bluuebunny/crossref_metadata_2025 huggingface dataset:
Dimorphic glioblastoma with glial and epithelioid phenotypes: Clonal evolution and immune selection
Authors: Mondia Mark Willy L. , Kritselis Michael A. , Donahue John E. , Elinzano Heinrich , Sarangi Sasmit , Bryant David , Capelletti Marzia , Korn W. Michael , Yu Esther , Yan Sherry , Toms Steven A. , Wong Eric T.
Published: January 2023

Purpose

Epithelioid glioblastoma is an unusual histologic variant of malignant glioma. The present study investigates both the genomic and transcriptomic determinants that may promote the development of this tumor.

Methods

Whole-exome sequencing (WES) and whole-transcriptome sequencing (WTS) were performed on an epithelioid glioblastoma, along with a specific bioinformatic pipeline to generate electronic karyotyping and investigate the tumor immune microenvironment. Microdissected sections containing typical glioblastoma features and epithelioid morphology were analyzed separately using the same methodologies.

Results

An epithelioid glioblastoma, with immunopositivity for GFAP, Olig-2, and ATRX but negative for IDH-1 and p53, was identified. The tumor cell content from microdissection was estimated to be 85–90% for both histologic tumor components. WES revealed that both glioma and epithelioid sections contained identical point mutations in PTEN, RB1, TERT promoter, and TP53. Electronic karyotype analysis also revealed similar chromosomal copy number alterations, but the epithelioid component showed additional abnormalities that were not found in the glioblastoma component. The tumor immune microenvironments were strikingly different and WTS revealed high levels of transcripts from myeloid cells as well as M1 and M2 macrophages in the glioma section, while transcripts from CD4+ lymphocytes and NK cells predominated in the epithelioid section.

Conclusion

Epithelioid glioblastoma may be genomically more unstable and oncogenically more advanced, harboring an increased number of mutations and karyotype abnormalities, compared to typical glioblastomas. The tumor immune microenvironment is also different.
Metabolomics as a potential tool for monitoring patients with aneurysmal subarachnoid hemorrhage
Authors: Lasica Nebojsa , Raicevic Vidak , Stojanovic Nikola M. , Djilvesi Djula , Horvat Igor , Jelaca Bojan , Pajicic Filip , Vulekovic Petar
Published: January 2023

Metabolomics has evolved into a particularly useful tool to study interactions between metabolites and serves as an aid in unraveling the complexity of entire metabolomes. Nonetheless, it is increasingly viewed as a methodology with practical applications in the clinical setting, where identifying and quantifying biomarkers of interest could prove useful for diagnostics. Starting from a concise overview of the most prominent analytical techniques employed in metabolomics, herein we present a review of its application in studies of brain metabolism and cerebrovascular diseases, paying most attention to its uses in researching aneurysmal subarachnoid hemorrhage. Both animal models and human studies are considered, and metabolites identified as potential biomarkers are highlighted.
Identification of chronic mild traumatic brain injury using resting state functional MRI and machine learning techniques
Authors: Vedaei Faezeh , Mashhadi Najmeh , Zabrecky George , Monti Daniel , Navarreto Emily , Hriso Chloe , Wintering Nancy , Newberg Andrew B. , Mohamed Feroze B.
Published: January 2023

Mild traumatic brain injury (mTBI) is a major public health concern that can result in a broad spectrum of short-term and long-term symptoms. Recently, machine learning (ML) algorithms have been used in neuroscience research for diagnostics and prognostic assessment of brain disorders. The present study aimed to develop an automatic classifier to distinguish patients suffering from chronic mTBI from healthy controls (HCs) utilizing multilevel metrics of resting-state functional magnetic resonance imaging (rs-fMRI). Sixty mTBI patients and forty HCs were enrolled and allocated to training and testing datasets with a ratio of 80:20. Several rs-fMRI metrics including fractional amplitude of low-frequency fluctuation (fALFF), regional homogeneity (ReHo), degree centrality (DC), voxel-mirrored homotopic connectivity (VMHC), functional connectivity strength (FCS), and seed-based FC were generated from two main analytical categories: local measures and network measures. Statistical two-sample t-test was employed comparing between mTBI and HCs groups. Then, for each rs-fMRI metric the features were selected extracting the mean values from the clusters showing significant differences. Finally, the support vector machine (SVM) models based on separate and multilevel metrics were built and the performance of the classifiers were assessed using five-fold cross-validation and via the area under the receiver operating characteristic curve (AUC). Feature importance was estimated using Shapley additive explanation (SHAP) values. Among local measures, the range of AUC was 86.67–100% and the optimal SVM model was obtained based on combined multilevel rs-fMRI metrics and DC as a separate model with AUC of 100%. Among network measures, the range of AUC was 80.42–93.33% and the optimal SVM model was obtained based on the combined multilevel seed-based FC metrics. The SHAP analysis revealed the DC value in the left postcentral and seed-based FC value between the motor ventral network and right superior temporal as the most important local and network features with the greatest contribution to the classification models. Our findings demonstrated that different rs-fMRI metrics can provide complementary information for classifying patients suffering from chronic mTBI. Moreover, we showed that ML approach is a promising tool for detecting patients with mTBI and might serve as potential imaging biomarker to identify patients at individual level.

Clinical trial registration

[clinicaltrials.gov], identifier [NCT03241732].
Dietary quality indices and recurrent chronic kidney disease in Taiwanese post-renal transplant recipients
Authors: Lin I-Hsin , Wong Te-Chih , Duong Tuyen Van , Nien Shih-Wei , Tseng I-Hsin , Wang Hsu-Han , Chiang Yang-Jen , Yang Shwu-Huey
Published: January 2023

Background

This study investigated the association between dietary quality indices and recurrent chronic kidney disease (rCKD) in Taiwanese post-renal transplant recipients (RTRs).

