bluuebunny/crossref_metadata_2025 huggingface dataset:
Single-Cell Sequencing Analysis Based on Public Databases for Constructing a Metastasis-Related Prognostic Model for Gastric Cancer
Authors: Xu Rubin , Chen Liang , Wei Wei , Tang Qikai , Yu You , Hu Yiming , Kadasah Sultan , Xie Jiaheng , Yu Hongzhu
Published: April 2022

Background. Although incidences of gastric cancer have decreased in recent years, the disease remains a significant danger to human health. Lack of early symptoms often leads to delayed diagnosis of gastric cancer, so that many patients miss the opportunity for surgery. Treatment for advanced gastric cancer is often limited. Immunotherapy, targeted therapy, and the mRNA vaccine have all emerged as potentially viable treatments for advanced gastric cancer. However, our understanding of the immune microenvironment of gastric cancer is far from sufficient; now is the time to explore this microenvironment. Methods. In our study, using TCGA dataset and the GEO dataset GSE62254, we performed in-depth transcriptome and single-cell sequencing analyses based on public databases. We analyzed differential gene expressions of immune cells in metastatic and nonmetastatic gastric cancer and constructed a prognostic model of gastric cancer patients based on these differential gene expressions. We also screened candidate vaccine genes for gastric cancer. Results. This prognostic model can accurately predict the prognosis of gastric cancer patients by dividing them into high-risk and low-risk groups. In addition to this, we identified a candidate vaccine gene for gastric cancer: PTPN6. Conclusions. Our study could provide new ideas for the treatment of gastric cancer.
Clinical Value Analysis of Combined Vaginal Ultrasound, Magnetic Resonance Dispersion Weighted Imaging, and Multilayer Spiral CT in the Diagnosis of Endometrial Cancer Using Deep VGG-16 AdaBoost Hybrid Classifier
Authors: Wang Xiaoyi , Zhang Rong
Published: April 2022

Endometrial carcinoma is one of the most common disorders of the female reproductive system. Every year, around 76,000 women die from endometrial cancer around the world. Endometrial cancer is a significant factor in women’s health, particularly in industrialized nations, where the prevalence of this tumor type is the greatest. It is an important concern in women’s health because of disease mortality and the rising number of new diagnoses. The aim of the study was to investigate the clinical value of combined transvaginal ultrasound, magnetic resonance dispersion weighted imaging, and multilayer spiral computed tomography (CT) in the diagnosis of early-stage endometrial cancer. Initially, the dataset is collected that consisted of a total of 100 cases and split into the control group and experimental group of 50 cases in each group. The control group is diagnosed using conventional Doppler ultrasound diagnostic machine. The experimental group is diagnosed with combined ultrasound method. The ultrasound images thus obtained are preprocessed using the speckle-free adaptive wiener filter. The preprocessed images are segmented using the fuzzy clustering segmentation method. The features are extracted by the independent component analysis (ICA) method. We have proposed the deep VGG-16 AdaBoost hybrid classifier for classifying the normal and abnormal images. The clinical value of the diagnosis is analyzed using the parameters like diagnostic accuracy, specificity, sensitivity, and kappa coefficient. It is observed that the clinical value is better for the experimental group than the control group.
Further Evidence of a Continuum in the Clinical Spectrum of Dominant PIEZO2-Related Disorders and Implications in Cerebellar Anomalies
Authors: Abdel-Salam Ghada M.H. , Afifi Hanan H. , Saleem Sahar N. , Gadelhak Mohamed I. , El-Serafy Manar A. , Sayed Inas S.M. , Abdel-Hamid Mohamed S.
Published: April 2022

Introduction: Pathogenic variants in the PIEZO family member 2 (PIEZO2) gene are known to cause Gordon syndrome (GS), Marden-Walker syndrome (MWS), and distal arthrogryposis type 5 (DA5). Out of these, MWS has a recognizable phenotype that can be discerned easily, but the distinction between GS and DA5 is less evident. Few children with pathogenic PIEZO2 variants have been reported to show posterior fossa anomalies. Methods and Results: By candidate gene targeting guided by proper clinical evaluation and neuroimaging findings, a patient with classic MWS harboring a de novo novel variant (c.8237G>A, p.W2746*) in the C-terminal region of PIEZO2 was identified. In addition, another girl with the typical clinical features of GS is also described carrying the most prevalent reported variant (c.8057G>A, p.R2686H) in PIEZO2. The brain MRI of the 2 patients showed Dandy-Walker malformation (DWM). Diffusion tensor imaging visualized anteroposterior and downward aligned thin middle cerebellar peduncle. The association of DWM with arthrogryposis in the presence of PIEZO2 variants remains quite interesting and provides more evidence that PIEZO2 plays a role in the development of hindbrain although the underlying mechanism remains unclear. Moreover, the 2 girls had distinct foot patterning in the form of shortening of the first and fifth toes. Conclusion: Phenotype analysis and a comprehensive review of the literature strongly support the previously published data and corroborate the evidence that heterozygous PIEZO2-related disorders represent a continuum with overlapping phenotypic features.
Neuroprotection in the Striatum of Hypoxic-Ischemic Piglets by Simultaneous Inhibition of Dopamine D1 and Adenosine A2A Receptors
Authors: Wang Bing , Kulikowicz Ewa , Koehler Raymond C. , Yang Zeng-Jin
Published: April 2022

