bluuebunny/crossref_metadata_2025_split huggingface dataset:
Safety and activity of pembrolizumab in combination with rituximab in relapsed or refractory follicular lymphoma
Authors: Nastoupil Loretta J. , Chin Collin K. , Westin Jason R. , Fowler Nathan H. , Samaniego Felipe , Cheng Xiaoyun , Ma Man Chun John , Wang Zhiqiang , Chu Fuliang , Dsouza Ly , Obi Chizobam , Mims Jennifer , Feng Lei , Zhou Shouhao , Green Michael , Davis Richard Eric , Neelapu Sattva S. 
Published: January 2022

AbstractPD-1 blockade enhances the function of antitumor T cells and antibody-dependent, cell-mediated cytotoxicity (ADCC) of NK cells. In a single-center, open-label, phase 2 trial, we tested the combination of pembrolizumab, an anti-PD-1 monoclonal antibody, and rituximab, an anti-CD20 monoclonal antibody that induces ADCC, in 30 patients with follicular lymphoma (FL) with rituximab-sensitive disease who had relapsed after ≥1 prior therapy. Pembrolizumab was administered at 200 mg IV every 3 weeks for up to 16 cycles, and rituximab was given at 375 mg/m2 IV weekly for 4 weeks in cycle 1 only. The most common grade 3/4 adverse events (AEs) were liver enzyme abnormalities (3%), diarrhea (3%), nausea (3%), aseptic meningitis (3%), and pancreatitis (3%). Low-grade immune-related AEs were reported in 80% of patients, including diarrhea (43%), liver enzyme abnormalities (33%), thyroid dysfunction (27%), and rash (23%). Grade 3 or 4 immune-related AEs occurred in 13% of the patients. Treatment-related AEs led to discontinuation in 6 (20%) patients. The overall response rate (primary end point) was 67%, and the complete response (CR) rate was 50%. Median progression-free survival (PFS) was 12.6 months (95% confidence interval, 8.2-27.6), the 3-year overall survival rate was 97%, and 23% of patients were in remission at a median follow-up of 35 months. The presence of a high CD8+ T-effector score at baseline in the tumor was associated with induction of a CR and improved PFS. In this single-arm, phase 2 study, the combination of pembrolizumab and rituximab demonstrates favorable efficacy and safety profile in relapsed FL. This trial is registered at www.clinicaltrials.gov as #NCT02446457.
A novel mouse model of type 2N VWD was developed by CRISPR/Cas9 gene editing and recapitulates human type 2N VWD
Authors: Shi Qizhen , Fahs Scot A. , Mattson Jeremy G. , Yu Hongyin , Perry Crystal L. , Morateck Patricia A. , Schroeder Jocelyn A. , Rapten Jessica , Weiler Hartmut , Montgomery Robert R. 
Published: January 2022

Abstract
Type 2N von Willebrand disease is caused by mutations in the factor VIII (FVIII) binding site of von Willebrand factor (VWF), resulting in dysfunctional VWF with defective binding capacity for FVIII. We developed a novel type 2N mouse model using CRISPR/Cas9 technology. In homozygous VWF2N/2N mice, plasma VWF levels were normal (1167 ± 257 mU/mL), but the VWF was completely incapable of binding FVIII, resulting in 53 ± 23 mU/mL of plasma FVIII levels that were similar to those in VWF-deficient (VWF−/−) mice. When wild-type human or mouse VWF was infused into VWF2N/2N mice, endogenous plasma FVIII was restored, peaking at 4 to 6 hours post-infusion, demonstrating that FVIII expressed in VWF2N mice is viable but short-lived unprotected in plasma due to dysfunctional 2N VWF. The whole blood clotting time and thrombin generation were impaired in VWF2N/2N but not in VWF−/− mice. Bleeding time and blood loss in VWF2N/2N mice were similar to wild-type mice in the lateral tail vein or ventral artery injury model. However, VWF2N/2N mice, but not VWF−/− mice, lost a significant amount of blood during the primary bleeding phase after a tail tip amputation injury model, indicating that alternative pathways can at least partially restore hemostasis when VWF is absent. In summary, we have developed a novel mouse model by gene editing with both the pathophysiology and clinical phenotype found in severe type 2N patients. This unique model can be used to investigate the biological properties of VWF/FVIII association in hemostasis and beyond.
The probable role and therapeutic potential of the PI3K/AKT signaling pathway in SARS-CoV-2 induced coagulopathy
Authors: Khezri Mohammad Rafi , Varzandeh Reza , Ghasemnejad-Berenji Morteza 
Published: January 2022

AbstractCoronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), is associated with a high mortality rate. The majority of deaths in this disease are caused by ARDS (acute respiratory distress syndrome) followed by cytokine storm and coagulation complications. Although alterations in the level of the number of coagulation factors have been detected in samples from COVID-19 patients, the direct molecular mechanism which has been involved in this pathologic process has not been explored yet. The PI3K/AKT signaling pathway is an intracellular pathway which plays a central role in cell survival. Also, in recent years the association between this pathway and coagulopathies has been well clarified. Therefore, based on the evidence on over-activity of the PI3K/AKT signaling pathway in SARS-CoV-2 infection, in the current review, the probable role of this cellular pathway as a therapeutic target for the prevention of coagulation complications in patients with COVID-19 is discussed.
Spatiotemporal expression profile of novel and known small RNAs throughout rice plant development focussing on seed tissues
Authors: Meijer Anikó , De Meyer Tim , Vandepoele Klaas , Kyndt Tina 
Published: January 2022

AbstractBackgroundSmall RNAs (sRNAs) regulate numerous plant processes directly related to yield, such as disease resistance and plant growth. To exploit this yield-regulating potential of sRNAs, the sRNA profile of one of the world’s most important staple crops – rice – was investigated throughout plant development using next-generation sequencing.ResultsRoot and leaves were investigated at both the vegetative and generative phase, and early-life sRNA expression was characterized in the embryo and endosperm. This led to the identification of 49,505 novel sRNAs and 5581 tRNA-derived sRNAs (tsRNAs). In all tissues, 24 nt small interfering RNAs (siRNAs) were highly expressed and associated with euchromatic, but not heterochromatic transposable elements. Twenty-one nt siRNAs deriving from genic regions in the endosperm were exceptionally highly expressed, mimicking previously reported expression levels of 24 nt siRNAs in younger endosperm samples. In rice embryos, sRNA content was highly diverse while tsRNAs were underrepresented, possibly due to snoRNA activity. Publicly available mRNA expression and DNA methylation profiles were used to identify putative siRNA targets in embryo and endosperm. These include multiple genes related to the plant hormones gibberellic acid and ethylene, and to seed phytoalexin and iron content.ConclusionsThis work introduces multiple sRNAs as potential regulators of rice yield and quality, identifying them as possible targets for the continuous search to optimize rice production.
Adaptation of the Patient Benefit Assessment Scale for Hospitalised Older Patients: development, reliability and validity of the P-BAS picture version
Authors: van der Kluit Maria Johanna , Dijkstra Geke J. , de Rooij Sophia E. 
Published: January 2022

Abstract
Background
The Patient Benefit Assessment Scale for Hospitalised Older Patients (P-BAS HOP) is a tool developed to both identify the priorities of the individual patient and to measure the outcomes relevant to him/her, resulting in a Patient Benefit Index (PBI), indicating how much benefit the patient had experienced from the hospitalisation. The reliability and the validity of the P-BAS HOP appeared to be not yet satisfactory and therefore the aims of this study were to adapt the P-BAS HOP and transform it into a picture version, resulting in the P-BAS-P, and to evaluate its feasibility, reliability, validity, responsiveness and interpretability.

Methods
Process of instrument development and evaluation performed among hospitalised older patients including pilot tests using Three-Step Test-Interviews (TSTI), test-retest reliability on baseline and follow-up, comparing the PBI with Intraclass Correlation Coefficient (ICC), and hypothesis testing to evaluate the construct validity. Responsiveness of individual P-BAS-P scores and the PBI with two different weighing schemes were evaluated using anchor questions. Interpretability of the PBI was evaluated with the visual anchor-based minimal important change (MIC) distribution method and computation of smallest detectable change (SDC) based on ICC.

Results
Fourteen hospitalised older patients participated in TSTIs at baseline and 13 at follow-up after discharge. After several adaptations, the P-BAS-P appeared feasible with good interviewer’s instructions. The pictures were considered relevant and helpful by the participants. Reliability was tested with 41 participants at baseline and 50 at follow-up. ICC between PBI1 and PBI2 of baseline test and retest was 0.76, respectively 0.73. At follow-up 0.86, respectively 0.85.
For the construct validity, tested in 169 participants, hypotheses regarding importance of goals were confirmed. Regarding status of goals, only the follow-up status was confirmed, baseline and change were not. The responsiveness of the individual scores and PBI were weak, resulting in poor interpretability with many misclassifications. The SDC was larger than the MIC.

