bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Expression of MMP2 and TIMP2 in Peripheral Blood Mononuclear Cells After Roux-en-Y Gastric Bypass
Authors: Nonino Carla Barbosa , Noronha Natália Yumi , de Araújo Ferreira-Julio Maysa , Moriguchi Watanabe Lígia , Cassia Karen Francislaine , Ferreira Nicoletti Carolina , Rossi Welendorf Caroline , Salgado Junior Wilson , Rossi Silva Souza Dorotéia , Augusta de Souza Pinhel Marcela
Published: October 2021

Matrix metalloproteinases (MMP) and their endogenous inhibitor, the tissue inhibitor of metalloproteinases (TIMP), are expressed in many different cell types and play an important role in physiologic and pathological degradation of extracellular matrix (ECM). Starting from these observations and considering the activation state of peripheral blood mononuclear cells (PBMCs) in obesity, we investigated the gene expression of metalloproteinases before and after Roux-en-Y gastric bypass (RYBG). The study was performed in the Ribeirão Preto Medical School University Hospital. Seventy-three women were divided into a study group (SG), composed of 53 individuals with severe obesity before and after 6 months of RYGB, and a control group (CG), composed of 20 normal-weight individuals. Anthropometric and body composition data were collected, and peripheral blood for ribonucleic acid (RNA) extraction. The biological samples were submitted to a quantitative real-time polymerase chain reaction to evaluate the expression of MMP2 and TIMP2 genes. Alterations in weight loss, body mass index (BMI), and fat mass (FM) were observed after 6 months of RYGB (p < 0.05). A reduction of gene expression of TIMP2 was observed after 6 months of RYGB, contributing positively to the weight loss (R2 = 0.33 p = 0.04). The enrichment analyses highlighted the interaction between TIMP2 and MMP2 genes and the molecular pathways involving the ECM remodeling in the obesity condition. RYGB contributes significantly to weight loss, improved BMI, reduced FM, and reduced TIMP2 expression in PBMCs, which might contribute to the ECM remodeling in the obesity and could be useful as a circulating biomarker.
Patterns of Legume Purchases and Consumption in the United States
Authors: Semba Richard D. , Rahman Nihaal , Du Shutong , Ramsing Rebecca , Sullivan Valerie , Nussbaumer Elizabeth , Love David , Bloem Martin W.
Published: October 2021

Background: Legumes are an inexpensive, healthy source of protein, fiber, and micronutrients, have low greenhouse gas and water footprints, and enrich soil through nitrogen fixation. Although higher legume consumption is recommended under US dietary guidelines, legumes currently comprise only a minor part of the US diet.

Objectives: To characterize the types of legumes most commonly purchased by US consumers and patterns of legume purchases by state and region, seasonality of legume purchases, and to characterize adults that have a higher intake of legumes.

Methods: We examined grocery market, chain supermarket, big box and club stores, Walmart, military commissary, and dollar store retail scanner data from Nielsen collected 2017–2019 and dietary intake from the National Health and Nutrition Examination Survey (NHANES), 2017–2018.

Results: The five leading types of legumes purchased in the US were pinto bean, black bean, kidney bean, lima bean, and chickpea. The mean annual per capita expenditure on legumes based on grocery purchases was $4.76 during 2017–2019. The annual per capita expenditure on legumes varied greatly by state with highest expenditure in Louisiana, South Carolina, Florida, Alabama, Mississippi, and lowest expenditure in Washington, New York, and Wisconsin. There were large regional differences in the most commonly purchased legumes. Of 4,741 adults who participated in the 24-h dietary recall in NHANES, 2017–2018, 20.5% reported eating any legumes in the previous 24 h. Those who consumed legumes were more likely to be Hispanic, with a higher education level, with a larger household size (all P < 0.05), but were not different by age, gender, or income level compared to those who did not consume legumes.

Conclusion: Although legumes are inexpensive, healthy, and a sustainable source of protein, per capita legume intake remains low in the US and below US dietary guidelines. Further insight is needed into barriers to legume consumption in the US.
Bone and Lean Mass Loss and Cognitive Impairment for Healthy Elder Adults: Analysis of the Nutrition and Health Survey in Taiwan 2013–2016 and a Validation Study With Structural Equation Modeling
Authors: Lin Sheng-Feng , Fan Yen-Chun , Pan Wen-Harn , Bai Chyi-Huey
Published: October 2021

Purpose: Bone and lean mass loss and cognitive impairment are prevalent in elder adults and have been hypothesized to share a potential link.

Methods: This nationwide cross-sectional study systemically sampled elder adults aged ≥65 years and conducted the door-to-door survey. The causal diagrams help to decide which covariates were included in the generalized linear mixed models (GLMMs). The structural equation modeling (SEM) was performed for the validation.

Results: A total of 535 participants were enrolled and categorized into the normal (67.3%), mild cognitive impairment (18.3%), and dementia groups (14.4%). With increasing in the severity of cognitive impairment, the bone marrow density and lean mass consistently showed the trend of decreasing values. In the GLMMs, a significant association existed between the decrease of the bone mineral density (BMD) and the Mini-Mental State Examination (MMSE) (β = 5.819 scores per g/cm2 decrease, p = 0.0305) with adjustment of the age, sex, and physical activity. The SEM models confirmed that the MMSE was significantly and directly predicted by the age (β = 0.1363, p = 0.0003) and BMD (β = 0.1251, p = 0.0006) independently and indirectly predicted by lean mass (β = 0.1138, p = 0.0003) through the bone density path.