Introduction: Striatal neurons of term newborns are highly vulnerable to hypoxia-ischemia (H-I). In a piglet model of H-I, a dopamine D1 receptor antagonist and an adenosine A2A receptor antagonist alone preferentially protect striatonigral and striatopallidal neurons, respectively. Here, we tested the hypothesis whether the combined treatment with SCH23390, a D1 receptor antagonist, and SCH58261, an A2A receptor antagonist, is more efficacious than individual D1 and A2A receptor antagonist treatment. Methods: Anesthetized newborn piglets were subjected to sham operation (n = 6) or 40 min of hypoxia and 7 min of airway occlusion. At 5 min of reoxygenation, piglets received the vehicle, SCH23390, SCH58261, or the combined treatment (n = 9 in each group). At 4 days of recovery, the number of viable neurons in the entire putamen was estimated by unbiased stereology. Results: Stereological results showed that sham-operated piglets had an estimated 2.9 × 106 neurons in the putamen, and the number of viable neurons in hypoxic-ischemic piglets was significantly reduced by 80% to 0.6 × 106/putamen. Treatment with SCH23390, SCH58261, and the combination increased the numbers of viable neurons to 1.4 × 106/putamen, 1.4 × 106/putamen, and 2.1 × 106/putamen, respectively. Notably, the combined treatment improved neuroprotection compared to individual therapy. Conclusion: We conclude that simultaneous inhibition of dopamine D1 receptors and adenosine A2A receptors saves more neurons than individual treatment in the highly vulnerable putamen of a large-animal neonatal H-I model.
Differential Association of Serum n-3 Polyunsaturated Fatty Acids with Various Cerebrovascular Lesions in Japanese Men
Authors: Kondo Keiko , Arima Hisatomi , Fujiyoshi Akira , Sekikawa Akira , Kadota Aya , Hisamatsu Takashi , Torii Sayuki , Shiino Akihiko , Morino Katsutaro , Miyagawa Naoko , Segawa Hiroyoshi , Watanabe Yoshiyuki , Maegawa Hiroshi , Nozaki Kazuhiko , Miura Katsuyuki , Ueshima Hirotsugu ,   for the SESSA Research Group
Published: April 2022

Background: An association between a high intake of marine-derived n-3 polyunsaturated fatty acids (n-3 PUFAs) with a lower risk of coronary heart disease was previously reported. However, the association between n-3 PUFAs and cerebrovascular lesions remains unclear. We evaluated this association in a general-population-based sample of Japanese men. Methods: Participants were community-dwelling men (40–79 years old) living in Kusatsu City, Shiga, Japan. Serum concentrations of n-3 PUFAs, defined as the sum of eicosapentaenoic and docosahexaenoic acids, were measured via gas-liquid chromatography between 2006 and 2008. Magnetic resonance imaging was used to assess cerebrovascular lesions (including intracerebral large-artery stenosis, lacunar infarction, and microbleeds) and white matter lesions between 2012 and 2015. Logistic regression adjusting for conventional cardiovascular risk factors was used to estimate the odds ratio of prevalent cerebrovascular lesions per 1 standard deviation higher serum concentration of n-3 PUFAs. Results: Of a total of 739 men, the numbers (crude prevalence in %) of prevalent cerebral large-artery stenoses, lacunar infarctions, microbleeds, and white matter lesions were 222 (30.0), 162 (21.9), 103 (13.9), and 164 (22.2), respectively. A 1 standard deviation higher concentration of n-3 PUFAs (30.5 μmol/L) was independently associated with lower odds of cerebral large-artery stenosis (multivariable-adjusted odds ratio, 0.80; 95% confidential interval, 0.67–0.97). There were no significant associations of n-3 PUFAs with the other types of lesions. Conclusions: n-3 PUFAs may have protective effects against large-artery stenosis, but not small vessel lesions, in the brain.
Mycophenolate Mofetil in the Treatment of Severe Corticosteroid-Dependent or Corticosteroid-Resistant Nail Lichen Planus: A Case Series of 5 Patients
Authors: Duplaine Alexandra , Cogrel Olivier
Published: April 2022

Introduction: Recent expert recommendations suggest mycophenolate mofetil (MMF) as a third-line therapy, in severe corticosteroid-dependent or corticosteroid-resistant nail lichen planus (NLP). However, there is currently no literature to support MMF use in this indication. This is a retrospective monocentric French case series of 5 patients with severe corticodependant or corticoresistant NLP treated by oral MMF (2–3 g/day), between 2013 and 2021. Case Presentation: The primary outcome was therapeutic success in a target fingernail. All 5 patients showed some clinical improvement, ranging from mild improvement (1/5) to clinical cure (2/5). Clinical improvement was more significant when the drug was taken for a longer period (24 months vs. 4 months) and at a higher dose (3 g/day vs. 2 g/day). Relapse occurred after stopping or tapering the MMF dose. MMF was well tolerated. Discussion/Conclusion: MMF may be a treatment to consider for severe corticosteroid-dependent or corticosteroid-resistant NLP. The long-term safety of this treatment warrants further investigation.
The Quick Dementia Rating System and Its Relationship to Biomarkers of Alzheimer’s Disease and Neuropsychological Performance
Authors: Duff Kevin , Wan Laura , Levine Deborah A. , Giordani Bruno , Fowler Nicole R. , Fagerlin Angela , King Jace B. , Hoffman John M.
Published: April 2022

