bluuebunny/crossref_metadata_2025 huggingface dataset:
Effectiveness of Integrated Maternal Nutrition Intervention Package on Birth Weight in Rwanda
Authors: Habtu Michael , Agena Alemayehu Gebremariam , Umugwaneza Maryse , Mochama Monica , Munyanshongore Cyprien
Published: July 2022

Inadequate maternal nutrition before and during pregnancy is a principal risk factor for poor fetal development, resulting in low birth weight (LBW) and subsequently, poor child growth. Most studies focus on the impact of nutritional interventions after birth while only a few interventions consider integrated nutrition service packages. Therefore, there is limited evidence on whether integrated maternal nutrition interventions have a positive effect on birthweight. Thus, a post-program quasi-experimental study was carried out to determine the effectiveness of the integrated maternal nutrition intervention package on low birth weight in Rwanda. A total of 551 mother–baby pairs from the intervention and 545 controls were included in the analysis. Data regarding socio-demographic, maternal anthropometric parameters, and dietary diversity were collected using a structured questionnaire. Birth weight was assessed right after delivery, within 24 h. Logistic regression, linear regression, and path analysis were fitted to determine the effectiveness of the intervention on birth weight. The study found that the intervention reduced LBW by 66.99% (p < 0.001) and increased average birth weight by 219 g (p < 0.001). Logistic regression identified reduced risk of LBW among the intervention group (AOR = 0.23; 95%CI = 0.12–0.43; p < 0.001). It was also observed that the direct effect of the intervention on birth weight was 0.17 (β = 0.17; p < 0.001) and the main indirect mediator was maternal MUAC (β = 0.05; p < 0.001). Moreover, maternal passive smoking exposure and MUAC < 23 cm were found as risk factors for LBW. This study has demonstrated that an integrated maternal nutritional intervention package can significantly reduce LBW in low-income settings and should, therefore, be considered to improve birth weight.
Polysaccharide immunization and colorectal cancer: A systematic review and network meta-analysis
Authors: Chen Yuefeng , Pan Xinnan , Tian Baoming , Hu Yajun
Published: July 2022

Polysaccharides have a variety of biological activities, and in the anti-tumor field, they produce tumor suppressive effects by regulating the polarization of tumor-associated macrophages (TAMs). In immunotherapy, it has significant activities in modulating cytokines and antibody production. We reviewed them and selected CD24, an immune target, for meta-analysis with colorectal cancer (CRC) to investigate the correlation between CD24 expression and CRC. Correlation of CD24 positive expression with clinical-pathological features: age, sex, Duke’s stage, diameter, depth of invasion, degree of differentiation, and lymph node metastasis. It showed that: CD24 expression in CRC was significantly correlated with advanced nuclear grade of CRC, lymph node metastasis, Duke’s stage of CRC and age of CRC patients, while there was no significant correlation with gender, tumor diameter and invasion depth. The aim is to clarify the specific mechanism of polysaccharide immune anti-tumor, combined with targeted site-specific anti-solid tumor.
Differential Expression and Prognostic Correlation of Immune Related Factors Between Right and Left Side Colorectal Cancer
Authors: Hu Yue , Ding Jie , Wu Chengjiang , Gao Hong , Ge Meiling , Shao Qixiang , Liu Yanhong , Ye Qing
Published: July 2022

Background

Growing evidence suggests that colorectal cancer (CRC) should be considered a heterogeneous disease. The right side (RCC) and left side (LCC) colorectal cancer have different clinical characteristics and immune landscapes. The aim of this study was to analyze differential expression and prognostic correlation of immune-related factors between RCC and LCC.

Methods

The gene expression profile and clinical characteristics of CRC patients were retrieved from The Cancer Genome Atlas data portal (n=525). Using a deconvolution algorithm, immune cell infiltration in RCC and LCC based on the RNA-seq data was analyzed. Differentially expressed genes (DEGs) were obtained by performing differential gene expression analysis. Immune-related DEGs were derived by the intersection with immune-related factors downloaded from the IMMPORT database. To further validate the findings, we applied immunohistochemical (IHC) staining of a CRC tissue microarray (TMA). The distribution of immune cells in RCC and LCC and changes in the expression of immune molecules on their membranes were verified. The expression levels of circulating cytokines were measured by flow cytometry to detect the cytokines secreted by immune cells in RCC and LCC. Furthermore, to reveal the prognostic value of differential immune factors on RCC and LCC patients, survival analysis based on mRNA levels using TCGA cohort and survival analysis using protein levels was performed using our CRC patients.