Conclusion: In conclusion, an independent association between bone loss and cognitive impairment was existed rather than the confounding effect and the decrease of lean mass indirectly contributed to cognitive impairment by influencing the bone density.
Cinnamaldehyde Promotes the Intestinal Barrier Functions and Reshapes Gut Microbiome in Early Weaned Rats
Authors: Qi Lili , Mao Haiguang , Lu Xiaohui , Shi Tingting , Wang Jinbo
Published: October 2021

Cinnamaldehyde is an aromatic aldehyde isolated from the essential oil of cinnamon. It has been proved to possess various bioactivities such as anti-inflammation, anti-bacteria and antihypertensive. Nevertheless, early weaning could lead to intestinal stress, causing a range of intestinal health problems. The aim of this study is to explore the effects of cinnamaldehyde on gut barrier integrity, inflammatory responses, and intestinal microbiome of early weaned rats. In this study, treatment with cinnamaldehyde (100 or 200 mg/kg bodyweight/day) for 2 weeks significantly promoted the production of mucins in the colonic epithelial tissue of rats. Cinnamaldehyde supplementation significantly upregulated the expression of Muc2, TFF3 and the tight junction proteins (ZO-1, claudin-1, and occludin). Hematoxylin and eosin staining results showed that colonic histopathological changes were recovered by cinnamaldehyde supplementation. The mRNA expression of IL-6 and TNF-α were significantly decreased in the cinnamaldehyde groups while the TNF-α protein levels were significantly decreased in the two cinnamaldehyde groups. Cinnamaldehyde treatment obviously attenuated the activation of NF-κB signaling pathway in rat colonic tissue and suppressed the production of inflammatory cytokines. Furthermore, cinnamaldehyde supplementation remodeled the gut microbiome structure, at the genus level, Akkermansia, Bacteroides, Clostridium III, Psychrobacter, Intestinimonas were increased, whereas those of Ruminococcus, Escherichia/Shigella were obviously decreased in the cinnamaldehyde treated groups. These findings indicated that cinnamaldehyde could effectively enhance intestinal barrier integrity, ameliorate inflammatory responses and remodel gut microbiome in early weaned rats.
Association Between Genetically Proxied Lipid-Lowering Drug Targets and Renal Cell Carcinoma: A Mendelian Randomization Study
Authors: Liu Luyang , Sheng Chao , Lyu Zhangyan , Dai Hongji , Chen Kexin
Published: October 2021

Observational studies suggested inconsistent associations between lipid-lowering drugs, such as statins, and renal cell carcinoma (RCC) risk. In a two-sample Mendelian randomization (MR) framework, we assessed the causal influence of lipid-lowering agents and circulating lipid traits on overall and sex-specific RCC risk. Genetic variants of six drug-target genes were selected to proxy the effects of low-density lipoprotein cholesterol (LDL-C) lowering therapies. Instrumental variables for circulating lipid traits were constructed from two large genome-wide association studies. We used endpoints for RCC from summary statistics of two studies [International Agency for Research on Cancer [IARC], N = 13,230; National Cancer Institute [NCI], N = 4,735]. The robustness of results was assessed through conventional MR sensitivity analyses. Overall, there was no significant association between genetically proxied HMG-CoA reductase (HMGCR) inhibition and RCC risk [Odds ratio [OR] = 1.42, 95% CI, 0.29–6.99]. In the sex-stratified analysis, we observed a positive association for genetically proxied drug targets with RCC risk. Specifically, genetically proxied proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibition was associated with a higher risk of RCC in men [OR = 2.20 [95% CI, 1.24–3.89]], and the difference by sex was moderate. This study suggested genetically proxied inhibition of HMGCR was not associated with RCC risk, while genetically proxied PCSK9 inhibition might be associated with a higher risk of RCC in male.
Clinical and CT Radiomics Nomogram for Preoperative Differentiation of Pulmonary Adenocarcinoma From Tuberculoma in Solitary Solid Nodule
Authors: Zhuo Yaoyao , Zhan Yi , Zhang Zhiyong , Shan Fei , Shen Jie , Wang Daoming , Yu Mingfeng
Published: October 2021

Aim

To investigate clinical and computed tomography (CT) radiomics nomogram for preoperative differentiation of lung adenocarcinoma (LAC) from lung tuberculoma (LTB) in patients with pulmonary solitary solid nodule (PSSN).

Materials and Methods

A total of 313 patients were recruited in this retrospective study, including 96 pathologically confirmed LAC and 217 clinically confirmed LTB. Patients were assigned at random to training set (n = 220) and validation set (n = 93) according to 7:3 ratio. A total of 2,589 radiomics features were extracted from each three-dimensional (3D) lung nodule on thin-slice CT images and radiomics signatures were built using the least absolute shrinkage and selection operator (LASSO) logistic regression. The predictive nomogram was established based on radiomics and clinical features. Decision curve analysis was performed with training and validation sets to assess the clinical usefulness of the prediction model.

Results

A total of six clinical features were selected as independent predictors, including spiculated sign, vacuole, minimum diameter of nodule, mediastinal lymphadenectasis, sex, and age. The radiomics nomogram of lung nodules, consisting of 15 selected radiomics parameters and six clinical features showed good prediction in the training set [area under the curve (AUC), 1.00; 95% confidence interval (CI), 0.99–1.00] and validation set (AUC, 0.99; 95% CI, 0.98–1.00). The nomogram model that combined radiomics and clinical features was better than both single models (p < 0.05). Decision curve analysis showed that radiomics features were beneficial to clinical settings.