Introduction: The Quick Dementia Rating System (QDRS) is a brief, patient-reported dementia staging tool that has approximated scores on the Clinical Dementia Rating Scale in patients with Alzheimer’s disease (AD). However, no studies have examined its relationship with AD-related biomarkers. Methods: One-hundred twenty-one older adults (intact, amnestic mild cognitive impairment, mild AD) completed the QDRS, and three biomarkers (amyloid deposition via positron emission tomography, hippocampal volume via magnetic resonance imaging, and apolipoprotein [APOE] ε4 status). Results: The Total score on the QDRS was statistically significantly related to all three biomarkers (after controlling for age, education, sex, and race), with greater levels of dementia severity being associated with greater amyloid deposition, smaller hippocampi, and having copies of APOE ε4 allele. Discussion: In participants across the cognitive spectrum, the QDRS showed modest relationships with amyloid deposition, hippocampal volumes, and APOE status. Therefore, the QDRS may offer a cost-effective screening method for clinical trials in AD.
Perioperative Cardiometabolic Targets and Coronary Artery Bypass Surgery Mortality in Patients With Diabetes
Authors: Skendelas John P. , Phan Donna K. , Friedmann Patricia , Rodriguez Carlos J. , Stein Daniel , Arbab‐Zadeh Armin , Forest Stephen J. , Slipczuk Leandro
Published: April 2022

Background

Coronary artery bypass graft (CABG) surgery represents the preferred revascularization strategy for most patients with diabetes and multivessel disease. We aimed to evaluate the role of optimized, perioperative cardiometabolic targets on long‐term survival in patients who underwent CABG.

Methods and Results

Single‐institution retrospective study was conducted in patients with diabetes who underwent CABG between January 2010 and June 2018. Demographic, surgical, and cardiometabolic determinants were identified during the perioperative period. Clinical characteristics and longitudinal survival outcomes data were obtained. A total of 1534 patients with CABG were considered for analysis and 1273 met inclusion criteria. The mean age of patients was 63.3 years (95% CI, 62.7–63.8 years), and most were men (65%) and Hispanic or Latino (47%). Comorbidities included hypertension (95%) and dyslipidemia (88%). In total, 490 patients (52%) had a low‐density lipoprotein cholesterol level >70 mg/dL. Furthermore, 390 patients (31%) had uncontrolled systolic blood pressure >130 mm Hg. Last, only 386 patients (29%) had a hemoglobin A
1c
level between 6% and 7%. At 5 years, 121 patients (10%) died. Failure to achieve goal systolic blood pressure was associated with all‐cause (hazard ratio [HR], 1.573; 95% CI, 1.048–2.362 [
P
=0.029]) and cardiovascular (HR, 2.023; 95% CI, 1.196–3.422 [
P
=0.009]) mortality at 5 years post‐CABG. In contrast, prescription of a statin during the perioperative interval demonstrated a protective effect for all‐cause (HR, 0.484; 95% CI, 0.286–0.819 [
P
=0.007]) and cardiovascular (HR, 0.459; 95% CI, 0.229–0.920 [
P
=0.028]) mortality. There was no association between achievement of low‐density lipoprotein cholesterol, triglycerides, non–high‐density lipoprotein cholesterol, or hemoglobin A
1c
level goals and mortality risk at 5 years.

Conclusions

Among patients with diabetes, blood pressure control and statin therapy were the most important perioperative cardiometabolic survival determinants 5 years after CABG.
Canonical Workflow for Machine Learning Tasks
Authors: Blanchi Christophe , Gebre Binyam , Wittenburg Peter
Published: April 2022

There is a huge gap between (1) the state of workflow technology on the one hand and the practices in the many labs working with data driven methods on the other and (2) the awareness of the FAIR principles and the lack of changes in practices during the last 5 years. The CWFR concept has been defined which is meant to combine these two intentions, increasing the use of workflow technology and improving FAIR compliance. In the study described in this paper we indicate how this could be applied to machine learning which is now used by almost all research disciplines with the well-known effects of a huge lack of repeatability and reproducibility.

Researchers will only change practices if they can work efficiently and are not loaded with additional tasks. A comprehensive CWFR framework would be an umbrella for all steps that need to be carried out to do machine learning on selected data collections and immediately create a comprehensive and FAIR compliant documentation. The researcher is guided by such a framework and information once entered can easily be shared and reused. The many iterations normally required in machine learning can be dealt with efficiently using CWFR methods.

Libraries of components that can be easily orchestrated using FAIR Digital Objects as a common entity to document all actions and to exchange information between steps without the researcher needing to understand anything about PIDs and FDO details is probably the way to increase efficiency in repeating research workflows. As the Galaxy project indicates, the availability of supporting tools will be important to let researchers use these methods. Other as the Galaxy framework suggests, however, it would be necessary to include all steps necessary for doing a machine learning task including those that require human interaction and to document all phases with the help of structured FDOs.
Evaluation of Application Possibilities for Packaging Technologies in Canonical Workflows
Authors: Jejkal Thomas , Chelbi Sabrine , Pfeil Andreas , Wittenburg Peter
Published: April 2022

In Canonical Workflow Framework for Research (CWFR) “packages” are relevant in two different directions. In data science, workflows are in general being executed on a set of files which have been aggregated for specific purposes, such as for training a model in deep learning. We call this type of “package” a data collection and its aggregation and metadata description is motivated by research interests. The other type of “packages” relevant for CWFR are supposed to represent workflows in a self-describing and self-contained way for later execution. In this paper, we will review different packaging technologies and investigate their usability in the context of CWFR. For this purpose, we draw on an exemplary use case and show how packaging technologies can support its realization. We conclude that packaging technologies of different flavors help on providing inputs and outputs for workflow steps in a machine-readable way, as well as on representing a workflow and all its artifacts in a self-describing and self-contained way.
Individual Differences in Cue Weighting in Sentence Comprehension: An Evaluation Using Approximate Bayesian Computation
Authors: Yadav Himanshu , Paape Dario , Smith Garrett , Dillon Brian W. , Vasishth Shravan
Published: April 2022