Methods

This prospective study recruited RTRs aged >18 years with a functioning allograft and without any acute rejection in the past 3 months from September 2016 to June 2018. Dietary quality indices included the Alternative Healthy Eating Index (AHEI) and AHEI-2010, and the Taiwanese version of the AHEI (AHEI-Taiwan) was calculated using 3-day dietary records, and calculated scores were divided into quartiles. Laboratory data were collected from medical records. rCKD was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m2. Logistic regression analysis was performed to analyze the associations.

Results

This study included 102 RTRs. The RTRs with higher AHEI, AHEI-Taiwan, and AHEI-2010 scores were older and had higher eGFRs and lower odds of rCKD. As compared with the lowest quartile, patients with the highest quartiles of the AHEI [odds ratio (OR), 0.10; 95% confidence interval (95% CI): 0.02, 0.49; p-trend = 0.004), AHEI-2010 (OR, 0.17; 95% CI: 0.04, 0.72; p-trend = 0.016], and AHEI-Taiwan (OR, 0.13; 95% CI: 0.03–0.59; p-trend = 0.008) had lower odds of rCKD, respectively. As compared with the lowest quartile, patients who consumed the highest quartiles of red and processed meat had 11.43 times higher odds of rCKD (OR, 11.43; 95% CI: 2.30–56.85; p for trend <0.01).

Conclusion

Higher dietary quality indices are associated with lower odds of rCKD in Taiwanese RTRs. Particularly, a positive association between a higher intake of red meat and processed meat and higher odds of rCKD remained exists after transplantation in Taiwanese RTRs. Further dietary guidelines and individualized dietary education were necessary for RTRs to prevent graft function deterioration.
Impact of enteropathogens on faltering growth in a resource-limited setting
Authors: Kabir Furqan , Iqbal Junaid , Jamil Zehra , Iqbal Najeeha Talat , Mallawaarachchi Indika , Aziz Fatima , Kalam Adil , Muneer Sahrish , Hotwani Aneeta , Ahmed Sheraz , Umrani Fayaz , Syed Sana , Sadiq Kamran , Ma Jennie Z. , Moore Sean R. , Ali Asad
Published: January 2023

Introduction

Environmental enteropathy is an important contributor to childhood malnutrition in the developing world. Chronic exposure to fecal pathogens leads to alteration in intestinal structure and function, resulting in impaired gut immune function, malabsorption, and growth faltering leading to environmental enteropathy.

Methods

A community-based intervention study was carried out on children till 24 months of age in Matiari district, Pakistan. Blood and fecal specimens were collected from the enrolled children aged 3–6 and 9 months. A real-time PCR-based TaqMan array card (TAC) was used to detect enteropathogens.

Results

Giardia, Campylobacter spp., enteroaggregative Escherichia coli (EAEC), Enteropathogenic Escherichia coli (EPEC), Enterotoxigenic Escherichia coli (ETEC), and Cryptosporidium spp. were the most prevailing enteropathogens in terms of overall positivity at both time points. Detection of protozoa at enrollment and 9 months was negatively correlated with rate of change in height-for-age Z (ΔHAZ) scores during the first and second years of life. A positive association was found between Giardia, fecal lipocalin (LCN), and alpha 1-Acid Glycoprotein (AGP), while Campylobacter spp. showed positive associations with neopterin (NEO) and myeloperoxidase (MPO).

Conclusion

Protozoal colonization is associated with a decline in linear growth velocity during the first 2 years of life in children living in Environmental enteric dysfunction (EED) endemic settings. Mechanistic studies exploring the role of cumulative microbial colonization, their adaptations to undernutrition, and their influence on gut homeostasis are required to understand symptomatic enteropathogen-induced growth faltering.
The effects of green tea supplementation on cardiovascular risk factors: A systematic review and meta-analysis
Authors: Zamani Mohammad , Kelishadi Mahnaz Rezaei , Ashtary-Larky Damoon , Amirani Niusha , Goudarzi Kian , Torki Iman Attackpour , Bagheri Reza , Ghanavati Matin , Asbaghi Omid
Published: January 2023

Purpose

A bulk of observational studies have revealed the protective role of green tea supplementation in cardiovascular diseases. The current systematic review and meta-analysis study aimed to establish the effects of green tea supplementation on cardiovascular risk factors including lipid profile, blood pressure, glycemic control markers and CRP.

Methods

A systematic literature search of randomized clinical trials (RCTs) that investigated the effects of green tea supplementation and cardiovascular risk factors was undertaken in online databases including PubMed/Medline, Scopus, Web of Science, and Embase using a combination of green tea and cardiovascular risk factors search terms. Meta-analyses were carried out using a random-effects model. The I2 index was used to assess the heterogeneity of RCTs.

Results

Among the initial 11,286 studies that were identified from electronic databases search, 55 eligible RCTs with 63 effect sizes were eligible. Results from the random effects meta-analysis showed that GTE supplementation significantly reduced TC (WMD = −7.62; 95% CI: −10.51, −4.73; P = < 0.001), LDL-C (WMD = −5.80; 95% CI: −8.30, −3.30; P = < 0.001), FBS (WMD = −1.67; 95% CI: −2.58, −0.75; P = < 0.001), HbA1c (WMD = −0.15; 95% CI: −0.26, −0.04; P = 0.008), DBP (WMD = −0.87; 95% CI: −1.45, −0.29; P = 0.003), while increasing HDL-C (WMD = 1.85; 95% CI: 0.87, 2.84; P = 0.010). Subgroup analyses based on the duration of supplementation (≥ 12 vs. < 12 weeks), dose of green tea extract (GTE) (≥1,000 vs. < 1,000 mg/d), sex (male, female, and both), baseline serum levels of lipid profile, and glycemic control factors demonstrated different results for some risk factors.