Conclusion

The radiomics nomogram, derived from unenhanced thin-slice chest CT images, showed favorable prediction efficacy for differentiating LAC from LTB in patients with PSSN.
Influence of Old Age on Risk of Lymph Node Metastasis and Survival in Patients With T1 Colorectal Cancer: A Population-Based Analysis
Authors: Ye Hua , Zheng Bin , Zheng Qi , Chen Ping
Published: October 2021

Background

We aimed at determining the influence of old age on lymph node metastasis (LNM) and prognosis in T1 colorectal cancer (CRC).

Methods

We collected data from eligible patients in Surveillance, Epidemiology, and End Results database between 2004 and 2015. Independent predictors of LNM were identified by logistic regression analysis. Cox regression analysis, propensity score-matched analysis, and competing risks analysis were used to analyze the associations between old age and lymph node (LN) status and to validate the prognostic value of old age on cancer-specific survival (CSS).

Results

In total, 10,092 patients were identified. Among them, 6,423 patients (63.6%) had greater than or equal to 12 examined lymph nodes (LNE ≥12), and 5,777 patients (57.7%) were 65 years or older. The observed rate of LNM was 4.6% (15 out of 325) in T1 CRC elderly patients, with tumor size <3 cm, well differentiated, with negative carcinoembryonic antigen (CEA) level, and adenocarcinoma. Logistic regression models demonstrated that tumor size ≥3 cm (odds ratio, OR = 1.316, P = 0.038), poorly differentiated (OR = 3.716, P < 0.001), older age (OR = 0.633 for ages 65–79 years, OR = 0.477 for age over 80 years, both P <0.001), and negative CEA level (OR = 0.71, P = 0.007) were independent prognostic factors. Cox regression analysis demonstrated that CSS was not significantly different between elderly patients undergoing radical resection with LNE ≥12 and those with LNE <12 (hazard ratio = 0.865, P = 0.153), which was firmly validated after a propensity score-matched analysis by a competing risks model.

Conclusions

The predictive value of tumor size, grading, primary site, histology, CEA level, and age for LNM should be considered in medical decision making about local resection. We found that tumor size was <3 cm, well differentiated, negative CEA level, and adenocarcinoma in elderly patients with T1 colorectal cancer which was suitable for local excision.
Mathematical Modeling of Locoregional Recurrence Caused by Premalignant Lesions Formed Before Initial Treatment
Authors: Takaki Mitsuaki , Haeno Hiroshi
Published: October 2021

Locoregional recurrence after surgery is a major unresolved issue in cancer treatment. Premalignant lesions are considered a cause of cancer recurrence. A study showed that premalignant lesions surrounding the primary tumor drove a high local cancer recurrence rate after surgery in head and neck cancer. Based on the multistage theory of carcinogenesis, cells harboring an intermediate number of mutations are not cancer cells yet but have a higher risk of becoming cancer than normal cells. This study constructed a mathematical model for cancer initiation and recurrence by combining the Moran and branching processes in which cells require two specific mutations to become malignant. There are three populations in this model: (i) normal cells with no mutation, (ii) premalignant cells with one mutation, and (iii) cancer cells with two mutations. The total number of healthy tissue is kept constant to represent homeostasis, and there is a rare chance of mutation every time a cell divides. If a cancer cell with two mutations arises, the cancer population proliferates, violating the homeostatic balance of the tissue. Once the number of cancer cells reaches a certain size, we conduct computational resection and remove the cancer cell population, keeping the ratio of normal and premalignant cells in the tissue unchanged. After surgery, we considered tissue dynamics and eventually observed the second appearance of cancer cells as recurrence. Consequently, we computationally revealed the conditions where the time to recurrence became short by parameter sensitivity analysis. Particularly, when the premalignant cells’ fitness is higher than normal cells, the proportion of premalignant cells becomes large after the surgical resection. Moreover, the mathematical model was fitted to clinical data on disease-free survival of 1,087 patients in 23 cancer types from the TCGA database. Finally, parameter values of tissue dynamics are estimated for each cancer type, where the likelihood of recurrence can be elucidated. Thus, our approach provides insights into the concept to identify the patients likely to experience recurrence as early as possible.
A Clinical Prognostic Model Based on Preoperative Hematological and Clinical Parameters Predicts the Progression of Primary WHO Grade II Meningioma
Authors: Gao Peng , Kong Tengxiao , Zhu Xuqiang , Zhen Yingwei , Li Hongjiang , Chen Di , Yuan Shanpeng , Zhang Dongtao , Jiao Henan , Li Xueyuan , Yan Dongming
Published: October 2021

Purpose

The purpose was to explore the correlation between hematological parameters and the progression of WHO grade II meningioma, and establish a clinical prognostic model based on hematological parameters and clinical prognostic factors to predict the progression-free survival (PFS) of patients.

Methods

A total of 274 patients with WHO grade II meningiomas were included. Patients were randomly divided into a training cohort (192, 70%) and a test cohort (82, 30%). In the training cohort, the least absolute shrinkage and selection operator Cox regression analysis were used to screen for hematological parameters with prognostic value, and the hematological risk model (HRM) was constructed based on these parameters; univariate and multivariate Cox regression analyses were utilized to screen for clinical prognostic factors, and a clinical prognostic model was constructed based on clinical prognostic factors and HRM. The prognostic stability and accuracy of the HRM and clinical prognostic model were verified in the test cohort. Subgroup analysis was performed according to the patients’ different clinical characteristics.