Results

The infiltration of immune cells differed between RCC and LCC, the infiltration degree of macrophages M0 was significantly higher in LCC, while the infiltration degree of differentiated macrophages M1 and M2, CD4+ T and CD8+ T cells was significantly higher in RCC. The expression of related molecules by immune cells also differed between RCC and LCC. The expression of 7 genes in RCC was higher than that in LCC, which were CCR5, CD209, CD8A, HCK, HLA-DPB1, HLA-DQA1, HLA-DRA, respectively. Meanwhile, the expression of 2 genes in LCC was higher than in RCC, which were IL-34 and PROCR. Patients with RCC having high expression of HLA-DQA1 mRNA or proteins had better survival and LCC patients with high expression of IL 34 mRNA or protein had better survival.

Conclusions

In this study, we comprehensively compared differences in immune cells and regulating factors between left and right colorectal cancer. Different expression patterns and their effects on survival were identified. The analysis of immune-related factors may provide a theoretical basis for precise immunotherapy of RCC and LCC.
Accuracy of ultrasonographic changes during neoadjuvant chemotherapy to predict axillary lymph node response in clinical node-positive breast cancer patients
Authors: Li Zhuoxuan , Tong Yiwei , Chen Xiaosong , Shen Kunwei
Published: July 2022

Purpose

To evaluate whether changes in ultrasound features during neoadjuvant chemotherapy (NAC) could predict axillary node response in clinically node-positive breast cancer patients.

Methods

Patients with biopsy-proven node-positive disease receiving NAC between February 2009 and March 2021 were included. Ultrasound (US) images were obtained using a 5-12-MHz linear array transducer before NAC, after two cycles, and at the completion of NAC. Long and short diameter, cortical thickness, vascularity, and hilum status of the metastatic node were retrospectively reviewed according to breast imaging-reporting and data system (BI-RADS). The included population was randomly divided into a training set and a validation set at a 2:1 ratio using a simple random sampling method. Factors associated with node response were identified through univariate and multivariate analyses. A nomogram combining clinical and changes in ultrasonographic (US) features was developed and validated. The receiver operating characteristic (ROC) and calibration plots were applied to evaluate nomogram performance and discrimination.

Results

A total of 296 breast cancer patients were included, 108 (36.5%) of whom achieved axillary pathologic complete response (pCR) and 188 (63.5%) had residual nodal disease. Multivariate regression indicated that independent predictors of node pCR contain ultrasound features in addition to clinical features, clinical features including neoadjuvant HER2-targeted therapy and clinical response, ultrasound features after NAC including cortical thickness, hilum status, and reduction in short diameter ≥50%. The nomogram combining clinical features and US features showed better diagnostic performance compared to clinical-only model in the training cohort (AUC: 0.799 vs. 0.699, P=0.001) and the validation cohort (AUC: 0.764 vs. 0.638, P=0.027).

Conclusions

Ultrasound changes during NAC could improve the accuracy to predict node response after NAC in clinically node-positive breast cancer patients.
Case Report: Atypical Solitary Brain Metastasis: The Role of MR Spectroscopy In Differential Diagnosis
Authors: Kozic Dusko , Lasica Nebojsa , Grujicic Danica , Raicevic Savo , Prvulovic Bunovic Natasa , Nosek Igor , Boban Jasmina
Published: July 2022

Background

Metastatic brain tumors are typically located at the cerebral hemispheres or the cerebellum and most frequently originate from primary breast or lung tumors. Metastatic lesions are usually associated with blood–brain barrier disruption, solid or ring-like contrast enhancement, and perilesional vasogenic edema on brain imaging. Even in cases where metastases are predominantly cystic, enhancement of the minor solid component can be detected. In contrast, non-enhancing secondary brain tumors were only reported in a patient after antiangiogenic treatment with bevacizumab.

Case report

We report a case of a 54-year-old male who presented with left-sided weakness and multiple seizures. Brain magnetic resonance imaging revealed a T2-weighted heterogeneous solid tumor in the right frontoparietal parasagittal region, with no apparent enhancement on T1-weighted post-contrast images and no evident perilesional edema. Further MRS analysis revealed markedly increased choline and lipid peaks. The patient underwent craniotomy for tumor removal. Histopathology revealed findings consistent with metastatic non-microcellular neuroendocrine lung cancer. positron emission tomography/computed tomography (PET/CT) revealed a stellate lesion within the right upper lung lobe, compatible with primary lung cancer.