Conclusions
The P-BAS-P appeared to be a feasible instrument, but there were methodological barriers for the evaluation of the reliability, validity, and responsiveness. We therefore recommend further research into the P-BAS-P.
Variable roles of interleukin-17F in different cancers
Authors: Mikkola Tiina , Almahmoudi Rabeia , Salo Tuula , Al-Samadi Ahmed 
Published: January 2022

AbstractBackgroundInterleukin (IL)-17 family is a group of six cytokines that plays a central role in inflammatory processes and participates in cancer progression. Interleukin-17A has been shown to have mainly a protumorigenic role, but the other members of the IL-17 family, including IL-17F, have received less attention.MethodsWe applied systematic review guidelines to study the role of IL-17F, protein and mRNA expression, polymorphisms, and functions, in cancer. We carried out a systematic search in PubMed, Ovid Medline, Scopus, and Cochrane libraries, yielding 79 articles that met the inclusion criteria.ResultsThe findings indicated that IL-17F has both anti- and protumorigenic roles, which depend on cancer type and the molecular form and location of IL-17F. As an example, the presence of IL-17F protein in tumor tissue and patient serum has a protective role in oral and pancreatic cancers, whereas it is protumorigenic in prostate and bladder cancers. These effects are proposed to be based on multiple mechanisms, such as inhibition of angiogenesis, vasculogenic mimicry and cancer cell proliferation, migration and invasion, and aggravating the inflammatory process. No solid evidence emerged for the correlation between IL-17F polymorphisms and cancer incidence or patients’ prognosis.ConclusionIL-17F is a multifaceted cytokine. There is a clear demand for more well-designed studies of IL-17F to elucidate its molecular mechanisms in different types of cancer. The studies presented in this article examined a variety of different designs, study populations and primary/secondary outcomes, which unfortunately reduces the value of direct interstudy comparisons.
Time trends in type 2 diabetes mellitus incidence across the BRICS from 1990 to 2019: an age-period-cohort analysis
Authors: Sun Panglin , Wen Haoyu , Liu Xiaoxue , Ma Yudiyang , Jang Jie , Yu Chuanhua 
Published: January 2022

Abstract
Background
The incidence rate of type 2 diabetes mellitus (T2DM) is rapidly increasing in Brazil, Russia, India, China, and South Africa (BRICS). The present study analyzed trends in T2DM incidence rate across the BRICS and associations with age, period, and birth cohort.

Methods
The incidence rate was estimated by the data obtained from GBD 2019 (Global Burden of Disease Study 2019) and was analyzed with the age-period-cohort framework. Incidence rates of T2DM (1990–2019) were collected for each 5-year age group (from 25 to 29 to 85–89 age group) stratified by gender from the Global Burden of Disease 2019 Study.

Results
In 2019, the the incidence rate of T2DM was 280.2 per 100,000 across the BRICS. Between 1990 and 2019, the incidence rate of T2DM among the BRICS population increased by 83.3%. In each period, as age increases, the incidence rate of T2DM in China and Russia first increased and then decreased, while the incidence rate of T2DM in Brazil, India and South Africa first increased and then decreased slightly with age group. Deteriorating period and cohort risks for incidence rate of T2DM were generally found across the BRICS.

Conclusions
The number of diabetic patients in the BRICS countries has continued to increase and the growth rate has been stable in the past 30 years, which is dependent on age and some other environmental factors. Some possible factors influencing T2DM incidence are analyzed and hypotheses generated through the age and period effects.
Association of healthy lifestyle with risk of obstructive sleep apnea: a cross-sectional study
Authors: Duan Xueru , Huang Jun , Zheng Murui , Zhao Wenjing , Lao Lixian , Li Haiyi , Wang Zhiwei , Lu Jiahai , Chen Weiqing , Deng Hai , Liu Xudong 
Published: January 2022

Abstract
Background
No studies investigated the whole effect of modifiable lifestyle factors on OSA risk. This study aimed to examine the individual and combined effects of lifestyle factors on OSA risk among Chinese adults.

Methods
This cross-sectional study included 9733 participants aged 35 to 74 years from the baseline survey of Guangzhou Heart Study. OSA was evaluated by Berlin Questionnaire. The healthy lifestyle score (HLS), representing the overall effect of lifestyles, was derived from seven lifestyle factors: active smoking, passive smoking, alcohol, diet, waist-hip ratio, leisure-time physical activity, and mental status. Odds ratio (OR) with 95% confidence interval (CI) was calculated using the multivariate logistic regression model.

