multiple partner fertility.

Conclusion
There is need to come up with policies and programs aimed at increasing the age at first sex so as to reduce the likelihood of multiple partner fertility among males in Uganda. Government and other stakeholders such as cultural and religious institutions should sensitize and educate the masses on the negative outcomes of having children with multiple partners and promote fidelity for those in marriage. There is also need to increase modern contraceptive use and coverage.
Rationale and design of REGULATE: an observational study protocol for relationship between plasma metabolome and the efficacy of systemic glucocorticoid in acute exacerbation of chronic obstructive pulmonary disease
Authors: Li Qiu-Yu , An Zhuo-Yu , Pan Zi-Han , Qi Rui-Ying 
Published: July 2021

Abstract
Background
Acute exacerbation of chronic obstructive pulmonary disease (AECOPD) significantly increases the mortality of patients with COPD. Guidelines have recommended systemic glucocorticoid as a regular treatment. Recently, evidence has shown that systemic glucocorticoid cannot be a benefit to all of the patients with AECOPD. Thus, the problem that how the clinicians can screen the patients who can benefit from systemic glucocorticoid needs to be solved urgently. This study is aimed to detect the metabolic biomarkers and metabolic pathways that are related to the efficacy of systemic glucocorticoid and contribute to the precise treatment of COPD.

Methods and design
In this study, we will utilize ultraperformance liquid chromatography/mass spectrometry (LC–MS) and gas chromatography/mass spectrometry (GC–MS) methods for the analysis of the metabolites in AECOPD patients and compare the metabolites profiles between patients with systemic glucocorticoid treatment success group and treatment failure group. We aim to detect the metabolic biomarkers and metabolic pathways that are related to the efficacy of systemic glucocorticoid and contribute to the precise treatment of COPD.

Discussion
Previous studies have found that plasma metabolome changed significantly after dexamethasone treatment in healthy participants. Furthermore, inter-person variability was high and remained uninfluenced by treatment, suggesting the potential of metabolomics for predicting the efficacy and side effects of systemic glucocorticoid. Therefore, we hypothesized that metabolome changes in patients with AECOPD may be associated with the efficacy of systemic glucocorticoid.
Trial registration Clinicaltrials.gov registration number NCT04710849. Registered 15 January 2021, https://clinicaltrials.gov/ct2/show/NCT04710849.