Conclusion

Non-enhancing brain metastatic tumors are rarely reported in the literature, usually following antiangiogenic treatment. Here, we report the first ever case of a non-enhancing metastatic brain tumor with no prior history of antiangiogenic treatment, with particular emphasis on the importance of MRS analysis in atypical brain lesions.
Role of non-coding RNAs in radiosensitivity of colorectal cancer: A narrative review
Authors: Huang Chun-Ming , Tsai Hsiang-Lin , Chen Yen-Cheng , Huang Ching-Wen , Li Ching-Chun , Su Wei-Chih , Chang Tsung-Kun , Yeh Yung-Sung , Chen Po-Jung , Huang Ming-Yii , Wang Jaw-Yuan
Published: July 2022

Colorectal cancer (CRC) is a global public health concern because of its high prevalence and mortality. Although radiotherapy is a key method for treating CRC, radioresistance is an obstacle to radiotherapy use. The molecular mechanisms underlying the radioresistance of CRC remain unclear. Increasing evidence has revealed the multiple regulatory functions of non-coding RNAs (ncRNAs) in numerous malignancies, including CRC. Several ncRNAs have been reported to be involved in the determination of radiosensitivity of CRC cells, and some have excellent potential to be prognostic biomarkers or therapeutic targets in CRC treatment. The present review discusses the biological functions and underlying mechanisms of ncRNAs (primarily lncRNA, miRNA, and circRNA) in the regulation of the radiosensitivity of CRC. We also evaluate studies that examined ncRNAs as biomarkers of response to radiation and as therapeutic targets for enhancing radiosensitivity.
Evaluation of Hybrid VMAT Advantages and Robustness Considering Setup Errors Using Surface Guided Dose Accumulation for Internal Lymph Mammary Nodes Irradiation of Postmastectomy Radiotherapy
Authors: Zhang Zhe , Li Daming , Peng Feng , Tan Zhibo , Yang Pengfei , Peng Zhaoming , Li Xin , Qi Xinyue , Sun Weixiao , Liu Yajie , Wang Yuenan
Published: July 2022

Objectives

Setup error is a key factor affecting postmastectomy radiotherapy (PMRT) and irradiation of the internal mammary lymph nodes is the most investigated aspect for PMRT patients. In this study, we evaluated the robustness, radiobiological, and dosimetric benefits of the hybrid volumetric modulated arc therapy (H-VMAT) planning technique based on the setup error in dose accumulation using a surface-guided system for radiation therapy.

Methods

We retrospectively selected 32 patients treated by a radiation oncologist and evaluated the clinical target volume (CTV), including internal lymph node irradiation (IMNIs), and considered the planning target volume (PTV) margin to be 5 mm. Three different planning techniques were evaluated: tangential-VMAT (T-VMAT), intensity-modulated radiation therapy (IMRT), and H-VMAT. The interfraction and intrafraction setup errors were analyzed in each field and the accumulated dose was evaluated as the patients underwent daily surface-guided monitoring. These parameters were included while evaluating CTV coverage, the dose required for the left anterior descending artery (LAD) and the left ventricle (LV), the normal tissue complication probability (NTCP) for the heart and lungs, and the second cancer complication probability (SCCP) for contralateral breast (CB).

Results

When the setup error was accounted for dose accumulation, T-VMAT (95.51%) and H-VMAT (95.48%) had a higher CTV coverage than IMRT (91.25%). In the NTCP for the heart, H-VMAT (0.04%) was higher than T-VMAT (0.01%) and lower than IMRT (0.2%). However, the SCCP (1.05%) of CB using H-VMAT was lower than that using T-VMAT (2%) as well as delivery efficiency. And T-VMAT (3.72) and IMRT (10.5).had higher plan complexity than H-VMAT (3.71).

Conclusions

In this study, based on the dose accumulation of setup error for patients with left-sided PMRT with IMNI, we found that the H-VMAT technique was superior for achieving an optimum balance between target coverage, OAR dose, complication probability, plan robustness, and complexity.
Serum Extracellular Vesicle Stratifin Is a Biomarker of Perineural Invasion in Patients With Colorectal Cancer and Predicts Worse Prognosis
Authors: Hou Wenyun , Pan Meng , Xiao Yi , Ge Wei
Published: July 2022