Conclusion

The current study suggests improvements in the lipid and glycemic profiles following green tea supplementation. These findings support previous evidence showing the health benefits of green tea supplementation on cardiometabolic risk factors.
Interrelation among one-carbon metabolic (OCM) pathway-related indicators and its impact on the occurence of pregnancy-induced hypertension disease in pregnant women supplemented with folate and vitamin B12: Real-world data analysis
Authors: Zhang Yanfei , Gu Chenhong , Lei Ying , Wang Jingwen , Sun Leiqin , Fan Junwei , Wang Yanlin , Zhang Xiaoqing
Published: January 2023

Background and objective

A considerable number of pregnant women who were supplemented with folate and vitamin B12 were selected as major participants in studying the one-carbon metabolic (OCM) pathway. Our study aimed to explore the effects of OCM-related indicators on pregnancy-induced hypertension (PIH) and preeclampsia (PE) in pregnant women with folate and vitamin B12 supplementation.

Subjects and methods

A total of 1,178 pregnant women who took multivitamin tablets containing 800 μg folate and 4 μg vitamin B12 daily from 3 months before pregnancy to 3 months after pregnancy were enrolled in this study. These pregnant women were classified into three groups: the normotensive group (n = 1,006), the PIH group (n = 131), and the PE group (n = 41). The information on age, weight, body mass index (BMI), number of embryos, gravidity, parity, and OCM-related indicators (serum level of homocysteine, folate, and vitamin B12; MTHFR C677T genotype) was collected.

Results

The accuracy of the prediction model based on the screened independent risk factors (hyperhomocysteine, OR = 1.170, 95% CI = 1.061–1.291; high folate status, OR = 1.018, 95% CI = 0.999–1.038; and high BMI, OR = 1.216, 95% CI = 1.140–1.297) for PIH in subjects with MTHFR CC genotype (AUC = 0.802) was obviously higher than that in subjects with MTHFR CT, TT genotype (AUC = 0.684,0.685, respectively) by receiver operating characteristic curve analysis. The homocysteine level of the PIH group was significantly higher than that of the normotensive group only in subjects with the MTHFR CC genotype (p = 0.005). A negative correlation between homocysteine and folate appeared in subjects with MTHFR CT + TT genotype (p = 0.005). A model including multiple embryos, nulliparas, and lower folate could predict the process from PIH to PE (AUC = 0.781, p < 0.0001).

Conclusion

The prediction model composed of homocysteine, folate, and BMI for PIH was suitable for subjects with MTHFR CC genotype in pregnant women with supplementation of folate and vitamin B12. Lower folate levels could be an independent risk factor in developing the process from PIH to PE.
Ferroportin depletes iron needed for cell cycle progression in head and neck squamous cell carcinoma
Authors: Belvin Benjamin Ross , Lewis Janina P.
Published: January 2023

Introduction

Ferroportin (FPN), the only identified eukaryotic iron efflux channel, plays an important role in iron homeostasis and is downregulated in many cancers. To determine if iron related pathways are important for Head and Neck Squamous Cell Carcinoma (HNSCC) progression and proliferation, we utilize a model of FPN over-expression to simulate iron depletion and probe associated molecular pathways.

Methods

The state of iron related proteins and ferroptosis sensitivity was assessed in a panel of metastatic HNSCC cell lines. Stable, inducible expression of FPN was confirmed in the metastatic HNSCC lines HN12 and JHU-022 as well as the non-transformed normal oral keratinocyte (NOK) cell line and the effect of FPN mediated iron depletion was assessed in these cell lines.

Results

HNSCC cells are sensitive to iron chelation and ferroptosis, but the non-transformed NOK cell line is not. We found that FPN expression inhibits HNSCC cell proliferation and colony formation but NOK cells are unaffected. Inhibition of cell proliferation is rescued by the addition of hepcidin. Decreases in proliferation are due to the disruption of iron homeostasis via loss of labile iron caused by elevated FPN levels. This in turn protects HNSCC cells from ferroptotic cell death. Expression of FPN induces DNA damage, activates p21, and reduces levels of cyclin proteins thereby inhibiting cell cycle progression of HNSCC cells, arresting cells in the S-phase. Induction of FPN severely inhibits Edu incorporation and increased β-galactosidase activity, indicating cells have entered senescence. Finally, in an oral orthotopic mouse xenograft model, FPN induction yields a significant decrease in tumor growth.

Conclusions

Our results indicate that iron plays a role in HNSCC cell proliferation and growth and is important for cell cycle progression. Iron based interventional strategies such as ferroptosis or iron chelation may have potential therapeutic benefits in advanced HNSCC.
Analytical exploratory tool for healthcare professionals to monitor cancer patients’ progress
Authors: Valero-Ramon Zoe , Fernandez-Llatas Carlos , Collantes Gonzalo , Valdivieso Bernardo , Billis Antonis , Bamidis Panagiotis , Traver Vicente
Published: January 2023

Introduction

Cancer is a primary public concern in the European continent. Due to the large case numbers and survival rates, a significant population is living with cancer needs. Consequently, health professionals must deal with complex treatment decision-making processes. In this context, a large quantity of data is collected during cancer care delivery. Once collected, these data are complex for health professionals to access to support clinical decision-making and performance review. There is a need for innovative tools that make clinical data more accessible to support cancer health professionals in these activities.

