bluuebunny/crossref_metadata_2025 huggingface dataset:
Modeling of pneumococcal serogroup 10 capsular polysaccharide molecular conformations provides insight into epitopes and observed cross-reactivity
Authors: Richardson Nicole I. , Kuttel Michelle M. , Ravenscroft Neil
Published: August 2022

Streptococcus pneumoniaeis an encapsulated gram-negative bacterium and a significant human pathogen.The capsular polysaccharide (CPS) is essential for virulence and a target antigen for vaccines. Although widespread introduction of pneumococcal conjugate vaccines (PCVs) has significantly reduced disease, the prevalence of non-vaccine serotypes has increased. On the basis of the CPS,S. pneumoniaeserogroup 10 comprises four main serotypes 10A, 10B, 10C, and 10F; as well as the recently identified 10D. As it is the most prevalent, serotype 10A CPS has been included as a vaccine antigen in the next generation PCVs. Here we use molecular modeling to provide conformational rationales for the complex cross-reactivity reported between serotypes 10A, 10B, 10C, and 10F anti-sera. Although the highly mobile phosphodiester linkages produce very flexible CPS, shorter segments are conformationally defined, with exposedβ-D-galactofuranose (βDGalf) side chains that are potential antibody binding sites. We identify four distinct conformational epitopes for the immunodominantβDGalfthat assist in rationalizing the complex asymmetric cross-reactivity relationships. In particular, we find that strongly cross-reactive serotypes share common epitopes. Further, we show that human intelectin-1 has the potential to bind the exposed exocyclic 1,2-diol of the terminalβDGalfin each serotype; the relative accessibility of three- or six-linkedβDGalfmay play a role in the strength of the innate immune response and hence serotype disease prevalence. In conclusion, our modeling study and relevant serological studies support the inclusion of serotype 10A in a vaccine to best protect against serogroup 10 disease.
Dance movement therapy for neurodegenerative diseases: A systematic review
Authors: Wu Cheng-Cheng , Xiong Huan-Yu , Zheng Jie-Jiao , Wang Xue-Qiang
Published: August 2022

Background

The proportion of the world's elderly population continues to rise, and the treatment and improvement of neurodegenerative diseases have become issue of public health importance as people live longer and many countries have aging populations. This systematic review aims to discuss the effects of dance movement therapy (DMT) on motor function, cognitive deficit, mood, and quality of life in people with neurodegenerative diseases, such as Parkinson's disease (PD), mild cognitive impairment (MCI), Alzheimer's disease (AD).

Methods

Two reviewers independently conducted systematic search on the Cochrane library, PubMed database, Web of Science Core Collection database, and Physiotherapy Evidence database until February 1, 2022. Only systematic analyses and randomized controlled trials were included and further analyzed.

Results

Thirty-three studies on PD, 16 studies on MCI, 4 studies on AD were obtained. This systematic review found that DMT substantially improved the global cognitive function, memory, and executive function on the population with MCI. Compared with the non-dance group, DMT remarkably improved general disease condition, balance, and gait for individuals with PD. The evidence of the efficacy of DMT on AD is insufficient, and further research is needed.

Conclusion

DMT can effectively improve the motor function and cognitive deficits in neurodegenerative diseases. Positive effects of DMT on the mood and quality of life in ND patients are controversial and require further evidence. Future research on the effects of DMT on AD requires scientific design, large sample size, long-term comprehensive intervention, and clear reporting standards.

Systematic review registration

www.osf.io/wktez, identifier: 10.17605/OSF.IO/UYBKT.
The impact of age-related hearing loss on structural neuroanatomy: A meta-analysis
Authors: Slade Kate , Reilly Johannes H. , Jablonska Kamila , Smith El , Hayes Lawrence D. , Plack Christopher J. , Nuttall Helen E.
Published: August 2022

This meta-analysis investigated the association between age-related hearing loss and structural neuroanatomy, specifically changes to gray matter volume. Hearing loss is associated with increased risk of cognitive decline. Hence, understanding the effects of hearing loss in older age on brain health is essential. We reviewed studies which compared older participants with hearing loss (age-related hearing loss: ARHL) to older adults without clinical hearing loss (no-ARHL), on neuroanatomical outcomes, specifically gray matter (GM) volume as measured by magnetic resonance imaging. A total of five studies met the inclusion criteria, three of which were included in an analysis of whole-brain gray matter volume (ARHL group n = 113; no-ARHL group n = 138), and three were included in analyses of lobe-wise gray matter volume (ARHL group n = 139; no-ARHL group n = 162). Effect-size seed-based d mapping software was employed for whole-brain and lobe-wise analysis of gray matter volume. The analysis indicated there was no significant difference between adults with ARHL compared to those with no-ARHL in whole-brain gray matter volume. Due to lacking stereotactic coordinates, the level of gray matter in specific neuroanatomical locations could only be observed at lobe-level. These data indicate that adults with ARHL show increased gray matter atrophy in the temporal lobe only (not in occipital, parietal, or frontal), compared to adults with no-ARHL. The implications for theoretical frameworks of the hearing loss and cognitive decline relationship are discussed in relation to the results. This meta-analysis was pre-registered on PROSPERO (CRD42021265375).

Systematic Review Registration:https://www.crd.york.ac.uk/prospero/display_record.php?RecordID=265375, PROSPERO CRD42021265375.
A machine learning model for predicting patients with major depressive disorder: A study based on transcriptomic data
Authors: Liu Sitong , Lu Tong , Zhao Qian , Fu Bingbing , Wang Han , Li Ginhong , Yang Fan , Huang Juan , Lyu Nan
Published: August 2022

Background

Identifying new biomarkers of major depressive disorder (MDD) would be of great significance for its early diagnosis and treatment. Herein, we constructed a diagnostic model of MDD using machine learning methods.