Previous studies have shown that the presence of perineural invasion (PNI) is associated with a significantly worse prognosis in colorectal cancer (CRC) patients. In this study, we performed a detailed analysis of the diversity of extracellular vesicles (EV) between NPNI (non-PNI) and PNI using quantitative proteomics and aim to investigate the mechanisms underlying PNI in colorectal cancer. Quantitative proteomics technology was used to identify the proteome of serum-purified EVs from CRC patients with and without PNI (PNI and non-PNI (NPNI) groups, respectively) and healthy volunteers. Mass spectrometry data were verified by ELISA and Western blot analyses. The proteomic profile of serum EVs from the PNI group differed from that of those in the NPNI group. Serum-derived EVs from the PNI promoted more significant cellular mobility than EVs derived from the NPNI group. EV stratifin (SFN) expression levels demonstrated an area under the receiver operating characteristic curve values of 0.84 for discriminating patients with PNI from NPNI patients. Moreover, EV SFN expression levels were an independent predictor of CRC prognosis. In this study, we identified SFN as a potential biomarker for the diagnosis of PNI in stage II CRC patients.
A Network-Guided Approach to Discover Phytochemical-Based Anticancer Therapy: Targeting MARK4 for Hepatocellular Carcinoma
Authors: Ahmed Sarfraz , Mobashir Mohammad , Al-Keridis Lamya Ahmed , Alshammari Nawaf , Adnan Mohd , Abid Mohammad , Hassan Md Imtaiyaz
Published: July 2022

MAP/microtubule affinity-regulating kinase 4 (MARK4) is associated with various biological functions, including neuronal migration, cell polarity, microtubule dynamics, apoptosis, and cell cycle regulation, specifically in the G1/S checkpoint, cell signaling, and differentiation. It plays a critical role in different types of cancers. Hepatocellular carcinoma (HCC) is the one of the most common forms of liver cancer caused due to mutations, epigenetic aberrations, and altered gene expression patterns. Here, we have applied an integrated network biology approach to see the potential links of MARK4 in HCC, and subsequently identified potential herbal drugs. This work focuses on the naturally-derived compounds from medicinal plants and their properties, making them targets for potential anti-hepatocellular treatments. We further analyzed the HCC mutated genes from the TCGA database by using cBioPortal and mapped out the MARK4 targets among the mutated list. MARK4 and Mimosin, Quercetin, and Resveratrol could potentially interact with critical cancer-associated proteins. A set of the hepatocellular carcinoma altered genes is directly the part of infection, inflammation, immune systems, and cancer pathways. Finally, we conclude that among all these drugs, Gingerol and Fisetin appear to be the highly promising drugs against MARK4-based targets, followed by Quercetin, Resveratrol, and Apigenin.
Alpha2beta1 Integrin Polymorphism in Diffuse Astrocytoma Patients
Authors: Teixeira Silvia A. , Burim Regislaine V. , Viapiano Mariano S. , Bidinotto Lucas T. , Nagashi Marie Suely K. , Fleury Malheiros Suzana M. , Oba-Shinjo Sueli M. , Andrade Augusto F. , Carlotti Carlos G.
Published: July 2022

Integrins are heterodimeric transmembrane glycoproteins resulting from the non-covalent association of an α and β chain. The major integrin receptor for collagen/laminin, α2β1 is expressed on a wide variety of cell types and plays an essential role in the adhesion of normal and tumor cells to the extracellular matrix. Integrin-triggered signaling pathways promote the invasion and survival of glioma cells by modifying the brain microenvironment. In this study, we investigated the association of a specific genetic polymorphism of integrin α2β1 with the incidence of diffusely infiltrating astrocytoma and the progression of these tumors. Single-nucleotide polymorphism in intron 7 of the integrin ITGA2 gene was examined in 158 patients and 162 controls using polymerase chain reaction and restriction enzyme analysis. The ITGA2 genotype +/+ (with a BglII restriction site in both alleles) exhibited higher frequency in grade II astrocytoma compared to control (P = 0.02) whereas the genotype -/- (lacking the BglII site) correlated with the poorest survival rate (P = 0.04). In addition, in silico analyses of ITGA2 expression from low-grade gliomas (LGG, n = 515) and glioblastomas (GBM, n = 159) indicated that the higher expression of ITGA2 in LGG was associated with poor overall survival (P < 0.0001). However, the distribution of integrin ITGA2 BglII genotypes (+/+, +/-, -/-) was not significantly different between astrocytoma subgroups III and IV (P = 0.65, 0.24 and 0.33; 0.29, 0.48, 0.25, respectively) compared to control. These results suggest a narrow association between the presence of this SNP and indicate that further studies with larger samples are warranted to analyze the relation between tumor grade and overall survival, highlighting the importance of determining these polymorphisms for prognosis of astrocytomas.
Immune-Related Biomarkers Improve Performance of Risk Prediction Models for Survival in Patients With Hepatocellular Carcinoma
Authors: Wan Haifeng , Lu Shan , Xu Lin , Yuan Kefei , Xiao Yang , Xie Kunlin , Wu Hong
Published: July 2022

Object

The prediction of hepatocellular carcinoma (HCC) prognosis faced great challenge due to tumor heterogeneity. The purpose of this study was to explore the correlation between the immune infiltrate and prognosis. Moreover, we aimed to establish a risk prediction model for survival in HCC patients based on clinicopathological and immune indicators.