Methods

Following a co-creation, an interactive approach thanks to the Interactive Process Mining paradigm, and data from a tertiary hospital, we developed an exploratory tool to present cancer patients' progress over time.

Results

This work aims to collect and report the process of developing an exploratory analytical Interactive Process Mining tool with clinical relevance for healthcare professionals for monitoring cancer patients' care processes in the context of the LifeChamps project together with a graphical and navigable Process Indicator in the context of prostate cancer patients.

Discussion

The tool presented includes Process Mining techniques to infer actual processes and present understandable results visually and navigable, looking for different types of patients, trajectories, and behaviors.
Reverse strategy to locally advanced breast implant-associated anaplastic large cell lymphoma: A case report
Authors: Cappelli Sonia , Marchesi Francesco , Clementi Marco , Perracchio Letizia , Palombi Francesca , Pelle Fabio , Botti Claudio , Costantini Maurizio
Published: January 2023

Breast implant-associated anaplastic large cell lymphoma (BIA-ALCL) is a rare T-cell lymphoma associated with textured breast implants. The most common presentation is a periprosthetic seroma that occurs at least 1 year after an aesthetic or reconstructive implantation, and in these cases, the surgical treatment seems to be successful. More rarely, BIA-ALCL presents with locally advanced mass-formed disease and a related regional lymph node involvement. In all these cases with worse prognosis, a multidisciplinary approach is required, including adjuvant chemotherapy, radiation therapy, and surgery. We present a clinical case of a 49-year-old woman who developed on the left side of the breast a mass-formed stage 3 BIA-ALCL 15 years after a bilateral breast augmentation with textured silicone implant. Our multidisciplinary team (MDT) scheduled the patient for a “reverse-strategy” sequential approach consisting of induction chemotherapy, hematopoietic stem cell mobilization, and harvest followed by autologous stem cell transplant (ASCT). After 100 days from the stem cell transplant, the patient showed a complete pathologic response and was a candidate for radical surgery. She underwent removal of both implants with total en bloc capsulectomy. On the left site, the periprosthetic mass was also en bloc removed. We did not perform any axillary dissection. Our surgical and hemato-oncological teams followed the patient every 3 months, and no local or systemic recurrences were observed 24 months after surgery. This case report has demonstrated the effectiveness of neoadjuvant chemotherapy as part of a “reverse strategy” in selected cases of advanced-stage BIA-ALCL in which it was not possible to perform an immediate radical surgery. Furthermore, in our case, the de-escalation strategy adopted permitted a less demolitic surgery with good functional and aesthetic results.
Genomic and clinical features of endoplasmic reticulum stress factor in digestive system pan-cancer studies
Authors: Yao Sheng , Yu Yuanquan , Xu Liyi , Pan Xiang
Published: January 2023

Introduction

Digestive system pan-cancer is one of the lethal malignant tumors, which have the propensity for poor prognosis and difficult treatment. Endoplasmic reticulum (ER) stress has served as a pivotal role in the progression of the tumor, while the implication of ER stress on digestive system pan-cancers still needs elucidation, especially from the perspective of clinical outcome and that of genomic features.

Methods

First, Among the ER STRESS factors from the REACTOME_UNFOLDED_PROTEIN_RESPONSE_UPR (113 genes) and HALLMARK_UNFOLDED_PROTEIN_RESPONSE (92 genes) terms, 153 ER STRESS regulators were identified after removing replicates. The somatic mutation data and copy number variation data of gastrointestinal pan-cancer were downloaded from The Cancer Genome Atlas (TCGA) database. Then, we explored the clinical outcome and genetic mutation of ER stress-related differentially expressed genes (DEGs) by multiple bioinformatics analysis. Subsequently, we analyzed the Spearman correlation between the drug sensitivity of 179 gastrointestinal anticancer drugs and the transcriptional expression of 153 ER stress factors in 769 cancer cell lines of the GDSC2 cohort. Next, ssGSEA method was used to quantify the immune cell infiltration scores in the tumor microenvironment, and Spearman correlation was used to calculate the correlation between ER stress scores and immune cell infiltration. Finally, we analyzed the cellular origin of ER stress factor dysregulation.

Results

We analyzed the genomic changes and clinical outcomes of ER stress factors in different tumors of gastrointestinal pan-cancer. Endoplasmic reticulum stress factor (ER) in digestive tract tumors showed high SNV mutation frequency, less methylation dysregulation and was associated with multiple oncogenic pathways. Endoplasmic reticulum stress factor (ER) is a risk factor for many cancers, but the effect on overall survival in rectal adenocarcinoma is opposite to that in other gastrointestinal tumors. And ER stress factors are highly correlated with drugs that target important pathways.

Discussion

Based on the clinical prognosis and genomic analysis of ER stress-related factors in patients with gastrointestinal pan-cancer, this study provides a new direction for further research on gastrointestinal pan-cancer.
The role of surgery in advanced thymic tumors: A retrospective cohort study
Authors: Qi Weifeng , Tian Hui
Published: January 2023

Background

There is no definitive and detailed treatment guideline for advanced thymic tumors, thus when lymph node and other organ metastasis are present, clinical guidelines recommend chemotherapy-based multidisciplinary treatment. A consensus has been reached that surgery has beneficial effects on partial patients with stage IVA whose metastatic lesions were isolated and resectable, but because of few cases of advanced thymic tumor s and the scarcity of reports, the role of surgery in stage IVB is still unknown. The current study aimed to systematically analyze the role of surgery in advanced thymic tumors based on the Surveillance, Epidemiology, and End Results (SEER) database, with a sufficient number of cases. A secondary aim was to clarify the prognostic value of surgery in advanced thymic tumors.