Methods

The GSE98793 and GSE19738 datasets were obtained from the Gene Expression Omnibus database, and the limma R package was used to analyze differentially expressed genes (DEGs) in MDD patients. Gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyses were performed to identify potential molecular functions and pathways. A protein-protein interaction network (PPI) was constructed, and hub genes were predicted. Random forest (RF) and artificial neural network (ANN) machine-learning algorithms were used to select variables and construct a robust diagnostic model.

Results

A total of 721 DEGs were identified in peripheral blood samples of patients with MDD. GO and KEGG analyses revealed that the DEGs were mainly enriched in cytokines, defense responses to viruses, responses to biotic stimuli, immune effector processes, responses to external biotic stimuli, and immune systems. A PPI network was constructed, and CytoHubba plugins were used to screen hub genes. Furthermore, a robust diagnostic model was established using a RF and ANN algorithm with an area under the curve of 0.757 for the training model and 0.685 for the test cohort.

Conclusion

We analyzed potential driver genes in patients with MDD and built a potential diagnostic model as an adjunct tool to assist psychiatrists in the clinical diagnosis and treatment of MDD.
Textural features reflecting local activity of the hippocampus improve the diagnosis of Alzheimer’s disease and amnestic mild cognitive impairment: A radiomics study based on functional magnetic resonance imaging
Authors: Wang Luoyu , Feng Qi , Ge Xiuhong , Chen Fenyang , Yu Bo , Chen Bing , Liao Zhengluan , Lin Biying , Lv Yating , Ding Zhongxiang
Published: August 2022

Background

Textural features of the hippocampus in structural magnetic resonance imaging (sMRI) images can serve as potential diagnostic biomarkers for Alzheimer’s disease (AD), while exhibiting a relatively poor discriminant performance in detecting early AD, such as amnestic mild cognitive impairment (aMCI). In contrast to sMRI, functional magnetic resonance imaging (fMRI) can identify brain functional abnormalities in the early stages of cerebral disorders. However, whether the textural features reflecting local functional activity in the hippocampus can improve the diagnostic performance for AD and aMCI remains unclear. In this study, we combined the textural features of the amplitude of low frequency fluctuation (ALFF) in the slow-5 frequency band and structural images in the hippocampus to investigate their diagnostic performance for AD and aMCI using multimodal radiomics technique.

Methods

Totally, 84 AD, 50 aMCI, and 44 normal controls (NCs) were included in the current study. After feature extraction and feature selection, the radiomics models incorporating sMRI images, ALFF values and their combinations in the bilateral hippocampus were established for the diagnosis of AD and aMCI. The effectiveness of these models was evaluated by receiver operating characteristic (ROC) analysis. The radiomics models were further validated using the external data from the Alzheimer’s Disease Neuroimaging Initiative (ADNI) database.

Results

The results of ROC analysis showed that the radiomics models based on structural images in the hippocampus had a better diagnostic performance for AD compared with the models using ALFF, while the ALFF-based model exhibited better discriminant performance for aMCI than the models with structural images. The radiomics models based on the combinations of structural images and ALFF were found to exhibit the highest accuracy for distinguishing AD from NCs and aMCI from NCs.

Conclusion

In this study, we found that the textural features reflecting local functional activity could improve the diagnostic performance of traditional structural models for both AD and aMCI. These findings may deepen our understanding of the pathogenesis of AD, contributing to the early diagnosis of AD.
Polymorphisms in gene MTHFR modify the association between gestational weight gain and adverse birth outcomes
Authors: Wu Weixiang , Luo Dan , Ruan Xiaolin , Gu Chunming , Lu Weiming , Lian Kailing , Mu Xiaoping
Published: August 2022

Evidence suggests a potential relationship between gestational weight gain (GWG) and adverse birth outcomes. However, the role of maternal genetic polymorphisms remains unclear. This study was conducted to investigate whether the relationship of GWG with risk of adverse birth outcomes was modified by methylenetetrahydrofolate reductase (MTHFR) polymorphisms. A total of 2,967 Chinese pregnant women were included and divided into insufficient, sufficient, and excessive groups based on the Institute of Medicine (IOM) criteria. Polymorphisms of C677T and A1298C in gene MTHFR were genotyped. Multivariable logistic regression models were introduced after controlling major confounders. Excessive GWG was found to increase the odds ratio (OR) for macrosomia [OR = 3.47, 95% confidence interval (CI): 1.86–6.48] and large-for-gestational age (LGA, OR = 3.25, 95% CI: 2.23–4.74), and decreased the OR for small-for-gestational age (SGA, OR = 0.60, 95% CI: 0.45–0.79). Pregnant women with insufficient GWG had a higher frequency of SGA (OR = 1.68, 95% CI: 1.32–2.13) and a lower rate of LGA (OR = 0.51, 95% CI: 0.27–0.96). Interestingly, significant associations of GWG categories in relation to low birth weight (LBW), macrosomia, and SGA were only suggested among pregnant women with MTHFR A1298C AA genotype. Among pregnant women with insufficient GWG group, an increased risk of 3.96 (95% CI: 1.57–10.01) for LBW was observed among subjects with the A1298C AA genotype, compared to the AC+CC genotype group. GWG categories are closely related to LBW, macrosomia, SGA and LGA, and the associations were modified by the polymorphism of MTHFR A1298C.
Co-exposure of potentially toxic elements in wheat grains reveals a probabilistic health risk in Southwestern Guizhou, China
Authors: Li Dashuan , Zhang Cheng , Li Xiangxiang , Li Fuming , Liao Shengmei , Zhao Yifang , Wang Zelan , Sun Dali , Zhang Qinghai
Published: August 2022