Cue-based retrieval theories of sentence processing assume that syntactic dependencies are resolved through a content-addressable search process. An important recent claim is that in certain dependency types, the retrieval cues are weighted such that one cue dominates. This cue-weighting proposal aims to explain the observed average behavior, but here we show that there is systematic individual-level variation in cue weighting. Using the Lewis and Vasishth cue-based retrieval model, we estimated individual-level parameters for reading speed and cue weighting using 13 published datasets; hierarchical approximate Bayesian computation (ABC) was used to estimate the parameters. The modeling reveals a nuanced picture of cue weighting: we find support for the idea that some participants weight cues differentially, but not all participants do. Only fast readers tend to have the predicted higher weighting for structural cues, suggesting that reading proficiency (approximated here by reading speed) might be associated with cue weighting. A broader achievement of the work is to demonstrate how individual differences can be investigated in computational models of sentence processing without compromising the complexity of the model.
Culex chrysothorax (Newstead & Thomas, 1910) (Diptera: Culicidae), preoccupied by Cx. chrysothorax (Peryassú, 1908) and recognized as a subjective synonym of Cx. trigeminatus Clastrier, 1970
Authors: SALLUM MARIA ANICE MUREB , DE SÁ IVY LUIZI RODRIGUES , HARBACH RALPH E.
Published: April 2022

Culex chrysothorax (Newstead & Thomas, 1910) (Diptera: Culicidae) is recognized as the junior secondary homonym of Culex chrysothorax (Peryassú, 1908). Both nominal species are currently regarded as nomina dubia (Pecor et al. 1991; Harbach 2018; Wilkerson et al. 2021). Based on critical examination of the lectotype female, the former nominal species, which was treated as species inquirenda by Forattini & Sallum (1989), is no longer regarded as a doubtful species, and is found to be conspecific with Cx. trigeminatus Clastrier, 1970. Because it is preoccupied by Cx. chrysothorax (Peryassú, 1908), it is placed in synonymy with Cx. trigeminatus, which is transferred from the Educator to the Atratus Group of the subgenus Melanoconion based on morphological features of the female. Culex chrysothorax (Peryassú, 1908) is retained in the Educator Group as a nomen dubium. Because the original description of Cx. chrysothorax (Newstead & Thomas) likely included misidentified specimens of Cx. theobaldi (Lutz, 1904), a more precise description of the lectotype female is provided.
How Does Sea Surface Temperature Drive the Intertropical Convergence Zone in the Southern Indian Ocean?
Authors: Zhang Honghai , Seager Richard , Xie Shang-Ping
Published: April 2022

The Indian Ocean has an intriguing intertropical convergence zone (ITCZ) south of the equator year-round, which remains largely unexplored. Here we investigate this Indian Ocean ITCZ and the mechanisms for its origin. With a weak semiannual cycle, this ITCZ peaks in January–February with the strongest rainfall and southernmost location and a northeast–southwest orientation from the Maritime Continent to Madagascar, reaches a minimum around May with a zonal orientation, grows until its secondary maximum around September with a northwest–southeast orientation, weakens slightly until December, and then regains its mature phase in January. During austral summer, the Indian Ocean ITCZ exists over maximum surface moist static energy (MSE), consistent with convective quasi-equilibrium theory. This relationship breaks up during boreal summer when the surface MSE maximizes in the northern monsoon region. The position and orientation of the Indian Ocean ITCZ can be simulated well in both a linear dynamical model and the state-of-the-art Community Atmosphere Model version 6 (CAM6) when driven by observed sea surface temperature (SST). To quantify the contributions of the planetary boundary layer (PBL) and free-atmosphere processes to this ITCZ, we homogenize the free-atmosphere diabatic heating over the Indian Ocean in CAM6. In response, the ITCZ weakens significantly, owing to a weakened circulation and deep convection. Therefore, in CAM6, the SST drives the Indian Ocean ITCZ directly through PBL processes and indirectly via free-atmosphere diabatic heating. Their contributions are comparable during most seasons, except during the austral summer when the free-atmosphere diabatic heating dominates the mature-phase ITCZ.

Significance Statement

The intertropical convergence zone (ITCZ) is the globe-encircling band where trade winds converge and strong rainfall occurs in the tropics. Its rains provide life-supporting water to billions of people. Its associated latent heating invigorates the tropical atmospheric circulation and influences climate and weather across the planet. The ITCZ is located north of the equator in most tropical oceans, except in the Indian Ocean where it sits south of the equator year-around. In contrast to the well-known northern ITCZs, the origin of the southern ITCZ in the Indian Ocean remains unknown. This work provides the first explanation for how ocean surface temperature works together with processes in the lower and upper atmosphere to shape the unique ITCZ in the Indian Ocean.
The contribution of rare copy number variants in FAS toward pathogenesis of autoimmune lymphoproliferative syndrome
Authors: Jevtich Kathleen , Price Susan , Similuk Morgan , Kulm Elaine , Yan Jia , Setzer Michael , Jamal Leila , Franco Luis M. , Ghosh Rajarshi , Walkiewicz Magdalena , Rao V. Koneti
Published: April 2022