Method

Data derived from a total of 979 patients with advanced thymoma or advanced thymic carcinoma were collected from the SEER database. Propensity score matching was performed to eliminate confounding factors, and Cox regression analyses were conducted to assess prognoses.

Results

Patients were assigned to four groups based on pathology and whether surgery was performed; thymoma (surgery), thymoma (no surgery), thymic carcinom a (surgery), and thymic carcinoma (no surgery). Disease-specific survival differed significantly in the thymoma (surgery) and thymoma (no surgery) groups, both before and after propensity score matching (both p < 0.001). Similarly, disease-specific survival differed significantly in the thymic carcinoma (surgery) and the thymic carcinoma (no surgery) groups (p < 0.001 before and p = 0.003 after). No total resection, distant metastasis, and thymic carcinoma were all unfavorable prognostic factors.

Conclusions

In the present study surgery had positive effects on advanced thymoma and advanced thymic carcinoma patients who could undergo surgical resection, significantly improving survival times. Total resection of the primary site was the most advantageous form of surgery. The study provides a reference for the clinical treatment of advanced thymic tumors.
Regulation of CD45 phosphatase by oncogenic ALK in anaplastic large cell lymphoma
Authors: Mura Giulia , Karaca Atabay Elif , Menotti Matteo , Martinengo Cinzia , Ambrogio Chiara , Giacomello Gloria , Arigoni Maddalena , Olivero Martina , Calogero Raffaele A. , Chiarle Roberto , Voena Claudia
Published: January 2023

Anaplastic Large Cell Lymphoma (ALCL) is a subtype of non-Hodgkin lymphoma frequently driven by the chimeric tyrosine kinase NPM-ALK, generated by the t (2,5)(p23;q35) translocation. While ALK+ ALCL belongs to mature T cell lymphomas, loss of T cell identity is observed in the majority of ALCL secondary to a transcriptional and epigenetic repressive program induced by oncogenic NPM-ALK. While inhibiting the expression of T cell molecules, NPM-ALK activates surrogate TCR signaling by directly inducing pathways downstream the TCR. CD45 is a tyrosine phosphatase that plays a central role in T cell activation by controlling the TCR signaling and regulating the cytokine responses through the JAK/STAT pathway and exists in different isoforms depending on the stage of T-cell maturation, activation and differentiation. ALK+ ALCL cells mainly express the isoform CD45RO in keeping with their mature/memory T cell phenotype. Because of its regulatory effect on the JAK/STAT pathway that is essential for ALK+ ALCL, we investigated whether CD45 expression was affected by oncogenic ALK. We found that most ALK+ ALCL cell lines express the CD45RO isoform with modest CD45RA expression and that NPM-ALK regulated the expression of these CD45 isoforms. Regulation of CD45 expression was dependent on ALK kinase activity as CD45RO expression was increased when NPM-ALK kinase activity was inhibited by treatment with ALK tyrosine kinase inhibitors (TKIs). Silencing ALK expression through shRNA or degradation of ALK by the PROTAC TL13-112 caused upregulation of CD45RO both at mRNA and protein levels with minimal changes on CD45RA, overall indicating that oncogenic ALK downregulates the expression of CD45. CD45 repression was mediated by STAT3 as demonstrated by ChIP-seq data on ALCL cells treated with the ALK-TKI crizotinib or cells treated with a STAT3 degrader. Next, we found that knocking-out CD45 with the CRISPR/Cas9 system resulted in increased resistance to ALK TKI treatment and CD45 was down-regulated in ALCL cells that developed resistance in vitro to ALK TKIs. Overall, these data suggest that CD45 expression is regulated by ALK via STAT3 and acts as a rheostat of ALK oncogenic signaling and resistance to TKI treatment in ALCL.
Diagnostic value of plasma RNF180 gene methylation for gastric cancer: A systematic review and meta-analysis
Authors: Wang Tongxin , Zhang Yating , Wang Jianrong , Li Yumin
Published: January 2023

Objective

A systematic evaluation of the diagnostic value of Ring finger protein 180 (RNF180) gene methylation as a novel tumor marker for gastric cancer (GC) is required to improve the early diagnosis of gastric cancer patients.

Methods

Computer searches of PubMed, Web of Science, Embase, The Cochrane Library, CNKI, CBM, WanFang Data, National Research Register, Cclinical Controlled Trials, Opengrey and VIP databases were conducted from the database’s inception to September 1, 2022. Two researchers independently screened the literature, extracted information, and assessed the risk of bias in studies that were included. The meta-analysis was carried out using RevMan 5.3 and Stata 16.0 software.

Results

A total of 9 studies with a total of 1531 subjects were included. A random-effects meta-analysis revealed that the combined sensitivity (SEN), specificity (SPE), positive likelihood ratio (PLR), negative likelihood ratio (NLR), and diagnostic odds ratio (DOR) of plasma RNF180 gene methylation for the diagnosis of GC were: 0.54 [95% CI (0.45, 0.62)], 0.80 [95% CI (0.72, 0.87)], 2.73 [95% CI (2.09, 3.57)], 0.58 [95% CI (0.51, 0.65)], 4.74 [95% CI (3.59, 6.62)], respectively.

Conclusion

The detection of RNF180 gene methylation in plasma has a high diagnostic value for GC and is expected to be a potential biomarker for the diagnosis of gastric cancer, according to current evidence.