Bijie is located at a typical karst landform of Southwestern Guizhou, which presented high geological background values of potentially toxic elements (PTEs). Recently, whether PTE of wheat in Bijie is harmful to human health has aroused people’s concern. To this end, the objectives of this study are to determine the concentrations of PTE [chromium (Cr), nickel (Ni), arsenic (As), lead (Pb), cadmium (Cd), and fluorine (F)] in wheat grains, identify contaminant sources, and evaluate the probabilistic risks to human beings. A total of 149 wheat grain samples collected from Bijie in Guizhou were determined using the inductively coupled plasma mass spectrometer (ICP-MS) and fluoride-ion electrode methods. The mean concentrations of Cr, Ni, As, Cd, Pb, and F were 3.250, 0.684, 0.055, 0.149, 0.039, and 4.539 mg/kg, respectively. All investigated PTEs met the standard limits established by the Food and Agriculture Organization except for Cr. For the source identification, Cr and Pb should be originated from industry activities, while Ni, As, and Cd might come from mixed sources, and F was possibly put down to the high geological background value. The non-carcinogenic and carcinogenic health risks were evaluated by the probabilistic approach (Monte Carlo simulation). The mean hazard quotient (HQ) values in the three populations were lower than the safety limit (1.0) with the exception of As (children: 1.03E+00). However, the mean hazard index (HI) values were all higher than 1.0 and followed the order: children (2.57E+00) > adult females (1.29E+00) > adult males (1.12E+00). In addition, the mean carcinogenic risk (CR) values for Cr, As, Pb, and Cd in three populations were all higher than 1E-06, which cannot be negligible. The mean threshold CR (TCR) values were decreased in the order of children (1.32E-02) > adult females (6.61E-03) > adult males (5.81E-03), respectively, all at unacceptable risk levels. Moreover, sensitivity analysis identified concentration factor (CW) as the most crucial parameter that affects human health. These findings highlight that co-exposure of PTE in wheat grains revealed a probabilistic human health risk. Corresponding measures should be undertaken for controlling pollution sources and reducing the risks for the local populace.
Differential prognostic impact of stratified additional chromosome abnormalities on disease progression among Malaysian chronic myeloid leukemia patients undergoing treatment with imatinib mesylate
Authors: Siti Mariam Ismail , Norhidayah Ramli , Zulaikha Abu Bakar , Nazihah Mohd Yunus , Rosline Hassan , Kausar Ghazali Anis , Sarina Sulong , Azlan Husin , Ankathil Ravindran
Published: August 2022

The emergence of additional chromosome abnormalities (ACAs) in chronic myeloid leukemia (CML) patients during treatment with a tyrosine kinase inhibitor (TKI) regime is generally associated with resistance to treatment and a sign of disease progression to accelerated phase or blast phase. We report the type, frequency, and differential prognostic impact of stratified ACAs with treatment response in 251 Malaysian CML patients undergoing TKI therapy. ACAs were observed in 40 patients (15.9%) of which 7 patients (17.5%) showed ACAs at time of initial diagnosis whereas 33 patients (82.5%) showed ACAs during the course of IM treatment. In order to assess the prognostic significance, we stratified the CML patients with ACAs into four groups, group 1 (+8/+Ph), group 2 (hypodiploidy), group 3 (structural/complex abnormalities); group 4 (high-risk complex abnormalities), and followed up the disease outcome of patients. Group 1 and group 2 relatively showed good prognosis while patients in group 3 and group 4 had progressed or transformed to AP or blast phase with a median survival rate of 12 months after progression. Novel ACAs consisting of rearrangements involving chromosome 11 and chromosome 12 were found to lead to myeloid BP while ACAs involving the deletion of 7q or monosomy 7 led toward a lymphoid blast phase. There was no evidence of group 2 abnormalities (hypodiploidy) contributing to disease progression. Compared to group 1 abnormalities, CML patients with group 3 and group 4 abnormalities showed a higher risk for disease progression. We conclude that the stratification based on individual ACAs has a differential prognostic impact and might be a potential novel risk predictive system to prognosticate and guide the treatment of CML patients at diagnosis and during treatment.
Current understanding of the human microbiome in glioma
Authors: Liang Jianhao , Li Ting , Zhao Jiajia , Wang Cheng , Sun Haitao
Published: August 2022

There is mounting evidence that the human microbiome is highly associated with a wide variety of central nervous system diseases. However, the link between the human microbiome and glioma is rarely noticed. The exact mechanism of microbiota to affect glioma remains unclear. Recent studies have demonstrated that the microbiome may affect the development, progress, and therapy of gliomas, including the direct impacts of the intratumoral microbiome and its metabolites, and the indirect effects of the gut microbiome and its metabolites. Glioma-related microbiome (gut microbiome and intratumoral microbiome) is associated with both tumor microenvironment and tumor immune microenvironment, which ultimately influence tumorigenesis, progression, and responses to treatment. In this review, we briefly summarize current knowledge regarding the role of the glioma-related microbiome, focusing on its gut microbiome fraction and a brief description of the intratumoral microbiome, and put forward the prospects in which microbiome can be applied in the future and some challenges still need to be solved.
Precision Breast Cancer Medicine: Early Stage Triple Negative Breast Cancer—A Review of Molecular Characterisation, Therapeutic Targets and Future Trends
Authors: Pinilla Karen , Drewett Lynsey M. , Lucey Rebecca , Abraham Jean E.
Published: August 2022