Results

Preoperative neutrophil-to-lymphocyte ratio, lymphocyte-to-monocyte ratio, platelet-to-lymphocyte ratio, albumin-to-globulin ratio, D-dimer, fibrinogen, and lactate dehydrogenase were associated with the PFS of patients. The areas under curve of the HRM were 0.773 (95% confidence interval [CI] 0.707–0.839) and 0.745 (95% CI 0.637–0.852) in the training cohort and test cohort, respectively. The progression risk was higher in the high-risk group than that in the low-risk group categorized by the optimal cutoff value (2.05) of hematological risk scores. The HRM, age, tumor location, tumor size, peritumoral edema, extent of resection, Ki-67 index, and postoperative radiotherapy were the prognostic factors for the progression of meningiomas. The corrected C-index of the clinical prognosis model was 0.79 in the training cohort. Clinical decision analysis showed that the clinical prognostic model could be used to obtain favorable clinical benefits. In the subgroup analysis, the HRM displayed excellent prognostic stability and general applicability in different subgroups.

Conclusions

Preoperative hematological parameters are associated with the postoperative progression of WHO grade II meningiomas. The clinical prognosis model constructed based on hematological parameters and clinical prognostic factors has favorable predictive accuracy and clinical benefits.
Acute Myeloid Leukemia Epigenetic Immune Escape From Nature Killer Cells by ICAM-1
Authors: Xiao Yang , Chen Jinghong , Wang Jia , Guan Wei , Wang Mengzhen , Zhang Linlin , Wang Zhiding , Wang Lixin , Yu Li
Published: October 2021

Acute myeloid leukemia (AML), a malignant disorder of hemopoietic stem cells. AML can escape immunosurveillance of natural killer (NK) by gene mutation, fusions, and epigenetic modification, while the mechanism is not clearly understood. Here we show that the expression of Intercellular adhesion molecule‐1 (ICAM‐1, CD54) is silenced in AML cells. Decitabine could upregulate ICAM-1 expression, which contributes to the NK-AML cell conjugates and helps NK cells kill AML cells. We also show that ICAM-1 high expression can reverse the AML immune evasion and activate NK cells function in vivo. This study suggests that a combination of the hypomethylating agent and NK cell infusion could be a new strategy to cure AML.
Electronic Medical Records as Input to Predict Postoperative Immediate Remission of Cushing’s Disease: Application of Word Embedding
Authors: Zhang Wentai , Li Dongfang , Feng Ming , Hu Baotian , Fan Yanghua , Chen Qingcai , Wang Renzhi
Published: October 2021

Background

No existing machine learning (ML)-based models use free text from electronic medical records (EMR) as input to predict immediate remission (IR) of Cushing’s disease (CD) after transsphenoidal surgery.

Purpose

The aim of the present study is to develop an ML-based model that uses EMR that include both structured features and free text as input to preoperatively predict IR after transsphenoidal surgery.

Methods

A total of 419 patients with CD from Peking Union Medical College Hospital were enrolled between January 2014 and August 2020. The EMR of the patients were embedded and transformed into low-dimensional dense vectors that can be included in four ML-based models together with structured features. The area under the curve (AUC) of receiver operating characteristic curves was used to evaluate the performance of the models.

Results

The overall remission rate of the 419 patients was 75.7%. From the results of logistic multivariate analysis, operation (p < 0.001), invasion of cavernous sinus from MRI (p = 0.046), and ACTH (p = 0.024) were strongly correlated with IR. The AUC values for the four ML-based models ranged from 0.686 to 0.793. The highest AUC value (0.793) was for logistic regression when 11 structured features and “individual conclusions of the case by doctor” were included.

Conclusion

An ML-based model was developed using both structured and unstructured features (after being processed using a word embedding method) as input to preoperatively predict postoperative IR.
The Role of PIEZO1 in Urinary Bladder Function and Dysfunction in a Rodent Model of Cyclophosphamide-Induced Cystitis
Authors: Beča Katharine I. K. , Girard Beatrice M. , Heppner Thomas J. , Hennig Grant W. , Herrera Gerald M. , Nelson Mark T. , Vizzard Margaret A.
Published: October 2021

In the urinary bladder, mechanosensitive ion channels (MSCs) underlie the transduction of bladder stretch into sensory signals that are relayed to the PNS and CNS. PIEZO1 is a recently identified MSC that is Ca2+ permeable and is widely expressed throughout the lower urinary tract. Recent research indicates that PIEZO1 is activated by mechanical stretch or by pharmacological agonism via Yoda1. Aberrant activation of PIEZO1 has been suggested to play a role in clinical bladder pathologies like partial bladder outlet obstruction and interstitial cystitis/bladder pain syndrome (IC/BPS). In the present study, we show that intravesical instillation of Yoda1 in female Wistar rats leads to increased voiding frequency for up to 16 hours after administration compared to vehicle treatment. In a cyclophosphamide (CYP) model of cystitis, we found that the gene expression of several candidate MSCs (Trpv1, Trpv4, Piezo1, and Piezo2) were all upregulated in the urothelium and detrusor following chronic CYP-induced cystitis, but not acute CYP-induced cystitis. Functionally with this model, we show that Ca2+ activity is increased in urothelial cells following PIEZO1 activation via Yoda1 in acute and intermediate CYP treatment, but not in naïve (no CYP) nor chronic CYP treatment. Lastly, we show that activation of PIEZO1 may contribute to pathological bladder dysfunction through the downregulation of several tight junction genes in the urothelium including claudin-1, claudin-8, and zona occludens-1. Together, these data suggest that PIEZO1 activation plays a role in dysfunctional voiding behavior and may be a future, clinical target for the treatment of pathologies like IC/BPS.
Analysis of Clinical Characteristics and Risk Factors of Severe Adenovirus Pneumonia in Children
Authors: Zhong Haiqin , Dong Xiaoyan
Published: October 2021

Objective:To analyze the clinical characteristics of adenovirus pneumonia (ADVP) in children and explore risk factors for severe ADVP.