Methods

In this study, 316 patients with HCC who underwent radical resection in West China Hospital from 2009 to 2014 were included. Clinicopathological data and pathological specimens were collected. H&E staining and immunohistochemical staining were performed on the pathological tissue sections. The evaluation of tumor-infiltrating lymphocyte (TIL) density was based on H&E slices, and the assessment of the expressions of CD8, CD68, Lymphocyte activation gene-3 (LAG-3), T cell immunoglobulin domain and mucin domain-3 (TIM-3), Programmed Cell Death Protein 1 (PD-1), Programmed Cell Death Ligand 1 (PD-L1), OX40, CD66b, and Tryptase. was performed on the immunohistochemical slices. A risk prediction model for survival in HCC patients was established by integrating immune-related biomarkers and clinicopathological indicators.

Results

The Barcelona Clinic Liver Cancer (BCLC) stage; the microvascular invasion status; the density of TILs; the expressing levels of CD66b, OX40, and PD-L1 in the immune cell; CD68; and CD8 were the predictors of patients’ overall survival (OS). The BCLC stage; the density of TILs; and the expressions of OX40, CD68, and CD8 were associated with disease-free survival (DFS). The expressions of CD66b, CD68, OX40, and CD8 had a cumulative effect on prognosis. The area under the curve of the prediction model for OS based on clinicopathological features was improved from 0.62 to 0.74 by adding to CD8, OX40, CD68, CD66b, and TILs, whereas it was improved from 0.59 to 0.73 for the DFS prediction model.

Conclusion

Our results, if confirmed, indicated that immune-related biomarkers should be taken into account or stratified in survival analysis for HCC.
A novel cuproptosis-related prognostic lncRNA signature and lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis in lung adenocarcinoma
Authors: Mo Xiaocong , Hu Di , Yang Pingshan , Li Yin , Bashir Shoaib , Nai Aitao , Ma Feng , Jia Guoxia , Xu Meng
Published: July 2022

Lung adenocarcinoma (LUAD) remains the most common subtype of lung malignancy. Cuproptosis is a newly identified cell death which could regulate tumor cell proliferation and progression. Long non-coding RNAs (lncRNAs) are key molecules and potential biomarkers for diagnosing and treating various diseases. However, the effects of cuproptosis-related lncRNAs on LUAD are still unclear. In our study, 7 cuproptosis-related lncRNAs were selected to establish a prognostic model using univariate Cox regression analysis, LASSO algorithm, and multivariate analysis. Furthermore, we evaluated AC008764.2, AL022323.1, ELN-AS1, and LINC00578, which were identified as protective lncRNAs, while AL031667.3, AL606489.1, and MIR31HG were identified as risk lncRNAs. The risk score calculated by the prognostic model proved to be an effective independent factor compared with other clinical features by Cox regression analyses [univariate analysis: hazard ratio (HR) = 1.065, 95% confidence interval (CI) = 1.043–1.087, P < 0.001; multivariate analysis: HR = 1.067, 95% CI = 1.044–1.091, P < 0.001]. In addition, both analyses (ROC and nomogram) were used to corroborate the accuracy and reliability of this signature. The correlation between cuproptosis-related lncRNAs and immune microenvironment was elucidated, where 7 immune cells and 8 immune-correlated pathways were found to be differentially expressed between two risk groups. Furthermore, our results also identified and verified the ceRNA of cuproptosis-related lncRNA MIR31HG/miR-193a-3p/TNFRSF21 regulatory axis using bioinformatics tools. MIR31HG was highly expressed in LUAD specimens and some LUAD cell lines. Inhibition of MIR31HG clearly reduced the proliferation, migration, and invasion of the LUAD cells. MIR31HG showed oncogenic features via sponging miR-193a-3p and tended to positively regulate TNFRSF21 expression. In a word, lncRNA MIR31HG acts as an oncogene in LUAD by targeting miR-193a-3p to modulate TNFRSF21, which may be beneficial to the gene therapy of LUAD.
Erring Characteristics of Deformable Image Registration-Based Auto-Propagation for Internal Target Volume in Radiotherapy of Locally Advanced Non-Small Cell Lung Cancer
Authors: Rich Benjamin J. , Spieler Benjamin O. , Yang Yidong , Young Lori , Amestoy William , Monterroso Maria , Wang Lora , Dal Pra Alan , Yang Fei
Published: July 2022