Personalised approaches to the management of all solid tumours are increasing rapidly, along with wider accessibility for clinicians. Advances in tumour characterisation and targeted therapies have placed triple-negative breast cancers (TNBC) at the forefront of this approach. TNBC is a highly heterogeneous disease with various histopathological features and is driven by distinct molecular alterations. The ability to tailor individualised and effective treatments for each patient is of particular importance in this group due to the high risk of distant recurrence and death. The mainstay of treatment across all subtypes of TNBC has historically been cytotoxic chemotherapy, which is often associated with off-target tissue toxicity and drug resistance. Neoadjuvant chemotherapy is commonly used as it allows close monitoring of early treatment response and provides valuable prognostic information. Patients who achieve a complete pathological response after neoadjuvant chemotherapy are known to have significantly improved long-term outcomes. Conversely, poor responders face a higher risk of relapse and death. The identification of those subgroups that are more likely to benefit from breakthroughs in the personalised approach is a challenge of the current era where several targeted therapies are available. This review presents an overview of contemporary practice, and promising future trends in the management of early TNBC. Platinum chemotherapy, DNA damage response (DDR) inhibitors, immune checkpoint inhibitors, inhibitors of the PI3K-AKT-mTOR, and androgen receptor (AR) pathways are some of the increasingly studied therapies which will be reviewed. We will also discuss the growing evidence for less-developed agents and predictive biomarkers that are likely to contribute to the forthcoming advances in this field. Finally, we will propose a framework for the personalised management of TNBC based upon the integration of clinico-pathological and molecular features to ensure that long-term outcomes are optimised.
Double heterozygous pathogenic variants prevalence in a cohort of patients with hereditary breast cancer
Authors: Megid Thais Baccili Cury , Barros-Filho Mateus C. , Pisani Janina Pontes , Achatz Maria Isabel
Published: August 2022

Hereditary breast cancer (BC) corresponds to 5% of all BC and a larger parcel of early-onset disease. The incorporation of next-generation sequencing (NGS) techniques reduced the cost of molecular testing and allowed the inclusion of additional cancer predisposition genes in panels that are more comprehensive. This enabled the identification of germline pathogenic variants in carriers and the introduction of risk-reducing strategies. It also resulted in the identification of the co-occurrence of more than one germline pathogenic variant in BC genes in some families. This is a rare event, and there are few reports on its impact on cancer risk. We conducted a single-institution retrospective study in which 1,156 women with early onset BC and/or a family history of cancer were tested by a germline multi-gene hereditary cancer panel. Germline pathogenic variants in high- and/or moderate-penetrance BC genes were identified in 19.5% of the individuals (n = 226). The most frequent variants were found in TP53 (69 of 226; 55 of them represented by p.R337H), BRCA1 (47 of 226), and BRCA2 (41 of 226). Double heterozygous (DH) variants were detected in 14 cases, representing 1.2% of all individuals assessed. There were no significant differences in age of BC onset and risk for bilateral BC in DH carriers when compared with those with one germline variant.
Circulating inflammatory cells in patients with metastatic breast cancer: Implications for treatment
Authors: Gianni Caterina , Palleschi Michela , Schepisi Giuseppe , Casadei Chiara , Bleve Sara , Merloni Filippo , Sirico Marianna , Sarti Samanta , Cecconetto Lorenzo , Di Menna Giandomenico , Schettini Francesco , De Giorgi Ugo
Published: August 2022

Adaptive and innate immune cells play a crucial role as regulators of cancer development.

Inflammatory cells in blood flow seem to be involved in pro-tumor activities and contribute to breast cancer progression. Circulating lymphocyte ratios such as the platelet-lymphocytes ratio (PLR), the monocyte-lymphocyte ratio (MLR) and the neutrophil-lymphocyte ratio (NLR) are new reproducible, routinely feasible and cheap biomarkers of immune response. These indexes have been correlated to prognosis in many solid tumors and there is growing evidence on their clinical applicability as independent prognostic markers also for breast cancer.

In this review we give an overview of the possible value of lymphocytic indexes in advanced breast cancer prognosis and prediction of outcome. Furthermore, targeting the immune system appear to be a promising therapeutic strategy for breast cancer, especially macrophage-targeted therapies. Herein we present an overview of the ongoing clinical trials testing systemic inflammatory cells as therapeutic targets in breast cancer.
Presence of the GFI1-36N single nucleotide polymorphism enhances the response of MLL-AF9 leukemic cells to CDK4/6 inhibition
Authors: Vorwerk Jan , Sun Kaiyan , Frank Daria , Neumann Felix , Hüve Jana , Budde Paulina Marie , Liu Longlong , Xie Xiaoqing , Patnana Pradeep Kumar , Ahmed Helal Mohammed Mohammed , Opalka Bertram , Lenz Georg , Jayavelu Ashok Kumar , Khandanpour Cyrus
Published: August 2022