Results
8107 participants were divided into the non-OSA group and 1626 participants into the OSA group. No passive smoking (OR 0.83, 95% CI 0.74–0.94), healthy waist-hip ratio (OR 0.67, 95% CI 0.58–0.77) and healthy mental status (OR 0.45, 95% CI 0. 29–0.73) were associated with a reduced risk of OSA after adjusting for confounders, while others not. Participants with higher HLS were negatively associated with OSA risk (P-trend < 0.001). In comparison to the participants with 0–3 HLS, the OR for participants with 4, 5, 6, and 7 HLS was 0.68 (95% CI 0.56–0.84), 0.71 (95% CI 0.59–0.86), 0.62 (95% CI 0.51–0.76) and 0.49 (95% CI 0.37–0.65) after adjusting for confounders. Every 1-score increment of HLS was associated with a 13% lower risk of OSA.

Conclusions
The results suggest that HLS reflecting the combined effect of multiple-dimensional lifestyle factors was inversely associated with OSA risk. Preventive strategies integrating multiple lifestyle factors may provide a more feasible approach for OSA prevention.
Association of SMAD7 genetic markers and haplotypes with colorectal cancer risk
Authors: Alidoust Maryam , Hamzehzadeh Leila , Khorshid Shamshiri Asma , Afzaljavan Fahimeh , Kerachian Mohammad Amin , Fanipakdel Azar , Aledavood Seyed Amir , Allahyari Abolghasem , Bari Alireza , Moosanen Mozaffari Hooman , Goshayeshi Ladan , Pasdar Alireza 
Published: January 2022

Abstract
Purpose
Colorectal cancer (CRC) is one of the common cancers with a high mortality rate worldwide. In Iran, there has been a trend of increased incidence of colorectal cancer in the last three decades that necessitates the early diagnosis. Genetic factors have an influential role in its etiology along with the conventional risk factors such as age, diet, and lifestyle. Results from GWAS have shown significant associations between SMAD7 gene variants and risk of CRC. This study aimed to assess the association of certain polymorphisms as well as haplotypes of this gene and risk of colorectal cancer.

Methods and materials
This study was designed as a case–control association study. After obtaining ethical approval and informed consent, blood samples from 209 patients with colorectal cancer were collected and DNA was extracted. Four variants: rs4939827, rs34007497, rs8085824 and rs8088297 were genotyped using ARMS-PCR method.

Results
SMAD7 rs4939827 in the recessive and co-dominant models was associated with colorectal cancer risk [TT/CT + CC: OR = 2.90, 95%CI (1.38–6.09), p = 0.005; CC + TT/CT: OR = 1.66, 95%CI (1.00–2.75), p = 0.01]. Haplotype analysis indicated that some SNP combinations including two for-SNPs haplotypes of T-T-C-C and T-C-C-A were significantly associated with CRC risk.

Conclusion
Based on the identified association of SMAD7 gene variations and haplotypes with colorectal cancer risk in our population, genetic variations in this gene region may have a role in CRC development. This data may shed light on the genetic predisposition of CRC which involves different pathways including TGF-β.
Validation of the German Benefit Finding Scale for Youth with chronic conditions
Authors: von Rezori Roman E. , Buchallik Friederike , Warschburger Petra 
Published: January 2022

Abstract
Background
Benefit finding, defined as perceiving positive life changes resulting from adversity and negative life stressors, gains growing attention in the context of chronic illness. The study aimed at examining the psychometric properties of the Benefit Finding Scale for Children (BFSC) in a sample of German youth facing chronic conditions.

Methods
A sample of adolescents with various chronic conditions (N = 304; 12 – 21years) completed the 10-item BFSC along with measures of intra- and interpersonal resources, coping strategies, and health-related quality of life (hrQoL). The total sample was randomly divided into two subsamples for conducting exploratory and confirmatory factor analyses (EFA/CFA).

Results
EFA revealed that the BFSC scores had a one-dimensional factor structure. CFA verified the one-dimensional factor structure with an acceptable fit. The BFSC exhibited acceptable internal consistency (α = 0.87 – 0.88) and construct validity. In line with our hypotheses, benefit finding was positively correlated with optimism, self-esteem, self-efficacy, sense of coherence, and support seeking. There were no correlations with avoidance, wishful thinking, emotional reaction, and hrQoL. Sex differences in benefit finding were not consistent across subsamples. Benefit finding was also positively associated with age, disease severity, and social status.