Autoimmune lymphoproliferative syndrome (ALPS) is characterized by chronic nonmalignant lymphadenopathy, splenomegaly, cytopenias, and other autoimmune manifestations. ALPS is caused by lymphocyte accumulation from defects in FAS-mediated apoptosis. Heterozygous germline or somatic pathogenic single nucleotide variants in FAS are the most common molecular etiology of ALPS. Through the Centralized Sequencing Program at the National Institute of Allergy and Infectious Diseases, we performed exome sequencing on subjects with a clinical diagnosis of ALPS, with a subset receiving copy number variant (CNV) analysis. In this cohort, we identified 3 subjects from unrelated families with CNVs at the FAS locus. One subject had a de novo ∼0.828 Mb copy number loss encompassing all of FAS. The second subject had a maternally inherited ∼1.004 Mb copy number loss encompassing all of FAS. The third subject had a paternally inherited ∼0.044 Mb copy number loss encompassing exons 7 through 9 of FAS. Subjects with deletions in FAS had clinical presentations and biomarker profiles similar to those with ALPS and with germline and somatic FAS variants. We demonstrate that CNV analysis should be pursued if there is clinical and biomarker evidence of ALPS because it can lead to a molecular diagnosis and appropriate treatment when FAS sequencing is inconclusive.
CD47 overexpression is common in intestinal non-GCB type diffuse large B-cell lymphoma and associated with 18q21 gain
Authors: Cho Junhun , Yoon Sang Eun , Kim Seok Jin , Ko Young Hyeh , Kim Won Seog
Published: April 2022

The CD47/signal regulatory protein α pathway is an emerging immune checkpoint that is a new therapeutic target. We investigated CD47 expression in diffuse large B-cell lymphoma (DLBCL) of various subtypes and organs. Moreover, the relationship between CD47 expression and genetic alterations was analyzed using panel-based massively parallel sequencing (next-generation sequencing [NGS]). CD8, CD68, and CD47 immunohistochemical staining were performed on 238 patients with DLBCL. CD47 was scored according to intensity on a 5-level scale, and CD8 and CD68 were quantitatively evaluated using QuPath software. Panel-based NGS was performed in 37 patients. In CD8 and CD68 quantitative analyses by organs, intestinal DLBCL showed significantly lower cytotoxic T-cell infiltration than that in others (P < .001). The CD47-high group comprised 24 of 58 (41.4%) patients in the group with DLBCL from intestine and 15 of 180 (8.3%) patients in the group with DLBCL from other organs (P < .001). The 18q21 gain/amplification was found in 10 of 37 patients, and all of them were CD47-high. Intestinal CD47-high DLBCL occurred in terminal ileum to ascending colon and was restricted to nongerminal center B-cell type. In the survival analyses, the prognosis of nonintestinal CD47-high DLBCL was poorer than that of intestinal CD47-high DLBCL (P = .025). CD47-high DLBCL was closely associated with 18q21 gain/amplification and showed a high prevalence in intestine. We propose to classify CD47-high DLBCL into intestinal and nonintestinal types. Further studies are necessary to assess whether the constellation of features seen here is reproducible and sufficient to consider primary intestinal DLBCL as a distinct biological entity.
Interleukin-15 augments NK cell–mediated ADCC of alemtuzumab in patients with CD52+ T-cell malignancies
Authors: Miljkovic Milos D. , Dubois Sigrid P. , Müller Jürgen R. , Bryant Bonita , Ma Elaine , Conlon Kevin C. , Waldmann Thomas A.
Published: April 2022

Interleukin-15 (IL-15) monotherapy substantially increases the number and activity of natural killer (NK) cells and CD8+ T cells but has not produced clinical responses. In a xenograft mouse model, IL-15 enhanced the NK cell–mediated antibody-dependent cell cytotoxicity (ADCC) of the anti-CD52 antibody alemtuzumab and led to significantly more durable responses than alemtuzumab alone. To evaluate whether IL-15 potentiates ADCC in humans, we conducted a phase 1 single-center study of recombinant human IL-15 and alemtuzumab in patients with CD52-positive mature T-cell malignances. We gave IL-15 subcutaneously 5 days per week for 2 weeks in a 3 + 3 dose escalation scheme (at 0.5, 1, and 2 μg/kg), followed by standard 3 times weekly alemtuzumab IV for 4 weeks. There were no dose-limiting toxicities or severe adverse events attributable to IL-15 in the 11 patients treated. The most common adverse events were lymphopenia (100%), alemtuzumab-related infusion reactions (90%), anemia (90%), and neutropenia (72%). There were 3 partial and 2 complete responses, with an overall response rate of 45% and median duration of response 6 months. Immediately after 10 days of IL-15, there was a median 7.2-fold increase in NK cells and 2.5-fold increase in circulating CD8+ T cells, whereas the number of circulating leukemic cells decreased by a median 38% across all dose levels. Treatment with IL-15 was associated with increased expression of NKp46 and NKG2D, markers of NK-cell activation, and increased ex vivo ADCC activity of NK cells, whereas inhibitory receptors PD1 and Tim3 were decreased. This trial was registered at www.clinicaltrials.gov as #NCT02689453.
Functional interaction between compound heterozygous TERT mutations causes severe telomere biology disorder
Authors: Niaz Aram , Truong Jia , Manoleras Annabel , Fox Lucy C. , Blombery Piers , Vasireddy Raja S. , Pickett Hilda A. , Curtin Julie A. , Barbaro Pasquale M. , Rodgers Jonathan , Roy John , Riley Lisa G. , Holien Jessica K. , Cohen Scott B. , Bryan Tracy M.
Published: April 2022