The zinc finger protein Growth Factor Independence 1 (GFI1) acts as a transcriptional repressor regulating differentiation of myeloid and lymphoid cells. A single nucleotide polymorphism of GFI1, GFI1-36N, has a prevalence of 7% in healthy Caucasians and 15% in acute myeloid leukemia (AML) patients, hence most probably predisposing to AML. One reason for this is that GFI1-36N differs from the wildtype form GFI1-36S regarding its ability to induce epigenetic changes resulting in a derepression of oncogenes. Using proteomics, immunofluorescence, and immunoblotting we have now gained evidence that murine GFI1-36N leukemic cells exhibit a higher protein level of the pro-proliferative protein arginine N-methyltransferase 5 (PRMT5) as well as increased levels of the cell cycle propagating cyclin-dependent kinases 4 (CDK4) and 6 (CDK6) leading to a faster proliferation of GFI1-36N leukemic cells in vitro. As a therapeutic approach, we subsequently treated leukemic GFI1-36S and GFI1-36N cells with the CDK4/6 inhibitor palbociclib and observed that GFI1-36N leukemic cells were more susceptible to this treatment. The findings suggest that presence of the GFI1-36N variant increases proliferation of leukemic cells and could possibly be a marker for a specific subset of AML patients sensitive to CDK4/6 inhibitors such as palbociclib.
Mapping phenotypic heterogeneity in melanoma onto the epithelial-hybrid-mesenchymal axis
Authors: Pillai Maalavika , Rajaram Gouri , Thakur Pradipti , Agarwal Nilay , Muralidharan Srinath , Ray Ankita , Barbhaya Dev , Somarelli Jason A. , Jolly Mohit Kumar
Published: August 2022

Epithelial to mesenchymal transition (EMT) is a well-studied hallmark of epithelial-like cancers that is characterized by loss of epithelial markers and gain of mesenchymal markers. Melanoma, which is derived from melanocytes of the skin, also undergo phenotypic plasticity toward mesenchymal-like phenotypes under the influence of various micro-environmental cues. Our study connects EMT to the phenomenon of de-differentiation (i.e., transition from proliferative to more invasive phenotypes) observed in melanoma cells during drug treatment. By analyzing 78 publicly available transcriptomic melanoma datasets, we found that de-differentiation in melanoma is accompanied by upregulation of mesenchymal genes, but not necessarily a concomitant loss of an epithelial program, suggesting a more “one-dimensional” EMT that leads to a hybrid epithelial/mesenchymal phenotype. Samples lying in the hybrid epithelial/mesenchymal phenotype also correspond to the intermediate phenotypes in melanoma along the proliferative-invasive axis - neural crest and transitory ones. As melanoma cells progress along the invasive axis, the mesenchymal signature does not increase monotonically. Instead, we observe a peak in mesenchymal scores followed by a decline, as cells further de-differentiate. This biphasic response recapitulates the dynamics of melanocyte development, suggesting close interactions among genes controlling differentiation and mesenchymal programs in melanocytes. Similar trends were noted for metabolic changes often associated with EMT in carcinomas in which progression along mesenchymal axis correlates with the downregulation of oxidative phosphorylation, while largely maintaining glycolytic capacity. Overall, these results provide an explanation for how EMT and de-differentiation axes overlap with respect to their transcriptional and metabolic programs in melanoma.
Revealing the intratumoral heterogeneity of non-DS acute megakaryoblastic leukemia in single-cell resolution
Authors: Su Narun , Li Zifeng , Yang Jiapeng , Fu Yang , Zhu Xiaohua , Miao Hui , Yu Yi , Jiang Wenjin , Le Jun , Qian Xiaowen , Wang Hongsheng , Qian Maoxiang , Zhai Xiaowen
Published: August 2022

Pediatric acute megakaryoblastic leukemia (AMKL) is a subtype of acute myeloid leukemia (AML) characterized by abnormal megakaryoblasts, and it is divided into the AMKL patients with Down syndrome (DS-AMKL) and AMKL patients without DS (non-DS-AMKL). Pediatric non-DS-AMKL is a heterogeneous disease with extremely poor outcome. We performed single-cell RNA sequencing (scRNA-seq) of the bone marrow from two CBFA2T3-GLIS2 fusion-positive and one RBM15-MKL1 fusion-positive non-DS-AMKL children. Meanwhile, we downloaded the scRNA-seq data of normal megakaryocyte (MK) cells of the fetal liver and bone marrow from healthy donors as normal controls. We conducted cell clustering, cell-type identification, inferCNV analysis, Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, and Monocle2 analysis to investigate the intratumoral heterogeneity of AMKL. Using canonical markers, we identified and characterized the abnormal blasts and other normal immune cells from three AMKL samples. We found intratumoral heterogeneity of AMKL in various cell-type proportions, malignant cells’ diverse copy number variations (CNVs), maturities, significant genes expressions, and enriched pathways. We also identified potential markers for pediatric AMKL, namely, RACK1, ELOB, TRIR, NOP53, SELENOH, and CD81. Our work offered insight into the heterogeneity of pediatric acute megakaryoblastic leukemia and established the single-cell transcriptomic landscape of AMKL for the first time.
Predicting chemotherapy response in non-small-cell lung cancer via computed tomography radiomic features: Peritumoral, intratumoral, or combined?
Authors: Chang Runsheng , Qi Shouliang , Zuo Yifan , Yue Yong , Zhang Xiaoye , Guan Yubao , Qian Wei
Published: August 2022

Purpose

This study aims to evaluate the ability of peritumoral, intratumoral, or combined computed tomography (CT) radiomic features to predict chemotherapy response in non-small cell lung cancer (NSCLC).

Methods

After excluding subjects with incomplete data or other types of treatments, 272 (Dataset 1) and 43 (Dataset 2, external validation) NSCLC patients who were only treated with chemotherapy as the first-line treatment were enrolled between 2015 and 2019. All patients were divided into response and nonresponse based on the response evaluation criteria in solid tumors, version 1.1. By using 3D slicer and morphological operations in python, the intra- and peritumoral regions of lung tumors were segmented from pre-treatment CT images (unenhanced) and confirmed by two experienced radiologists. Then radiomic features (the first order, texture, shape, et al.) were extracted from the above regions of interest. The models were trained and tested in Dataset 1 and further validated in Dataset 2. The performance of models was compared using the area under curve (AUC), confusion matrix, accuracy, precision, recall, and F1-score.