Methods:Clinical data from 7,008 hospitalized children with community-acquired pneumonia and 211 with ADVP were retrospectively analyzed between July 2014 and June 2019. Eighty-six patients were diagnosed with severe pneumonia, and related risk factors were analyzed.

Results:ADVP accounts for 3.01% (211/7008) of CAP in hospitalized children. Among 211 patients, 167 (64.9%) children aged 1–5 years old, and the onset was in winter and spring for 126 (59.7%) children. All patients had cough, and 116 (92.8%) patients with mild cases and 82 (95.4%) patients with severe cases had varying degrees of fever. The duration of fever in the severe ADVP group and mild ADVP group was 7.3 and 5.4 days, respectively. The average hospital stays were 9.8 and 5.8 days, respectively. There was no significant difference in the levels of WBC and ESR between the two groups, but the levels ofN%, CRP, PCT and LDH in children with severe ADVP were significantly higher than those in the mild ADVP group. The univariate analysis showed that there were significant differences between the severe ADVP group and the mild ADVP group in ≥7 days of fever and high IgE (P< 0.05). There was no significant difference in sex, age, onset season, mycoplasma infection, bacterial infection between the two groups (P> 0.05). The multivariate logistic analysis showed that ≥7 days of fever and high IgE were independent risk factors for severe ADVP (P< 0.05).

Conclusions:Children with severe ADVP have long fever duration, a strong inflammatory response and immune function disturbance. Fever duration (≥7 days) and high IgE were independent risk factors for severe ADVP.
Effectiveness of T-Cell Replete Haploidentical Hematopoietic Stem Cell Transplantation for Refractory/Relapsed B Cell Acute Lymphoblastic Leukemia in Children and Adolescents
Authors: Sano Hideki , Mochizuki Kazuhiro , Kobayashi Shogo , Ohara Yoshihiro , Takahashi Nobuhisa , Kudo Shingo , Waragai Tomoko , Ikeda Kazuhiko , Ohto Hitoshi , Kikuta Atsushi
Published: October 2021

Background: The prognosis of refractory/relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL) remains dismal owing to acquired resistance to chemotherapeutic agents. This study aimed to evaluate the efficacy of T-cell replete HLA haploidentical hematopoietic stem cell transplantation (TCR-haplo-HSCT) for pediatric refractory/relapsed BCP-ALL (RR-BCP-ALL).

Methods: Nineteen pediatric patients with RR-BCP-ALL underwent TCR-haplo-HSCT between 2010 and 2019 at the Fukushima Medical University Hospital. The disease status at TCR-haplo-HSCT included complete remission (CR) in eight patients and non-CR with active disease in 11 patients. Total body irradiation-based, busulfan-based, and reduced-intensity conditioning regimens were employed in 11, 6, and 2 patients, respectively. Low-dose anti-thymocyte globulin (thymoglobulin, 2.5 mg/kg) was used in all patients. Graft-vs.-host disease (GVHD) prophylaxis was administered with tacrolimus, methotrexate, and prednisolone.

Results: All patients received peripheral blood stem cells as the stem cell source. The HLA disparities in graft vs. host directions were 2/8 in one, 3/8 in five, and 4/8 in 13 patients. Among 18 patients who achieved primary engraftment, acute GVHD occurred in all 18 evaluable patients (grade II, 9; grade III, 8; grade IV, 1), and chronic GVHD was observed in 10 out of 15 evaluable patients. Three patients died because of transplant-related mortality. The 3-year overall survival (OS) and leukemia-free survival rates were 57.4 and 42.1%, respectively. Compared to patients older than 10 years in age (N = 10), those younger than 10 years in age (N = 9) showed an excellent OS rate (3-year OS rate: patients < 10 years old, 100%; patients > 10 years old, 20% [95% confidence interval, 3.1–47.5]; p = 0.002).

Conclusions: We suggest that TCR haplo-HSCT with low-dose ATG conditioning has the potential to improve the transplantation outcomes in patients with RR-BCP.
Evaluation of Pirfenidone and Nintedanib in a Human Lung Model of Fibrogenesis
Authors: Roach KM , Castells E , Dixon K , Mason S , Elliott G , Marshall H , Poblocka MA , Macip S , Richardson M , Khalfaoui L , Bradding P
Published: October 2021

Introduction: Idiopathic pulmonary fibrosis (IPF) is a progressive, fatal lung disease with a poor prognosis and increasing incidence. Pirfenidone and nintedanib are the only approved treatments for IPF but have limited efficacy and their mechanisms of action are poorly understood. Here we have examined the effects of pirfenidone and nintedanib in a human model of lung fibrogenesis, and compared these with the putative anti-fibrotic compounds Lipoxin A4 (LXA4), and senicapoc, a KCa3.1 ion channel blocker.

Methods: Early fibrosis was induced in cultured human lung parenchyma using TGFβ1 for 7 days, ± pirfenidone, nintedanib, or LXA4. Pro-fibrotic responses were examined by RT-PCR, immunohistochemistry and soluble collagen secretion.