Telomere biology disorders (TBDs) are a spectrum of multisystem inherited disorders characterized by bone marrow failure, resulting from mutations in the genes encoding telomerase or other proteins involved in maintaining telomere length and integrity. Pathogenicity of variants in these genes can be hard to evaluate, because TBD mutations show highly variable penetrance and genetic anticipation related to inheritance of shorter telomeres with each generation. Thus, detailed functional analysis of newly identified variants is often essential. Herein, we describe a patient with compound heterozygous variants in the TERT gene, which encodes the catalytic subunit of telomerase, hTERT. This patient had the extremely severe Hoyeraal-Hreidarsson form of TBD, although his heterozygous parents were clinically unaffected. Molecular dynamic modeling and detailed biochemical analyses demonstrate that one allele (L557P) affects association of hTERT with its cognate RNA component hTR, whereas the other (K1050E) affects the binding of telomerase to its DNA substrate and enzyme processivity. Unexpectedly, the data demonstrate a functional interaction between the proteins encoded by the two alleles, with wild-type hTERT rescuing the effect of K1050E on processivity, whereas L557P hTERT does not. These data contribute to the mechanistic understanding of telomerase, indicating that RNA binding in one hTERT molecule affects the processivity of telomere addition by the other molecule. This work emphasizes the importance of functional characterization of TERT variants to reach a definitive molecular diagnosis for patients with TBD, and, in particular, it illustrates the importance of analyzing the effects of compound heterozygous variants in combination, to reveal interallelic effects.
Comparative analysis of Thalassionema chloroplast genomes revealed hidden biodiversity
Authors: Zhang Mengjia , Chen Nansheng
Published: April 2022

The cosmopolitanThalassionemaspecies are often dominant components of the plankton diatom flora and sediment diatom assemblages in all but the Polar regions, making important ecological contribution to primary productivity. Historical studies concentrated on their indicative function for the marine environment based primarily on morphological features and essentially ignored their genomic information, hindering in-depth investigation onThalassionemabiodiversity. In this project, we constructed the complete chloroplast genomes (cpDNAs) of sevenThalassionemastrains representing three different species, which were also the first cpDNAs constructed for any species in the order Thalassionematales that includes 35 reported species and varieties. The sizes of theseThalassionemacpDNAs, which showed typical quadripartite structures, varied from 124,127 bp to 140,121 bp. Comparative analysis revealed thatThalassionemacpDNAs possess conserved gene content inter-species and intra-species, along with several gene losses and transfers. Besides, their cpDNAs also have expanded inverted repeat regions (IRs) and preserve large intergenic spacers compared to other diatom cpDNAs. In addition, substantial genome rearrangements were discovered not only among differentThalassionemaspecies but also among strains of a same speciesT. frauenfeldii, suggesting much higher diversity than previous reports. In addition to confirming the phylogenetic position ofThalassionemaspecies, this study also estimated their emergence time at approximately 38 Mya. The availability of theThalassionemaspecies cpDNAs not only helps understand theThalassionemaspecies, but also facilitates phylogenetic analysis of diatoms.
Prevalence of potentially inappropriate medications based on the STOPPFrail criteria in frail older patients with limited life expectancy: a cross-sectional study
Authors: Chae Hyun-Woo , Kim Yoonhee , Suh Yewon , Lee Junghwa , Lee Eunsook , Lee Euni , Choi Jung-Yeon , Kim Kwang-il , Lee Ju-Yeun
Published: April 2022

Background

The recently developed Screening Tool of Older Persons' Prescriptions in Frail adults with a limited life expectancy (STOPPFrail) criteria can be helpful for screening medications (PIMs), but it is yet to be widely used in clinical practice. Herein, we aimed to investigate the prevalence of PIMs based on the STOPPFrail criteria (STOPPFrail-PIM) among frail older adults with limited life expectancy admitted to the geriatric center.

Methods

This was a retrospective cross-sectional study conducted in the geriatric center at an academic tertiary care hospital in Korea. We evaluated frail older adults with limited life expectancy who received comprehensive geriatric assessment (CGA) admitted between 1 January, 2019 and 30 June, 2020. Frail older adults with limited life expectancy were identified by geriatricians with retrospective records and the prevalence of STOPPFrail-PIMs was analysed by trained pharmacists. Descriptive analysis, t-test, and chi-square test were conducted using IBM SPSS software version 25.0.

Results

Among 504 older adults who underwent CGA after admission, 171 frail older adults with limited life expectancy were identified by geriatricians and included in the study. An average of 11.3 ± 4.7 medications were administered regularly to each patient before admission. Overall, 97.1% (166/171) had at least one STOPPFrail-PIM, and the mean number of STOPPFrail-PIM was 4.2 ± 2.8. Drugs without clear clinical indication (A2) were the most frequent pre-admission STOPPFrail-PIM, followed by lipid-lowering therapies (B1) and neuroleptic antipsychotics (D1). The number of STOPPFrail-PIM was significantly lower at discharge than that at admission, with the decrease being the highest for A2 at 94.7%.