Systematic review registration

https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=370903, identifier CRD42022370903.
Case report: Ponatinib as a bridge to CAR-T cells and subsequent maintenance in a patient with relapsed/refractory Philadelphia-like acute lymphoblastic leukemia
Authors: Giglio Fabio , Campodonico Edoardo , Lorentino Francesca , Noviello Maddalena , Xue Elisabetta , Greco Raffaella , Lazzari Lorenzo , Bruno Alessandro , Lupo Stanghellini Maria Teresa , Carrabba Matteo Giovanni , La Starza Roberta , Casucci Monica , Bonini Chiara , Chiaretti Sabina , Peccatori Jacopo , Foà Robin , Ciceri Fabio
Published: January 2023

Philadelphia (Ph)-like acute lymphoblastic leukemia (ALL) constitutes a heterogeneous subset of ALL with a uniformly unfavorable prognosis. The identification of mutations amenable to treatment with tyrosine kinase-inhibitors (TKIs) represents a promising field of investigation. We report the case of a young patient affected by relapsed/refractory Ph-like ALL treated with chimeric antigen receptor T (CAR-T) cells after successful bridging with compassionate-use ponatinib and low-dose prednisone. We restarted low-dose ponatinib maintenance three months later. Twenty months later, measurable residual disease negativity and B-cell aplasia persist. To the best of our knowledge, this is the first case reporting the use of ponatinib in Ph-like ALL as a bridge to and maintenance after CAR-T cell therapy.
Comprehensive biomarker analysis from phase II study of nivolumab in patients with thymic carcinoma
Authors: Katsuya Yuki , Kitano Shigehisa , Yamashita Makiko , Ouchi Mayu , Yagishita Shigehiro , Hamada Akinobu , Nakamura Hiromi , Hosoda Fumie , Shibata Tatsuhiro , Motoi Noriko , Nakayama Takayuki , Seto Takashi , Umemura Shigeki , Hosomi Yukio , Satouchi Miyako , Nishio Makoto , Kozuki Toshiyuki , Hida Toyoaki , Ohe Yuichiro , Horinouchi Hidehito
Published: January 2023

In a phase II trial of nivolumab in advanced thymic carcinoma (UMIN000022007), long SD (SD for more than 24 weeks) was seen in three patients and irAE (Gr2 or higher) was seen in four patients among 15 patients. Here, we report preplanned comprehensive biomarker analyses. We obtained tumor samples for immunohistochemistry, peripheral blood mononuclear cells (PBMCs), plasma and serum for pharmacokinetic analysis of nivolumab and cytokine evaluations, and whole blood for immuno pharmacogenomic (PGx) analysis. PD-L1 expression on tumor cells were not associated with therapeutic efficacy, but FOXP3 expression in tumor area and stroma, CD204 expression in stroma, and MHC class I in tumor area were all low among long SD patients. PBMC of long SD patients presented with larger number of naïve/memory cells prior to treatment, suggesting priming after nivolumab administration. Immuno-PGx analysis showed non-synonymous SNVs in ITGAX and PDCD1 had some correlation with PFS. Concentration of nivolumab in blood during the treatment was not related to PFS, with their overall trend towards decreased nivolumab concentration in patients with irAEs. Low immunogenicity of thymic carcinoma demonstrated in our study may require the activation of immune systems via a combination of immune checkpoint blockades.
Stress-induced changes in nociceptive responding post-surgery in preclinical rodent models
Authors: Bella Ariadni , Diego Alba M. , Finn David P. , Roche Michelle
Published: January 2023

Chronic post-surgical pain affects up to 85% of individuals depending on the type of surgery, the extent of inflammation, tissue and/or nerve damage. Pre-surgical stress is associated with greater pain intensity, prolonged recovery and is one of the main risk factors for the development of chronic post-surgical pain. Clinically valid animal models provide an important means of examining the mechanisms underlying the effects of stress on post-surgical pain and identifying potential novel therapeutic targets. This review discusses the current data from preclinical animal studies examining the effect of stress on post-surgical pain, the potential underlying mechanisms and gaps in the knowledge that require further investigation.
Frequent torsades de pointes in a child with novel AKAP9 mutation: A case report and literature review
Authors: Wang Yefeng , Zuo Chao , Wang Xiang , Xiao Yunbin , Liu Qiming , Chen Zhi
Published: January 2023

Introduction

The aim of the present study is to report the diagnosis and treatment of a rare case of frequent torsades de pointes (Tdp) in a child with a novel AKAP9 mutation. A 13-year-old girl suffered from repeated syncope and frequent Tdp. An electrocardiogram (ECG) showed frequent multisource premature ventricular contractions with the R-ON-T phenomenon. The QTc ranged from 410 to 468 ms. The genetic test indicated a heterozygous mutation, namely, c.11714T > C (p.M3905T), in the AKAP9 gene, which is a controversial gene in long QT syndrome. After treatment with propranolol, recurrent syncope occurred, and the patient received an implantable cardioverter defibrillator (ICD). Due to frequent electrical storms at home, the child was additionally treated with propafenone to prevent arrhythmia. The antitachycardia pacing (ATP) function in the ICD was turned off, and the threshold of ventricular tachycardia (VT) assessment was adjusted from 180 beats/min to 200 beats/min. The patient was followed up for 12 months without malignant arrhythmia and electric shock.