Results: Thirty six out of eighty four IPF and fibrosis-associated genes tested were significantly upregulated by TGFβ1 in human lung parenchyma with a ≥0.5 log2FC (n = 32). Nintedanib (n = 13) reduced the mRNA expression of 14 fibrosis-associated genes including MMPs (MMP1,−4,−13,−14), integrin α2, CXCR4 and PDGFB, but upregulated α-smooth muscle actin (αSMA). Pirfenidone only reduced mRNA expression for MMP3 and −13. Senicapoc (n = 11) previously attenuated the expression of 28 fibrosis-associated genes, including αSMA, several growth factors, collagen type III, and αV/β6 integrins. Pirfenidone and nintedanib significantly inhibited TGFβ1-induced fibroblast proliferation within the tissue, but unlike senicapoc, neither pirfenidone nor nintedanib prevented increases in tissue αSMA expression. LXA4 was ineffective.

Conclusions: Pirfenidone and nintedanib demonstrate modest anti-fibrotic effects and provide a benchmark for anti-fibrotic activity of new drugs in human lung tissue. Based on these data, we predict that the KCa3.1 blocker senicapoc will show greater benefit than either of these licensed drugs in IPF.
Case Report: Afatinib-Induced Interstitial Pneumonia: Experiences and Lessons From Two Patients
Authors: Liu Xiao , Ma Baozhen , Li Tiepeng , Zhao Lingdi
Published: October 2021

Background: Afatinib has shown good efficacy in patients harboring uncommon EGFR mutations, but the incidence of afatinib-induced interstitial pneumonia should be alert as its rapid progression. Here, we report two cases of interstitial pneumonia during afatinib treatment.

Case presentation: The first case was of a 58-year-old male with advanced lung adenocarcinoma (cT4bN3M1b) with exon 18 G719X and exon 20 S781I EGFR mutations and received afatinib therapy. After 68 days of therapy, he developed shortness of breath and fever. Drug-induced pneumonia was not diagnosed timely, the patient received empirical antibiotics and low-dose glucocorticoids. The pulmonary inflammation rapidly progressed and the patient died 15 days after symptom onset. The second case was of a 57-year-old man with stage IV (cT3N3M1b) lung adenocarcinoma with exon 21 L861Q EGFR mutation. He received afatinib as second-line therapy. Fever and shortness of breath occurred 22 days after afatinib therapy, he received empirical antibiotic therapy. Five days later, CT showed aggravated pulmonary inflammation, and afatinib-induced interstitial pneumonia was diagnosed. He received glucocorticoid therapy, and the pneumonia quickly improved.

Conclusion: Although the incidence of EGFR-TKI-associated pneumonia is uncommon, high vigilance for drug-induced interstitial pneumonia is necessary during treatment. Early diagnosis and early glucocorticoid therapy could reverse lung injury.
The Current Application and Future Prospects of Astragalus Polysaccharide Combined With Cancer Immunotherapy: A Review
Authors: Kong Fanming , Chen Tianqi , Li Xiaojiang , Jia Yingjie
Published: October 2021

So far, immunotherapy has been shown to have impressive effects on different cancers in clinical trials. All those immunotherapies are generally derived from three main therapeutic approaches: immune checkpoint inhibitors, immune cell vaccination, and adoptive cellular immunotherapy. Our research systematically reviewed a wide range of clinical trials and laboratory studies of astragalus polysaccharide (APS) and elucidated the potential feasibility of using APS in activating adoptive immunotherapy. Apart from being effective in adaptive “passive” immunotherapy such as lymphokine-activated killer treatment and dendritic cell (DC)–cytokine–induced killer treatment, APS could also regulate the anti-programmed cell death protein 1 (PD-1)/PD-L1 on the surface of the immune cells, as a part in the immune checkpoint inhibitory signaling pathway by activating the immune-suppressed microenvironment by regulating cytokines, toll-like receptor 4 (TLR4), nuclear factor kappa B (NF-κB), and mitogen-activated protein kinase (MAPK) pathways, and immune cells, such as DCs, macrophages, NK cells, and so on. In view of the multiple functions of APS in immunotherapy and tumor microenvironment, a combination of APS and immunotherapy in cancer treatment has a promising prospect.
An In Vitro Anticancer Activity Evaluation of Neolamarckia cadamba (Roxb.) Bosser Leaves’ Extract and its Metabolite Profile
Authors: Razali Shakirah , Firus Khan Al’aina Yuhainis , Khatib Alfi , Ahmed Qamar Uddin , Abdul Wahab Ridhwan , Zakaria Zainul Amiruddin
Published: October 2021

The leaves of Neolamarckia cadamba (NC) (Roxb.) Bosser (family: Rubiaceae) are traditionally used to treat breast cancer in Malaysia; however, this traditional claim is yet to be scientifically verified. Hence, this study was aimed to evaluate the anticancer effect of NC leaves’ ethanol extract against breast cancer cell line (MCF-7 cells) using an in vitro cell viability, cytotoxicity, and gene expression assays followed by the gas chromatography analysis to further confirm active principles. Results revealed 0.2 mg/ml as the half maximal inhibitory concentration (IC50) against MCF-7. The extract exerted anticancer effect against MCF-7 cells in a dose- and time-dependent manner. The cell cycle assay showed that the extract arrested MCF-7 cells in the G0/G1 phase, and apoptosis was observed after 72 h by the Annexin-V assay. The gene expression assay revealed that the cell cycle arrest was associated with the downregulation of CDK2 and subsequent upregulation of p21 and cyclin E. The extract induced apoptosis via the mediation of the mitochondrial cell death pathways. A chromatography analysis revealed the contribution of D-pinitol and myo-inositol as the two major bioactive compounds to the activity observed. Overall, the study demonstrated that NC leaves’ ethanol extract exerts anticancer effect against MCF-7 human breast cancer cells through the induction of apoptosis and cell cycle arrest, thereby justifying its traditional use for the treatment of breast cancer in Malaysia.
European Network to Advance Best Practices and Technology on Medication Adherence: Mission Statement
Authors: van Boven Job FM , Tsiligianni Ioanna , Potočnjak Ines , Mihajlović Jovan , Dima Alexandra L. , Nabergoj Makovec Urska , Ágh Tamás , Kardas Prezmyslaw , Ghiciuc Cristina Mihaela , Petrova Guenka , Bitterman Noemi , Kamberi Fatjona , Culig Josip , Wettermark Björn ,   European Network to Advance Best Practices and Technology on Medication AdherencE (ENABLE)
Published: October 2021