Conclusions

Most frail older adults with limited life expectancy had at least one STOPPFrail-PIM at admission, and the rate of STOPPFrail-PIM decreased significantly at discharge after the geriatric multidisciplinary team care. Further studies are needed to investigate the association between the use of STOPPFrail-PIM and adverse consequences in frail older adults.
Rationale and design of a prospective, multicenter, phase II clinical trial of safety and efficacy evaluation of long course neoadjuvant chemoradiotherapy plus tislelizumab followed by total mesorectal excision for locally advanced rectal cancer (NCRT-PD1-LARC trial)
Authors: Yang Zhengyang , Zhang Xiao , Zhang Jie , Gao Jiale , Bai Zhigang , Deng Wei , Chen Guangyong , An Yongbo , Liu Yishan , Wei Qi , Han Jiagang , Li Ang , Liu Gang , Sun Yi , Kong Dalu , Yao Hongwei , Zhang Zhongtao
Published: April 2022

Background

Long course radiotherapy plus neoadjuvant chemotherapy followed by resection (total mesorectal excision, TME) has accepted widespread recognized in the treatment of locally advanced rectal cancer (LARC). Tislelizumab, an anti-PD1 humanized IgG4 monoclonal antibody, has been demonstrated with clinical activity and is approved for treating recurrent/refractory classical Hodgkin lymphoma and locally advanced/metastatic urothelial carcinoma in China. However, the safety and efficacy of long course (neoadjuvant chemoradiotherapy, NCRT) plus tislelizumab followed by TME for LARC is still uncertain.

Methods

This NCRT-PD1-LARC trial will be a prospective, multicenter and phase II clinical trial designed to evaluate the safety and efficacy of LARC patients treated with long course NCRT plus tislelizumab followed by TME. This trial will consecutively enroll 50 stage II/III LARC patients (cT3N0M0 and cT1-3N1-2M0) with the tumor distal location ≤ 7 cm from anal verge at 7 centers in China. The enrolled patients will receive long course radiotherapy (50 Gy/25 f, 2 Gy/f, 5 days/week) and three 21-day cycles capecitabine (1000 mg/m2, bid, po, day1-14) plus three 21-day cycles tislelizumab (200 mg, iv.gtt, day8), followed by TME 6–8 weeks after the end of radiotherapy. The primary efficacy endpoint will be the pathological complete response (pCR) rate, which is defined as absence of viable tumor cells in the primary tumor and lymph nodes.

Discussion

To our knowledge, this trial is the first multicenter clinical trial in China to assess the safety and efficacy of NCRT plus anti-PD1 therapy followed by TME to treat patients with LARC. NCRT followed by TME was recognized as the most recommended treatment against LARC while could not be completely satisfied in clinic. This study expects to provide a solid basis and encouraging outcomes for this promising combination of radiotherapy, chemotherapy and immunotherapy in LARC.

Trial registration

Name of the registry: ClinicalTrials.gov. Trial
registration number: NCT04911517. Date of registration: 23 May 2021. URL of
trial registry record: https://www.clinicaltrials.gov/ct2/show/NCT04911517?id=BFH-NCRTPD&draw=2&rank=1.
The identification of liver metastasis- and prognosis-associated genes in pancreatic ductal adenocarcinoma
Authors: Luan Hong , He Ye , Zhang Tuo , Su Yanna , Zhou Liping
Published: April 2022

Background

Pancreatic ductal adenocarcinoma (PDAC) is an often fatal malignancy with an extremely low survival rate. Liver metastasis, which causes high mortality, is the most common recurring metastasis for PDAC. However, the mechanisms underlying this liver metastasis and associated candidate biomarkers are unknown.

Methods

We performed mRNA profiling comparisons in 8 primary tumors (T) and 12 liver metastases (M) samples using the Gene Expression Omnibus (GEO) database. After determining differentially expressed genes (DEG), gene ontology (GO), pathway enrichment and protein–protein interaction (PPI) network analyses were performed to determine DEG functions. Then, Cytoscape was used to screen out significant hub genes, after which their clinical relevance was investigated using The Cancer Genome Atlas (TCGA) resources. Furthermore, prognosis-associated gene expression was validated using Oncomine and TCGA database. Lastly, associations between prognosis-associated genes, immune cells and immunological checkpoint genes were evaluated using the Tumor Immune Estimation Resource (TIMER).

Results

In total, 102 genes were related to liver metastasis and predominantly involved in cell migration, motility, and adhesion. Using Cytoscape, this number was narrowed down to 16 hub genes. Elevated mRNA expression levels for two of these genes, SPARC (P = 0.019) and TPM1 (P = 0.037) were significantly correlated with poor disease prognosis. For the remaining 14, expression was not related to overall patient survival. SPARC had higher expression in patients with metastatic PDAC than those with non-metastatic PDAC in TCGA dataset. SPARC and TPM1 levels were also positively correlated with the immune infiltration of specific cell types. Additionally, both genes exhibited strong co-expression associations with immune checkpoint genes.

Conclusions

Combined, we suggest SPARC has high potential as biomarker to predict liver metastasis during PDAC. Additionally, both SPARC and TPM1 appeared to recruit and regulate immune-infiltrating cells during these pathophysiological processes.
The relationship between occupational physical activity and dyslipidaemia in farmers with varying working modes in southwest China: the China multi-ethnic cohort study
Authors: Du Lunwei , Hong Feng , Luo Peng , Wang Ziyun , Zeng Qibing , Guan Han , Liu Haiyan , Yuan Zhiping , Xu Degan , Nie Fang , Wang Junhua
Published: April 2022

Background

Farmers are the integral members of rural communities. In the present study, we determined the association between occupational physical activity (OPA) of farmers and dyslipidaemia.