Purpose

Respiratory motion of locally advanced non-small cell lung cancer (LA-NSCLC) adds to the challenge of targeting the disease with radiotherapy (RT). One technique used frequently to alleviate this challenge is an internal gross tumor volume (IGTV) generated from manual contours on a single respiratory phase of the 4DCT via the aid of deformable image registration (DIR)-based auto-propagation. Through assessing the accuracy of DIR-based auto-propagation for generating IGTVs, this study aimed to identify erring characteristics associated with the process to enhance RT targeting in LA-NSCLC.

Methods

4DCTs of 19 patients with LA-NSCLC were acquired using retrospective gating with 10 respiratory phases (RPs). Ground-truth IGTVs (GT-IGTVs) were obtained through manual segmentation and union of gross tumor volumes (GTVs) in all 10 phases. IGTV auto-propagation was carried out using two distinct DIR algorithms for the manually contoured GTV from each of the 10 phases, resulting in 10 separate IGTVs for each patient per each algorithm. Differences between the auto-propagated IGTVs (AP-IGTVs) and their corresponding GT-IGTVs were assessed using Dice coefficient (DICE), maximum symmetric surface distance (MSSD), average symmetric surface distance (ASSD), and percent volume difference (PVD) and further examined in relation to anatomical tumor location, RP, and deformation index (DI) that measures the degree of deformation during auto-propagation. Furthermore, dosimetric implications due to the analyzed differences between the AP-IGTVs and GT-IGTVs were assessed.

Results

Findings were largely consistent between the two algorithms: DICE, MSSD, ASSD, and PVD showed no significant differences between the 10 RPs used for propagation (Kruskal–Wallis test, ps > 0.90); MSSD and ASSD differed significantly by tumor location in the central–peripheral and superior–inferior dimensions (ps < 0.0001) while only in the central–peripheral dimension for PVD (p < 0.001); DICE, MSSD, and ASSD significantly correlated with the DI (Spearman’s rank correlation test, ps < 0.0001). Dosimetric assessment demonstrated that 79% of the radiotherapy plans created by targeting planning target volumes (PTVs) derived from the AP-IGTVs failed prescription constraints for their corresponding ground-truth PTVs.

Conclusion

In LA-NSCLC, errors in DIR-based IGTV propagation present to varying degrees and manifest dependences on DI and anatomical tumor location, indicating the need for personalized consideration in designing RT internal target volume.
Oncogenic Role of miR-217 During Clear Cell Renal Carcinoma Progression
Authors: Zamora-Fuentes Jose María , Hernández-Lemus Enrique , Espinal-Enríquez Jesús
Published: July 2022

Clear cell renal carcinoma (ccRC) comprises a set of heterogeneous, fast-progressing pathologies with poor prognosis. Analyzing ccRC progression in terms of modifications at the molecular level may provide us with a broader understanding of the disease, paving the way for improved diagnostics and therapeutics. The role of micro-RNAs (miRs) in cancer by targeting both oncogenes and tumor suppressor genes is widely known. Despite this knowledge, the role of specific miRs and their targets in the progression of ccRC is still unknown. To evaluate the action of miRs and their target genes during ccRC progression, here we implemented a three-step method for constructing miR–gene co-expression networks for each progression stage of ccRC as well as for adjacent-normal renal tissue (NT). In the first step, we inferred all miR–gene co-expression interactions for each progression stage of ccRC and for NT. Afterwards, we filtered the whole miR–gene networks by differential gene and miR expression between successive stages: stage I with non-tumor, stage II with stage I, and so on. Finally, all miR–gene interactions whose relationships were inversely proportional (overexpressed miR and underexpressed genes and vice versa) were kept and removed otherwise. We found that miR-217 is differentially expressed in all contrasts; however, its targets were different depending on the ccRC stage. Furthermore, the target genes of miR-217 have a known role in cancer progression—for instance, in stage II network, GALNTL6 is overexpressed, and it is related to cell signaling, survival, and proliferation. In the stage III network, WNK2, a widely known tumor suppressor, is underexpressed. For the stage IV network, IGF2BP2, a post-transcriptional regulator of MYC and PTEN, is overexpressed. This data-driven network approach has allowed us to discover miRs that have different targets through ccRC progression, thus providing a method for searching possible stage-dependent therapeutic targets in this and other types of cancer.
Case Report: 18F-PSMA PET/CT Scan in Castration Resistant Prostate Cancer With Aggressive Neuroendocrine Differentiation
Authors: Bergamini Marco , Dalla Volta Alberto , Caramella Irene , Bercich Luisa , Fisogni Simona , Bertoli Mattia , Valcamonico Francesca , Grisanti Salvatore , Poliani Pietro Luigi , Bertagna Francesco , Berruti Alfredo
Published: July 2022