Medication non-adherence is associated with almost 200,000 deaths annually and €80–125 billion in the European Union. Novel technological advances (smart pill bottles, digital inhalers and spacers, electronic pill blisters, e-injection pens, e-Health applications, big data) could help managing non-adherence. Healthcare professionals seem however inadequately informed about non-adherence, availability of technological solutions in daily practice is limited, and collaborative efforts to push forward their implementation are scarce. The European Network to Advance Best practices and technoLogy on medication adherencE (ENABLE, COST Action 19132) aims to 1) raise awareness of adherence enhancing solutions, 2) foster knowledge on medication adherence, 3) accelerate clinical application of novel technologies and 4) work collaboratively towards economically viable policy, and implementation of adherence enhancing technology across healthcare systems.
Predictors of Mortality in Progressive Fibrosing Interstitial Lung Diseases
Authors: Chen Xianqiu , Guo Jian , Yu Dong , Jie Bing , Zhou Ying
Published: October 2021

Background: Progressive fibrosing interstitial lung disease (PF-ILD) and idiopathic pulmonary fibrosis (IPF) share similar progression phenotype but with different pathophysiological mechanism. The purpose of this study was to assess clinical characteristics and outcomes of patients with PF-ILD in a single-center cohort.

Methods: Patients with PF-ILD treated in Shanghai Pulmonary Hospital from Jan. 2013 to Dec. 2014 were retrospectively analyzed. Baseline characteristics and clinical outcomes were collected for survival analysis to identifying clinical predictors of mortality.

Results: Among 608 patients with ILD, 132 patients met the diagnostic criteria for PF-ILD. In this single-center cohort, there were 51 (38.6%) cases with connective tissue disease-associated interstitial lung disease (CTD-ILD) and 45 (34.1%) with unclassifiable ILDs. During follow-up, 83 patients (62.9%) either died (N = 79, 59.8%) or underwent lung transplantations (N = 4, 3.0%) with a median duration follow-up time of 53.7 months. Kaplan-Meier survival curves revealed that the 1, 3 and 5-years survival of PF-ILD were 90.9, 58.8 and 48.1%, respectively. In addition, the prognosis of patients with PF-ILD was similar to those with IPF, while it was worse than non-PF-ILD ones. Multivariate Cox regression analysis demonstrated that high-resolution computed tomography (HRCT) scores (HR 1.684, 95% CI 1.017–2.788, p = 0.043) and systolic pulmonary artery pressure (SPAP) > 36.5 mmHg (HR 3.619, 95%CI 1.170–11.194, p = 0.026) were independent risk factors for the mortality of PF-ILD.

Conclusion: Extent of fibrotic changes on HRCT and pulmonary hypertension were predictors of mortality in patients with PF-ILD.
Sodium–Glucose Co-Transporter 2 Inhibition With Empagliflozin Improves Cardiac Function After Cardiac Arrest in Rats by Enhancing Mitochondrial Energy Metabolism
Authors: Tan Yunke , Yu Kai , Liang Lian , Liu Yuanshan , Song Fengqing , Ge Qiulin , Fang Xiangshao , Yu Tao , Huang Zitong , Jiang Longyuan , Wang Peng
Published: October 2021

Empagliflozin is a newly developed antidiabetic drug to reduce hyperglycaemia by highly selective inhibition of sodium–glucose co-transporter 2. Hyperglycaemia is commonly seen in patients after cardiac arrest (CA) and is associated with worse outcomes. In this study, we examined the effects of empagliflozin on cardiac function in rats with myocardial dysfunction after CA. Non-diabetic male Sprague–Dawley rats underwent ventricular fibrillation to induce CA, or sham surgery. Rats received 10 mg/kg of empagliflozin or vehicle at 10 min after return of spontaneous circulation by intraperitoneal injection. Cardiac function was assessed by echocardiography, histological analysis, molecular markers of myocardial injury, oxidative stress, mitochondrial ultrastructural integrity and metabolism. We found that empagliflozin did not influence heart rate and blood pressure, but left ventricular function and survival time were significantly higher in the empagliflozin treated group compared to the group treated with vehicle. Empagliflozin also reduced myocardial fibrosis, serum cardiac troponin I levels and myocardial oxidative stress after CA. Moreover, empagliflozin maintained the structural integrity of myocardial mitochondria and increased mitochondrial activity after CA. In addition, empagliflozin increased circulating and myocardial ketone levels as well as heart β-hydroxy butyrate dehydrogenase 1 protein expression. Together, these metabolic changes were associated with an increase in cardiac energy metabolism. Therefore, empagliflozin favorably affected cardiac function in non-diabetic rats with acute myocardial dysfunction after CA, associated with reducing glucose levels and increasing ketone body oxidized metabolism. Our data suggest that empagliflozin might benefit patients with myocardial dysfunction after CA.
Tongue Displacement Device in Decreasing the Radiation Dose to Tongue and Preventing Proton Beam Overshoot in Proton Therapy for Unilateral Head and Neck Cancer
Authors: Hong Chae-Seon , Oh Dongryul , Ju Sang Gyu , Ahn Yong Chan , Kim Yeong-bi , Park Seyjoon , Lee Woojin
Published: October 2021