Conclusion

Genetic testing may be a useful tool to determine the origin of channelopathy, but the results should be interpreted in combination with the actual situation. Rational parameter settings for the ICD and application of antiarrhythmic drugs can reduce the mortality rates of children.
Delayed elimination communication is a crucial factor in disposable diaper dependence in Chinese preschool-aged children
Authors: Yu Jia-ting , Mao Qiu-fang , Ji Feng-ping , Zhao Ying , Hu Hui-jie , Zhang Yan-ping , Yang Jing , Wang Qing-wei , Lu Wei , Wen Jian Guo
Published: January 2023

Purpose

Elimination communication (EC) is considered to be a milestone in a child's development. Nowadays, a trend toward an older age at EC initiation has been observed globally, probably due to the convenience of disposable diaper use in daily life. The study aimed to identify potential risk factors for disposable diaper dependence (DDD) and evaluate whether an early/proper EC can reduce the risk of DDD among children in China.

Methods

A cross-sectional study was performed on 13,500 children in mainland China from October 2019 to March 2020. An anonymous questionnaire was used to collect information including the sociodemographic characteristics, details about DDD and EC, and the effect of DDD on the quality of life of children. Data were analyzed by SPSS and R software.

Results

The overall prevalence of DDD was 4.17% (4.31% in boys; 4.02% in girls) and decreased with age, from 8.71% at 2 years to 0.73% at 6 years (χ2trend = 210.392, P < 0.001). In univariable analysis, age, location or EC were associated with DDD. Four independent factors—age, location (urban), caregivers with high education levels (junior college or above) and delayed EC (after 12 months of age)—were identified to be significantly associated with DDD risk in logistic regression model. Compared with EC onset after 12 months of age, EC onset before 12 months of age was associated with a 79.6% (model 2) reduction in DDD. Four independent factors were selected to establish the nomogram for DDD based on the results of logistic regression analysis. The C-index (0.770) and the AUC (>0.7) indicated satisfactory discriminative ability of the nomogram. The calibration diagrams showed favorable consistency between the prediction of the nomogram and actual observations.

Conclusion

Our findings indicate the joint contribution of age, location, caregivers’ education level and EC to DDD in Chinese preschool-aged children. Timely cessation of the use of disposable diapers and early/proper EC may help to reduce the risk of DDD in children.
Management and effects of residual limbus inversion following closed reduction in developmental hip dysplasia: Protocol for a multicenter randomized controlled trial
Authors: Li Chenyang , Zhou Weizheng , Chen Yufan , Canavese Federico , Li Lianyong
Published: January 2023

Closed reduction is a common treatment method for developmental dysplasia of the hip (DDH) in children aged 6–18 months. Residual acetabular dysplasia (RAD) is the most common complication associated with closed reduction. Residual limbus inversion (RLI) is a common condition following DDH closed reduction. Previously, we confirmed that when limbus inversion exceeds 32.2% of the acetabular depth after closed reduction, RLI persists and leads to RAD; however, this was based on a small cohort with a short-term follow-up period. The long-term fate of RLI and the correlation between RLI and RAD have yet to be verified. Therefore, this multicenter clinical study protocol was designed in three parts to investigate the effect of RLI on acetabular development after closed reduction of DDH (a multicenter retrospective cohort study), effect of RLI clearance on acetabular development (a multicenter retrospective and prospective randomized controlled study), and influence of inverted limbus clearance on acetabular development during DDH reduction (a multicenter prospective cohort study). Statistical analysis was performed by assessing the basic measures of acetabular development including the acetabular index and central-edge angle using frontal pelvic radiographs; the magnitude of limbus inversion, cartilaginous acetabular index, and T1ρ mapping values were measured using magnetic resonance imaging. The multicenter retrospective cohort studies required 5 years of follow-up period at minimum, and the prospective randomized controlled studies required reviews of frontal pelvic radiographs every 6 months as well as data pooling every 2 years to compare the short- and mid-term outcomes of hip joint morphological development between the two groups of pediatric patients. This research program is expected to verify that RLI following closed reduction of DDH can affect acetabular development and that limbus excision during DDH reduction can improve postoperative RAD. Therefore, the indication and timing of surgical intervention for RLI after closed reduction of DDH provide a basis for revising the acceptable criteria for utilizing closed reduction of DDH to reduce the incidence of osteoarthritis caused by RAD following DDH treatment.

Clinical Trial:http://www.chictr.org.cn/showproj.aspx?proj=35045 (ChiCTR1900020996)
Single-incision laparoscopic splenectomy in children with massive splenomegaly: A prospective, monocentric pilot study
Authors: Wang Congjun , Su Cheng , Chen Chao , Tang Xianming , Wang Hong , Li Wei , Li Yanqiang , Liu Qiang , Chen Peng , Li Yong , Luo Yige
Published: January 2023

Background

Single-incision laparoscopic splenectomy (SILS) remains a challenging procedure because of the technical difficulty. In this prospective study, we aimed to evaluate the efficacy and safety of SILS in children with massive splenomegaly.

Methods

Pediatric patients with massive splenomegaly were recruited for SILS in a university-affiliated hospital. The data on patient demographics, clinical features, operative variables, and perioperative outcomes were collected prospectively and analyzed. According to the different surgical instruments, the patients were randomly assigned into two groups: the SILS with straight surgical instrument (SILS-S) group and the SILS with curved surgical instrument (SILS-C) group. A two-group comparative analysis was conducted using perioperative data from the different surgical instrumentation systems.