The development of a neuroendocrine phenotype as a mechanism of resistance to hormonal treatment is observed in up to 20% of advanced prostate cancer patients. High grade neuroendocrine prostate cancer (NEPC) is associated to poor prognosis and the therapeutic armamentarium is restricted to platinum-based chemotherapy. Prostate-specific membrane antigen (PSMA)-based positron emission tomography (PET)/computed tomography (CT) imaging has recently emerged as a potential new standard for the staging of prostate cancer and PSMA-based radioligand therapy (RLT) as a therapeutic option in advanced metastatic castration resistant prostate cancer (mCRPC). PSMA-based theranostic is not currently applied in the staging and treatment of NEPC since PSMA expression on neuroendocrine differentiated cells was shown to be lost. In this case series, we present 3 consecutive mCRPC patients with histologically proven high grade neuroendocrine differentiation who underwent PSMA-PET/CT and surprisingly showed high tracer uptake. This observation stimulates further research on the use of PSMA-based theranostic in the management of NEPC.
PD-L1 Amino Acid Position 88 Represents a Hotspot for PD-L1 Stability With Relevance for PD-L1 Inhibition
Authors: Claaß Luise Victoria , Schultheiß Christoph , Scholz Rebekka , Paschold Lisa , Simnica Donjete , Heinemann Volker , Stintzing Sebastian , Binder Mascha
Published: July 2022

The two most common antibody targeting principles in oncology are the induction of direct antitumor effects and the release of antitumor T cell immunity by immune checkpoint blockade. These two principles, however, may be overlapping if the targeted checkpoint molecule is not located on the immune cell but on the tumor cell itself. Secondary resistance by epitope escape may therefore remain a challenge in both settings. We previously reported epitope escape through L88S and truncating programmed cell death ligand 1 (PD-L1) gene mutations in colorectal cancer patients on selective pressure with avelumab, a PD-L1-directed checkpoint blocker that—in addition to T cell disinhibition—allows direct tumor cell killing via its unmodified Fc portion. Here, we confirmed this principle by liquid biopsy monitoring in a colorectal cancer patient from an independent clinical trial. In this patient, both PD-L1 L88E and L88fs mutations emerged under selective pressure with avelumab. By ectopically expressing PD-L1 L88E, we show that this mutation leads to a reduction of full-length glycosylated PD-L1 and greatly reduced avelumab surface binding. Further experiments indicated that PD-L1 L88E represents a phosphomimetic variant of PD-L1 L88S leading to loss of protein stability and increased proteasomal degradation. The association of this PD-L1 mutation with the high-affinity FCGR3A single nucleotide polymorphism rs396991 confirms prior evidence that patients harboring this polymorphism experience the strongest selective pressure by avelumab. Together, position 88 of PD-L1 is a hotspot residue critically regulating PD-L1 cell surface expression with clinical significance in the context of immune checkpoint blockade.
LC–MS-Based Urine Metabolomics Analysis for the Diagnosis and Monitoring of Medulloblastoma
Authors: Liu Xiaoyan , Li Jing , Hao Xiaolei , Sun Haidan , Zhang Yang , Zhang Liwei , Jia Lulu , Tian Yongji , Sun Wei
Published: July 2022

Medulloblastoma (MB) is the most common type of brain cancer in pediatric patients. Body fluid biomarkers will be helpful for clinical diagnosis and treatment. In this study, liquid chromatography–mass spectrometry (LC–MS)-based metabolomics was used to identify specific urine metabolites of MB in a cohort, including 118 healthy controls, 111 MB patients, 31 patients with malignant brain cancer, 51 patients with benign brain disease, 29 MB patients 1 week postsurgery and 80 MB patients 1 month postsurgery. The results showed an apparent separation for MB vs. healthy controls, MB vs. benign brain diseases, and MB vs. other malignant brain tumors, with AUCs values of 0.947/0.906, 0.900/0.873, and 0.842/0.885, respectively, in the discovery/validation group. Among all differentially identified metabolites, 4 metabolites (tetrahydrocortisone, cortolone, urothion and 20-oxo-leukotriene E4) were specific to MB. The analysis of these 4 metabolites in pre- and postoperative MB urine samples showed that their levels returned to a healthy state after the operation (especially after one month), showing the potential specificity of these metabolites for MB. Finally, the combination of two metabolites, tetrahydrocortisone and cortolone, showed diagnostic accuracy for distinguishing MB from non-MB, with an AUC value of 0.851. Our data showed that urine metabolomics might be used for MB diagnosis and monitoring.
Sex differences of language abilities of preschool children with autism spectrum disorder and their anatomical correlation with Broca and Wernicke areas
Authors: Zhang Yun , Qin Bin , Wang Longlun , Chen Jie , Cai Jinhua , Li Tingyu
Published: July 2022