The aim of this study was to evaluate the dosimetric characteristics of a semi-customized tongue displacement device (SCTDD) fabricated using a 3D printer for patients receiving unilateral head and neck irradiation with intensity-modulated proton therapy (IMPT) and assess its feasibility as a proton beam stopper compared to a standard mouthpiece (SMP). Seven consecutive patients, three with tonsil cancer, and four with oral cavity cancer were included in this retrospective study. Planning computed tomography (CT) images of each patient were acquired for each device. Both the SCTDD and SMP plans were generated using a single-field optimized IMPT. The clinically relevant dose-volume parameters for the organs at risk (OARs), especially the tongue, were compared between the SCTDD and SMP plans. Additionally, to assess the feasibility of SCTDD as a proton beam stopper, the dose to the contralateral oral mucosa (COM) was compared with that from sMP use. The use of scTDD resulted in a statistically significant decrease in the radiation dose to the tongue and COM compared to sMP. The median mean dose to the tongue was significantly reduced with SCTDD (18.3 Gy(RBE)) compared to the SMP (22.9 Gy(RBE)) (p = 0.016). The percentages of tongue volume receiving doses between 15 and 60 Gy(RBE) were significantly lower with SCTDD. In the COM, SCTDD resulted in a significantly lower median mean (2.9 Gy(RBE) vs. 7.9 Gy(RBE), p = 0.018) and maximum dose (39.1 Gy(RBE) vs. 41.6 Gy(RBE), p = 0.018) doses compared to SMP. The SCTDD effectively decreased the radiation dose to the tongue compared to SMP in patients undergoing unilateral head and neck irradiation with IMPT and acted as a proton beam stopper to protect normal tissues located behind the target volume, such as the COM.
The Robustness of Interdependent Directed Networks With Intra-layer Angular Correlations
Authors: Wu Zongning , Di Zengru , Fan Ying
Published: October 2021

The robustness of interdependent networks is a frontier topic in current network science. A line of studies has so far been investigated in the perspective of correlated structures on robustness, such as degree correlations and geometric correlations in interdependent networks, in-out degree correlations in interdependent directed networks, and so on. Advances in network geometry point that hyperbolic properties are also hidden in directed structures, but few studies link those features to the dynamical process in interdependent directed networks. In this paper, we discuss the impact of intra-layer angular correlations on robustness from the perspective of embedding interdependent directed networks into hyperbolic space. We find that the robustness declines as increasing intra-layer angular correlations under targeted attacks. Interdependent directed networks without intra-layer angular correlations are always robust than those with intra-layer angular correlations. Moreover, empirical networks also support our findings: the significant intra-layer angular correlations are hidden in real interdependent directed networks and contribute to the prediction of robustness. Our work sheds light that the impact of intra-layer angular correlations should be attention, although in-out degree correlations play a positive role in robustness. In particular, it provides an early warning indicator by which the system decoded the intrinsic rules for designing efficient and robust interacting directed networks.
Consistency in Geometry Among Coronary Atherosclerotic Plaques Extracted From Computed Tomography Angiography
Authors: Liu Haipeng , Wingert Aleksandra , Wang Xinhong , Zhang Jucheng , Sun Jianzhong , Chen Fei , Khalid Syed Ghufran , Gong Yinglan , Xia Ling , Jiang Jun , Wang Jian'an , Zheng Dingchang
Published: October 2021

Background: The three-dimensional (3D) geometry of coronary atherosclerotic plaques is associated with plaque growth and the occurrence of coronary artery disease. However, there is a lack of studies on the 3D geometric properties of coronary plaques. We aim to investigate if coronary plaques of different sizes are consistent in geometric properties.

Methods: Nineteen cases with symptomatic stenosis caused by atherosclerotic plaques in the left coronary artery were included. Based on attenuation values on computed tomography angiography images, coronary atherosclerotic plaques and calcifications were identified, 3D reconstructed, and manually revised. Multidimensional geometric parameters were measured on the 3D models of plaques and calcifications. Linear and non-linear (i.e., power function) fittings were used to investigate the relationship between multidimensional geometric parameters (length, surface area, volume, etc.). Pearson correlation coefficient (r), R-squared, and p-values were used to evaluate the significance of the relationship. The analysis was performed based on cases and plaques, respectively. Significant linear relationship was defined as R-squared > 0.25 and p < 0.05.

Results: In total, 49 atherosclerotic plaques and 56 calcifications were extracted. In the case-based analysis, significant linear relationships were found between number of plaques and number of calcifications (r = 0.650, p = 0.003) as well as total volume of plaques (r = 0.538, p = 0.018), between number of calcifications and total volume of plaques (r = 0.703, p = 0.001) as well as total volume of calcification (r = 0.646, p = 0.003), and between the total volumes of plaques and calcifications (r = 0.872, p < 0.001). In plaque-based analysis, the power function showed higher R-squared values than the linear function in fitting the relationships of multidimensional geometric parameters. Two presumptions of plaque geometry in different growth stages were proposed with simplified geometric models developed. In the proposed models, the exponents in the power functions of geometric parameters were in accordance with the fitted values.

Conclusion: In patients with coronary artery disease, coronary plaques and calcifications are positively related in number and volume. Different coronary plaques are consistent in the relationship between geometry parameters in different dimensions.