Results

A total of 120 patients were included, of which 103 patients (success group, 85.83%) had complete SILS, the other 17 (failure group, 14.17%) patients were converted to open (n = 4, 3.33%) or multi-incision laparoscopic surgery (n = 13, 10.83%). The major cause for surgical failure is uncontrollable bleeding (n = 14, 82.35%), and age, height, and weight were the risk factors for failure of SILS, but none of the parameters were independent risk factors. The blood loss in the success group was less than that in the failure group, but no significant differences in other operative and outcome indicators. For SILS, the mean (±SD) operative time was 188 (±48.70) minutes, the median intraoperative blood loss (min, max) was 20 (5, 290) ml, the mean (±SD) time of first anal exhaust was 23.9 (±7.73) hours, and the mean (±SD) postoperative hospital stay was 4.72 (±1.03) days. The median pain score was 3 on 1 day, and 1 on 3 days after the operation. Postoperative complications were identified in 8 (7.77%) cases. However, there were no peri-operative deaths in this series. The SILS-C group had a significantly shorter operation time than the SILS-S group (mean ± SD, 172 ± 44.21 vs. 205 ± 47.90 min). There were no significant differences between the two groups in other perioperative data (P < 0.05).

Conclusion

SILS is a safe and feasible treatment in pediatric patients with massive splenomegaly, and curved surgical instrumentation has contributed to developing surgical manipulation.
Vaccinology in pediatric rheumatology: Past, present and future
Authors: Bizjak Masa , Heshin-Bekenstein Merav , Jansen Marc H. A. , Ziv Amit , Angevare Saskya , Uziel Yosef , Wulffraat Nicolaas M. , Toplak Natasa ,   for the PReS Vaccination Working Party
Published: January 2023

With the introduction of biological disease-modifying antirheumatic drugs (bDMARDs), the treatment of pediatric patients with autoimmune/inflammatory rheumatic diseases (pedAIIRD) has advanced from the “Stone Age” to modern times, resulting in much better clinical outcomes. However, everything comes with a price, and use of new bDMARDs has resulted in an increased risk of infections. Therefore, preventing infections in pedAIIRD patients is one of the top priorities. The most effective preventive measure against infection is vaccination. The first study on humoral immunity after vaccination in pediatric rheumatology was published in 1974 and on safety in 1993. For many years, data about safety and immunogenicity in pedAIIRD patients were available only for non-live vaccines and the first studies on live-attenuated vaccines in pedAIIRD patients treated with immunosuppressive therapy were available only after 2007. Even today the data are limited, especially for children treated with bDMARDs. Vaccinations with non-live vaccines are nowadays recommended, although their long-term immunogenicity and efficacy in pedAIIRD patients are still under investigation. Vaccinations with live-attenuated vaccines are not universally recommended in immunosuppressed patients. However, measles-mumps-rubella booster and varicella zoster virus vaccination can be considered under specific conditions. Additional research is needed to provide more evidence on safety and immunogenicity, especially regarding live-attenuated vaccines in immunosuppressed patients with pedAIIRD. Due to the limited number of these patients, well-designed, prospective, international studies are needed. Further challenges were presented by the COVID-19 pandemic. This mini review article reviews past and present data and discusses the future of vaccinology in pediatric rheumatology.
Effect of massage therapy on infants with congenital muscular torticollis: A retrospective comparative study
Authors: Tang Wei , Li Zhoujin , Xu Weihui , Ye Yong , Wang Huijuan , Wang Ying , Shao Xiangning , Wang Mengqing , Xu Jianda
Published: January 2023

Objective

To detect the effect and safety of massage therapy on infants with congenital muscular torticollis.

Methods

A total of 56 infants with unilateral congenital muscular torticollis were enrolled in this retrospective comparative study. The subjects were divided in two groups, namely, the control group and the massage group. The control group (n = 28) received the treatment of sternocleidomastoid muscle (SCM) stretching, while the massage group (n = 28) received massage therapy combined with SCM stretching. The following parameters were compared: the cervical range of motion (ROM) and functional level (muscle function scale and ratio of muscle function scale scores). Complications, if any, were also recorded.

Results

Of the 56 infants, 7 infants (12.5%) underwent surgery with little functional improvement. The total effective rate of conservative treatment was 87.5%. No significance was found in terms of the surgery rate between both groups (14.29 vs. 10.71%, P = 0.693). After treatment, the ROM (including rotation and lateral flexion) and the ratio of muscle function scale scores improved significantly (P < 0.05). In the latest follow-up, the massage group showed a greater improvement in rotation and lateral flexion. However, no significant difference in the muscle function scale score ratio was found (P = 0.126). Importantly, no adverse events related to blood vessels, nerves, and SCM occurred.

Conclusions

Providing massage therapy in infants with congenital muscular torticollis is a safe and effective method to improve the cervical range of motion and function. However, this study did not find any decrease in the surgical rate between two groups of patients despite adding such therapy.
Exploring the chemotherapeutic potential of currently used kinase inhibitors: An update
Authors: Naik Rajashri R. , Shakya Ashok K.
Published: January 2023

Protein kinases are enzymes that transfer phosphate to protein, resulting in the modification of the protein. The human genome encodes approximately 538 kinases. Kinases play a role in maintaining a number of cellular processes, including control of the cell cycle, metabolism, survival, and differentiation. Protein kinase dysregulation causes several diseases, and it has been shown that numerous kinases are deregulated in cancer. The oncogenic potential of these kinases is increased by a number of processes, including overexpression, relocation, fusion point mutations, and the disruption of upstream signaling. Understanding of the mechanism or role played by kinases has led to the development of a large number of kinase inhibitors with promising clinical benefits. In this review, we discuss FDA-approved kinase inhibitors and their mechanism, clinical benefits, and side effects, as well as the challenges of overcoming some of their side effects and future prospects for new kinase inhibitor discovery.