Conclusions
The BFSC is a psychometrically sound instrument to assess benefit finding in adolescents with chronic illness and may facilitate further research on positive adaptation processes in adolescents, irrespective of their specific diagnosis.
Espiritismo and Santeria: a gateway to child mental health services among Puerto Rican families?
Authors: Zerrate M. Carolina , VanBronkhorst Sara B. , Klotz Jaimie , Caraballo Angel A. , Canino Glorisa , Bird Hector R. , Duarte Cristiane S. 
Published: January 2022

AbstractBackgroundBarriers to mental health care access among Latinx children contribute to mental health disparities. It is unclear whether traditional spiritual guides in Latinx communities may function more as gateway providers or in some instances as deterrents to mental health treatment. This study assesses whether family involvement in Espiritismo and/or Santeria, two forefront non-Christian spiritual traditions among Latinx families, is associated with mental health care utilization among Puerto Rican children in two contexts.MethodsData are from Waves 1–3 (2000–2004) of the Boricua Youth Study, a population-based longitudinal cohort study of Puerto Rican children from San Juan and Caguas, Puerto Rico (PR), and the South Bronx, New York (SBx), 5 to 17 years of age (N = 2491).ResultsAt baseline, 5.02% (n = 58) of the families reported involvement with Espiritismo and/or Santeria in the SBx and 3.64% (n = 52) in PR. Logistic regression models predicting mental health service use found, after adjusting for multiple risk and protective factors, that families involved with Espiritismo and/or Santeria were 2.41 times more likely (p = 0.0034) to use mental health services over the course of 3 years than children with no family involvement in these practices in the SBx. The same association was not found in PR.ConclusionsThe findings among PR families in the SBx lend support to the gateway provider model in which spiritual guides open doors to mental health treatment. Forming community connections between mental health providers and traditional spiritual groups may be a culturally considerate, fruitful approach to reducing barriers to mental health treatment among Latinx families.
Omics analysis coupled with gene editing revealed potential transporters and regulators related to levoglucosan metabolism efficiency of the engineered Escherichia coli
Authors: Chang Dongdong , Wang Cong , Ul Islam Zia , Yu Zhisheng 
Published: January 2022

Abstract
Background
Bioconversion of levoglucosan, a promising sugar derived from the pyrolysis of lignocellulose, into biofuels and chemicals can reduce our dependence on fossil-based raw materials. However, this bioconversion process in microbial strains is challenging due to the lack of catalytic enzyme relevant to levoglucosan metabolism, narrow production ranges of the native strains, poor cellular transport rate of levoglucosan, and inhibition of levoglucosan metabolism by other sugars co-existing in the lignocellulose pyrolysate. The heterologous expression of eukaryotic levoglucosan kinase gene in suitable microbial hosts like Escherichia coli could overcome the first two challenges to some extent; however, no research has been dedicated to resolving the last two issues till now.

Results
Aiming to resolve the two unsolved problems, we revealed that seven ABC transporters (XylF, MalE, UgpB, UgpC, YtfQ, YphF, and MglA), three MFS transporters (KgtP, GntT, and ActP), and seven regulatory proteins (GalS, MhpR, YkgD, Rsd, Ybl162, MalM, and IraP) in the previously engineered levoglucosan-utilizing and ethanol-producing E. coli LGE2 were induced upon exposure to levoglucosan using comparative proteomics technique, indicating these transporters and regulators were involved in the transport and metabolic regulation of levoglucosan. The proteomics results were further verified by transcriptional analysis of 16 randomly selected genes. Subsequent gene knockout and complementation tests revealed that ABC transporter XylF was likely to be a levoglucosan transporter. Molecular docking showed that levoglucosan can bind to the active pocket of XylF by seven H-bonds with relatively strong strength.

Conclusion
This study focusing on the omics discrepancies between the utilization of levoglucosan and non-levoglucosan sugar, could provide better understanding of levoglucosan transport and metabolism mechanisms by identifying the transporters and regulators related to the uptake and regulation of levoglucosan metabolism. The protein database generated from this study could be used for further screening and characterization of the transporter(s) and regulator(s) for downstream enzymatic/genetic engineering work, thereby facilitating more efficient microbial utilization of levoglucosan for biofuels and chemicals production in future.