Methods

We included 7649 farmers from The China Multi-Ethnic Cohort (CMEC) Study. The working modes of all farmers were divided into four types according to their self-reported seasonal changes in farming work and/or other job changes (1: no change; 2: changing job; 3: seasonal changes; and 4: seasonal and job changes). OPA was self-reported, and the OPA levels in the four groups were classified as Q1, Q2–Q3, and Q4 by quantile. Dyslipidaemia was defined as the presence of abnormalities in lipid indicators. Binary logistic regression was used to estimate the association between OPA and dyslipidaemia.

Results

Compared with those in the no change group, the participants in other three groups were younger with lower level of education, annual income, and leisure-time physical activity (LTPA). Active OPA could reduce the risk of dyslipidaemia in the no change [men: odds ratios (OR) = 0.21, 95% confidence intervals (CI): 0.07–0.64; women: OR = 0.43, 95% CI: 0.20–0.93] and seasonal change (men: OR = 0.46, 95% CI: 0.27–0.77; women: OR = 0.59, 95% CI: 0.41–0.86) groups. However, in the seasonal and job change group (men: OR = 3.23, 95% CI: 1.06–9.80; women: OR = 3.24, 95% CI: 1.42–7.41), active OPA increased the risk of dyslipidaemia.

Conclusions

Different OPA levels might lead to differences in association with blood lipid levels. Thus, OPA guidelines must be developed for farmers, especially for those who experience seasonal changes in farming work and job changes.
Relationship between bone mineral density and ovarian function and thyroid function in perimenopausal women with endometriosis: a prospective study
Authors: Uehara Mari , Wada-Hiraike Osamu , Hirano Mana , Koga Kaori , Yoshimura Noriko , Tanaka Sakae , Osuga Yutaka
Published: April 2022

Background

In women with endometriosis, the association between ovarian function, hormones, and bone mineral density (BMD) is unclear. Therefore, this study aimed to elucidate the association between changes in bone mineral density (BMD) and clinical data, such as ovarian reserves, in perimenopausal women with endometriosis.

Methods

In this prospective study, we evaluated 207 female patients who visited the Department of Obstetrics and Gynecology at the University of Tokyo Hospital between December 2015 and December 2020. We included patients aged ≥ 40 years with a history of endometriosis or who presented with endometriosis lesions. Patients with a history of smoking, steroid administration, autoimmune diseases, dyslipidaemia, and heart disease were excluded. During the study period, patients who underwent two tests, an initial and a follow-up test (n = 142, average age: 45.02 years, average BMD: 1.16 g/cm2), were evaluated at regular intervals based on the annual rate of change in BMD.

Results

There was a weak negative correlation between the follicle-stimulating hormone (FSH) and BMD and a weak positive correlation between the anti-Müllerian hormone (AMH) and BMD. The annual rate of change in BMD showed a very weak correlation with thyroid-stimulating hormone (TSH) levels. A large decline in BMD was associated with high TSH levels and higher average age at menopause. Patients with higher TSH exhibited a higher rate of decrease in BMD than those without.

Conclusions

High FSH or low AMH levels are associated with decreased BMD. Decreased ovarian reserve is associated with decreased BMD in perimenopausal women with endometriosis. High TSH levels increase the risk of BMD loss. This finding may suggest that women with endometriosis should undergo bone scanning to rule out the possibility of reduced bone mass and subsequent increased risk of fracture.
How does interprofessional education influence students’ perceptions of collaboration in the clinical setting? A qualitative study
Authors: Teuwen Carolyn , van der Burgt Stéphanie , Kusurkar Rashmi , Schreurs Hermien , Daelmans Hester , Peerdeman Saskia
Published: April 2022

Background

Interprofessional education (IPE) aims to improve students’ collaborative competencies and behaviour. The effect of classroom IPE on students’ perceptions of collaboration in clinical practice, and how knowledge is possibly transferred, has yet to be investigated. The research question of this study was: How does IPE in a classroom setting influence students’ perceptions of collaboration in clinical practice? Social capital theory is used as the theoretical lens. Social capital theory describes how social relationships generate benefits for the individuals involved. Social capital can be divided into three forms of social cohesion: bonding, bridging and linking social capital. Bonding refers to connections that are close and strong, such as family. Bridging social capital occurs in more distant relationships. Linking social capital refers to relationships between individuals with different power or social status.

Methods

A qualitative study with semi-structured face-to-face interviews was conducted to explore students’ perceptions and experiences. Nursing and medical students who had participated in four classroom IPE-sessions were asked about the perceived influence of the IPE-sessions they had attended on their interprofessional collaboration. Thematic analysis was conducted, with sensitising concepts of ‘bonding’, ‘bridging’ and ‘linking social capital’ from the social capital theory.

Results

Twenty-two interviews were conducted. Students experienced: 1) exchange of discipline specific knowledge, 2) general knowledge about each other’s responsibilities, 3) reduction of hierarchy, and 4) improvement in patient care. The first two themes reflect bridging social capital, since students experience that the other student is from a different group. The third theme reflects linking social capital, since students experience a difference in (social) status. The fourth theme most explicitly reflects ‘getting ahead’ or doing better, what is referred to as an effect of increased social capital.

Conclusion

This study reveals new insights regarding how increased social capital of undergraduate students after IPE-sessions in a classroom setting influences the way they conceptualise and experience interprofessional collaboration in clinical practice. These insights contribute to the understanding of the effectiveness of IPE in undergraduate curricula. Further research on long-term effects is underway.