Results

The radiomic model using features from the peritumoral region of 0–3 mm outperformed that using features from 3–6, 6–9, 9–12 mm peritumoral region, and intratumoral region (AUC: 0.95 versus 0.87, 0.86, 0.85, and 0.88). By the fusion of features from 0–3 and 3–6 mm peritumoral regions, the logistic regression model achieved the best performance, with an AUC of 0.97. This model achieved an AUC of 0.85 in the external cohort. Moreover, among the 20 selected features, seven features differed significantly between the two groups (p < 0.05).

Conclusions

CT radiomic features from both the peri- and intratumoral regions can predict chemotherapy response in NSCLC using machine learning models. Combined features from two peritumoral regions yielded better predictions.
Survival outcomes analysis according to mismatch repair status in locally advanced rectal cancer patients treated with neoadjuvant chemoradiotherapy
Authors: Chen Lin , Yang Xudong , Zhang Yuanyuan , Liu Jie , Jiang Qixin , Ji Fang , Gao Jinli , Zhou Zhuqing , Wang Hao , Huang Jun , Fu Chuangang
Published: August 2022

Background

The predictive role of mismatch repair (MMR) status for survival outcomes and sensitivity in neoadjuvant chemoradiotherapy settings for patients with locally advanced rectal cancer (LARC) has been inconclusive.

Methods

A retrospective cohort of patients with LARC treated with neoadjuvant chemoradiotherapy (nCRT) was recruited. After adjusting for baseline characteristics, we used propensity score matching to reduce the effect of potential confounding factors on MMR status. The primary analysis was based on overall survival as the more important endpoint.

Results

This study included 269 patients. Patients with defective MMR (dMMR) were younger (58.5% vs. 60.0%, p=0.0274) and had lower body mass indices (p=0.0091), higher differentiation grades (p=0.0889), and more advanced rectal cancers (clinical T4 or T4b, p=0.0851; M1, p=0.0055) than those with proficient MMR (pMMR). However, propensity score-matched patients with dMMR (p=0.0013) exhibited superior overall survival, even in the M1 subgroup. More importantly, patients with proficient MMR who undergo early pathological downstaging, especially lymph node pathological downstaging, can achieve a prognosis similar to that of patients with dMMR.

Conclusion

The clinical significance of this retrospective study mainly includes two points: (1) Data from our study confirmed that LARC patients with dMMR status had better overall survival rates after nCRT, even in the M1 subgroup. (2) Similar survival outcomes were observed in older and female patients with early lymph node pathological downstaging, regardless of dMMR or pMMR.
SkinNet-16: A deep learning approach to identify benign and malignant skin lesions
Authors: Ghosh Pronab , Azam Sami , Quadir Ryana , Karim Asif , Shamrat F. M. Javed Mehedi , Bhowmik Shohag Kumar , Jonkman Mirjam , Hasib Khan Md. , Ahmed Kawsar
Published: August 2022

Skin cancer these days have become quite a common occurrence especially in certain geographic areas such as Oceania. Early detection of such cancer with high accuracy is of utmost importance, and studies have shown that deep learning- based intelligent approaches to address this concern have been fruitful. In this research, we present a novel deep learning- based classifier that has shown promise in classifying this type of cancer on a relevant preprocessed dataset having important features pre-identified through an effective feature extraction method.

Skin cancer in modern times has become one of the most ubiquitous types of cancer. Accurate identification of cancerous skin lesions is of vital importance in treating this malady. In this research, we employed a deep learning approach to identify benign and malignant skin lesions. The initial dataset was obtained from Kaggle before several preprocessing steps for hair and background removal, image enhancement, selection of the region of interest (ROI), region-based segmentation, morphological gradient, and feature extraction were performed, resulting in histopathological images data with 20 input features based on geometrical and textural features. A principle component analysis (PCA)-based feature extraction technique was put into action to reduce the dimensionality to 10 input features. Subsequently, we applied our deep learning classifier, SkinNet-16, to detect the cancerous lesion accurately at a very early stage. The highest accuracy was obtained with the Adamax optimizer with a learning rate of 0.006 from the neural network-based model developed in this study. The model also delivered an impressive accuracy of approximately 99.19%.
Volumetric modulated arc therapy versus tomotherapy for late T-stage nasopharyngeal carcinoma
Authors: Chen Qian , Tang Lingwei , Zhu Zhe , Shen Liangfang , Li Shan
Published: August 2022

Purpose

To compare the dosimetric parameters and clinical outcomes between volumetric modulated arc therapy (VMAT) and tomotherapy for treating late T-stage nasopharyngeal carcinoma (NPC).

Methods

Patients with non-metastatic late T-stage NPC who received definitive radiotherapy with tomotherapy or VMAT were selected. 1:1 propensity score matching (PSM) was used to control the balance of confounding factors. The dosimetric parameters and clinical outcomes were compared.

Results

A total of 171 patients were enrolled before matching, with 61 patients in the VMAT group and 110 patients in the tomotherapy group. In the post-PSM cohort, 54 sub-pairs of 108 patients were included after matching. Tomotherapy was superior to VMAT in the dosimetric parameters of planning target volumes, brainstem, spinal cord, lenses, and parotid glands but inferior in the optic nerves and optic chiasm. The tomotherapy group had a lower incidence of grade ≥ 3 acute mucositis (22.2% vs. 40.7%, p = 0.038) and a higher rate of complete response (83.3% vs. 66.7%, p = 0.046) after radiotherapy. However, there were no significant differences in locoregional failure-free survival (p = 0.375), distant metastasis-free survival (p = 0.529), or overall survival (p = 0.975) between the two groups.

Conclusion

Tomotherapy is superior to VMAT in terms of most dosimetric parameters, with less acute mucositis and better short-term efficacy. There are no significant differences in the survival outcomes between the VMAT and tomotherapy groups.
The role of hypoxia-inducible factor-1 alpha in multidrug-resistant breast cancer
Authors: Yong Liyun , Tang Shasha , Yu Haixin , Zhang Hongyi , Zhang Yi , Wan Yuan , Cai Fengfeng
Published: August 2022

Breast cancer is the most common cancer in women worldwide with increasing incidence. Significant therapeutics advances in the field of breast cancer have resulted in a growing number of treatment options, whereas de novo or acquired resistance is still a persistent clinical challenge. Drug resistance involves a variety of mechanisms, and hypoxia is one of the many causes. Hypoxia-inducible Factor-1 Alpha (HIF-1α) is a key transcription factor which can regulate the response of cells to hypoxia. HIF-1α can trigger anaerobic glycolysis of tumor cells, induce angiogenesis, promote the proliferation, invasion, and migration of tumor cells, and lead to multidrug resistance. This review mainly discusses the role of HIF-1α in the drug-resistant breast cancer and highlighted the potential of HIF-1α -targeted therapy.
Case report: Application of nirmatrelvir/ritonavir to treat COVID-19 in a severe aplastic anemia child after allogeneic hematopoietic stem cell transplantation
Authors: Huang Jinhua , Yin Di , Qin Xia , Yu Mei , Jiang Beilei , Chen Jing , Cao Qing , Tang Zhiguo
Published: August 2022

We present a case report of successful treatment with nirmatrelvir/ritonavir (Paxlvoid) for a severe aplastic anemia child with COVID-19, cytopenia, and mixed chimerism of donor hematopoietic cells at 3 months after allogeneic hematopoietic stem cell transplantation. After the 5-day entire course of treatment, the clinical symptoms were relieved, cycle threshold values of ORF1a/b and N genes increased from 22.60 and 22.15 to 34.52 and 33.84, respectively, and the peripheral blood counts gradually recovered without graft failure. Nirmatrelvir/ritonavir can effectively inhibit the replication of SARS-CoV-2 without any significant adverse effects.
Molecular mechanisms of sacubitril/valsartan in cardiac remodeling
Authors: Mustafa Nor Hidayah , Jalil Juriyati , Zainalabidin Satirah , Saleh Mohammed S.M. , Asmadi Ahmad Yusof , Kamisah Yusof
Published: August 2022

Cardiovascular diseases have become a major clinical burden globally. Heart failure is one of the diseases that commonly emanates from progressive uncontrolled hypertension. This gives rise to the need for a new treatment for the disease. Sacubitril/valsartan is a new drug combination that has been approved for patients with heart failure. This review aims to detail the mechanism of action for sacubitril/valsartan in cardiac remodeling, a cellular and molecular process that occurs during the development of heart failure. Accumulating evidence has unveiled the cardioprotective effects of sacubitril/valsartan on cellular and molecular modulation in cardiac remodeling, with recent large-scale randomized clinical trials confirming its supremacy over other traditional heart failure treatments. However, its molecular mechanism of action in cardiac remodeling remains obscure. Therefore, comprehending the molecular mechanism of action of sacubitril/valsartan could help future research to study the drug’s potential therapy to reduce the severity of heart failure.
Wenshenyang recipe treats infertility through hormonal regulation and inflammatory responses revealed by transcriptome analysis and network pharmacology
Authors: Xie Lan , Zhao Shuai , Zhang Xiaoling , Huang Wenting , Qiao Liansheng , Zhan Delin , Ma Chengmei , Gong Wei , Dang Honglei , Lu Hua
Published: August 2022

The Wenshenyang recipe (WSYR) has the effect of treating infertility, but the mechanisms underlying this activity have not been fully elucidated. In this study, network pharmacology and RNA sequencing were combined, with database-based “dry” experiments and transcriptome analysis-based “wet” experiments used conjointly to analyse the mechanism of WSYR in the treatment of infertility. In the dry analysis, 43 active compounds in WSYR and 44 therapeutic targets were obtained through a database search, 15 infertility pathways were significantly enriched, and key targets, such as ESR1, TP53, AKT1, IL-6, and IL-10 were identified. Then the wet experiments were performed to detect the expression changes of the 412 genes from 15 infertility pathways identified by dry analysis. HK-2 cells were treated with the three herbs of WSYR and subjected to targeted RNA sequencing. Based on the results, 92 of the 412 genes in 15 infertility pathways were identified as DEGs. Additionally, key targets, such as ESR2, STAT1, STAT3, and IL6, were also identified in the wet experiments. RT-qPCR experiments further verified that WSYR played an anti-inflammatory role by upregulating IL-4 and IL-10 and Epimedium brevicornu Maxim (Yinyanghuo) showed broader effect than Drynaria fortunei (Kunze) J. Sm (Gusuibu) and Cistanche deserticola Y.C.Ma (Roucongrong). By screening compounds of WSYR using molecular docking models of ESR1 and ESR2, it was further found that xanthogalenol in Gusuibu, arachidonate in Roucongrong, and anhydroicaritin in Yinyanghuo had good affinity for estrogen receptors. These findings provide evidence for an estrogen-regulating role of the three herbs in WSYR.
Curcumin and its nano-formulations: Defining triple-negative breast cancer targets through network pharmacology, molecular docking, and experimental verification
Authors: Deng Zhicheng , Chen Guanghui , Shi Yonghui , Lin Ying , Ou Jiebin , Zhu Hua , Wu Junyan , Li Guocheng , Lv Li
Published: August 2022

Background: Curcumin (CUR) displays the capability of suppressing the proliferation and metastasis of various cancer cells. However, the effects and underline mechanisms of CUR to treat triple-negative breast cancer (TNBC) have not been systematically elucidated with an appropriate method.

Methods: In the present research, a combination method of network pharmacology, molecular docking, and in vitro bio-experiment was used to investigate the pharmacological actions and underline mechanisms of CUR against TNBC. First, common targets of CUR and TNBC were screened via Venny 2.1.0 after potential CUR-related targets and targets of TNBC were got from several public databases. Then, the Gene Ontology (GO) function and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment were performed on the Metascape website, and the network of compound-targets-pathways was constructed via Cytoscape software. Moreover, the network of protein-protein interaction was constructed by the STRING database to screen potential targets. Moreover, molecular docking was applied to affirm the interaction of CUR with the screened top 10 potential targets. Finally, in vitro experiments were used to further verify the effects and mechanisms of CUR and its nano-formulation (CUR-NPs) against TNBC.

Results: Forty potential targets of CUR against TNBC were obtained. STAT3, AKT1, TNF, PTGS2, MMP9, EGFR, PPARG, NFE2L2, EP300, and GSK3B were identified as the top 10 targets of CUR against TNBC. In vitro experiment verified that CUR and CUR-NPs could not only restrain the invasion, migration, and proliferation of MDA-MB-231 cells but also induce their apoptosis. In addition, molecular docking demonstrated that CUR could bind spontaneously with the screened top 10 targeted proteins, and a real-time PCR experiment demonstrated that both CUR and CUR-NPs could downregulate the genetic expression levels of the 10 targets. Moreover, according to the CUR-targets-pathways network, PI3K-Akt, EGFR tyrosine kinase inhibitor resistance, JAK-STAT, Foxo, and HIF-1 signaling pathways were identified as the important pathways of CUR effects on TNBC. Among them, the inhibiting effects of CUR and CUR-NPs on the JAK-STAT signaling pathway were further verified by the western blot analysis.

Conclusion: Taken together, the present research demonstrates that CUR and CUR-NPs have pharmacological effects against TNBC via a multi-target and multi-pathway manner.
Investigation of market herbal products regulated under different categories: How can HPTLC help to detect quality problems?
Authors: Frommenwiler Débora A. , Reich Eike , Sharaf Maged H. M. , Cañigueral Salvador , Etheridge Christopher J.
Published: August 2022

Background: Herbal products regulated under different categories were found to be of different quality. This has been demonstrated by the increasing number of reports on the quality of herbal products in the scientific literature. Proper identification is an effective way to address this concerning issue early on in a products’ manufacturing process.

Objectives: To assess the quality of milk thistle, coneflower and black cohosh herbal drugs, preparations and products commercialized under different regulatory categories, and to illustrate the usefulness of HPTLC as a tool for evaluating quality.

Methods: HPTLC methods were adapted from the European Pharmacopeia’s monographs for milk thistle fruits, black cohosh and purple coneflower. Additional detection modes beyond those described in the monographs were employed, and the entire HPTLC fingerprints were used for examination of identity and purity of the investigated samples.

Results: All products regulated as Traditional Herbal Medicinal Products were shown to be of high quality: their fingerprints were consistent and without unexpected zones. A significant number of food supplements show quality issues (mainly adulterations): 52.4% of milk thistle, 33.3% of coneflower, and 45.5% of black cohosh products. The same was observed in 66.6% of black cohosh herbal drugs and preparations.
Comprehensive analyses of PDHA1 that serves as a predictive biomarker for immunotherapy response in cancer
Authors: Deng Langmei , Jiang Anqi , Zeng Hanqing , Peng Xiaoji , Song Liying
Published: August 2022

Recent studies have proposed that pyruvate dehydrogenase E1 component subunit alpha (PDHA1), a cuproptosis-key gene, is crucial to the glucose metabolism reprogram of tumor cells. However, the functional roles and regulated mechanisms of PDHA1 in multiple cancers are largely unknown. The Cancer Genome Atlas (TCGA), GEPIA2, and cBioPortal databases were utilized to elucidate the function of PDHA1 in 33 tumor types. We found that PDHA1 was aberrantly expressed in most cancer types. Lung adenocarcinoma (LUAD) patients with high PDHA1 levels were significantly correlated with poor prognosis of overall survival (OS) and first progression (FP). Kidney renal clear cell carcinoma (KIRC) patients with low PDHA1 levels displayed poor OS and disease-free survival (DFS). However, for stomach adenocarcinoma (STAD), the downregulated PDHA1 expression predicted a good prognosis in patients. Moreover, we evaluated the mutation diversity of PDHA1 in cancers and their association with prognosis. We also analyzed the protein phosphorylation and DNA methylation of PDHA1 in various tumors. The PDHA1 expression was negatively correlated with tumor-infiltrating immune cells, such as myeloid dendritic cells (DCs), B cells, and T cells in pan-cancers. Mechanically, we used single-cell sequencing to discover that the PDHA1 expression had a close link with several cancer-associated signaling pathways, such as DNA damage, cell invasion, and angiogenesis. At last, we conducted a co-expressed enrichment analysis and showed that aberrantly expressed PDHA1 participated in the regulation of mitochondrial signaling pathways, including oxidative phosphorylation, cellular respiration, and electron transfer activity. In summary, PDHA1 could be a prognostic and immune-associated biomarker in multiple cancers.