Objective

People with autism spectrum disorder (ASD) often have language difficulties. This study focuses on whether there are sex differences in language ability in children with ASD and aims to analyze whether such differences may arise from developmental imbalances in the anatomical structures of Broca and Wernicke areas.

Methods

The language development quotient (DQ) scores of Gesell Developmental Scale (GDS) and the scores of language communication of Childhood Autism Rating Scale (CARS) were used to judge the language ability, and the FREESURFER software extracted the anatomical structures of Broca and Wernicke areas on 3DT1 sequences. We analyzed the correlation between the anatomical structure of Broca/Wernicke areas and language abilities assessments.

Results

The study initially included 44 cases of ASD, with 36 males (81.8 %) and 8 females (18.2%), and the age range was 24–72 months. Males have better language abilities than females. Specifically, the GDS verbal DQ of males was significantly higher than that of females (56.50 ± 18.02 vs. 29.23 ± 6.67, p < 0.001). Broca thickness-L was positively correlated with verbal DQ scores in GDS (r = 0.382, p = 0.011) and lower than grade 2 and 3 on the CARS verbal communication grade 4 (5.76 ± 0.17 vs. 6.21 ± 0.30 and 6.11 ± 0.35), with statistically significant differences between groups (p < 0.05).

Conclusion

There were sex differences in the language abilities of preschoolers with ASD, which may be due to an imbalance development of certain structures in Broca and Wernicke areas, especially Broca area.
Should we give antibiotics to neonates with mild non-progressive symptoms? A comparison of serial clinical observation and the neonatal sepsis risk calculator
Authors: Berardi Alberto , Zinani Isotta , Bedetti Luca , Vaccina Eleonora , Toschi Alessandra , Toni Greta , Lecis Marco , Leone Federica , Monari Francesca , Cozzolino Michela , Zini Tommaso , Boncompagni Alessandra , Iughetti Lorenzo , Miselli Francesca , Lugli Licia
Published: July 2022

Objective

To compare two strategies [the neonatal sepsis risk calculator (NSC) and the updated serial clinical observation approach (SCO)] for the management of asymptomatic neonates at risk of early-onset sepsis (EOS) and neonates with mild non-progressive symptoms in the first hours of life.

Methods

This was a single-center, retrospective cohort study conducted over 15 months (01/01/2019–31/03/2020). All live births at ≥34 weeks of gestation were included. Infants were managed using SCO and decisions were compared with those retrospectively projected by the NSC. The proportion of infants recommended for antibiotics or laboratory testing was compared in both strategies. McNemar's non-parametric test was used to assess significant differences in matched proportions.

Results

Among the 3,445 neonates (late-preterm, n = 178; full-term, n = 3,267) 262 (7.6%) presented with symptoms of suspected EOS. There were no cases of culture-proven EOS. Only 1.9% of the neonates were treated with antibiotics (median antibiotic treatment, 2 days) and 4.0% were evaluated. According to NSC, antibiotics would have been administered in 5.4% of infants (absolute difference between SCO and NSC, 3.51%; 95% CI, 3.14–3.71%; p <0.0001) and 5.6% of infants would have undergone “rule out sepsis” (absolute difference between SCO and NSC, 1.63%, 95% CI 1.10–2.05; p <0.0001).

Conclusion

SCO minimizes laboratory testing and unnecessary antibiotics in infants at risk of EOS or with mild non-progressive symptoms, without the risk of a worse neonatal outcome. The NSC recommends almost three times more antibiotics than the SCO without improving neonatal outcomes.
The Relationship Between Maternal and Neonatal Microbiota in Spontaneous Preterm Birth: A Pilot Study
Authors: Tirone Chiara , Paladini Angela , De Maio Flavio , Tersigni Chiara , D’Ippolito Silvia , Di Simone Nicoletta , Monzo Francesca Romana , Santarelli Giulia , Bianco Delia Mercedes , Tana Milena , Lio Alessandra , Menzella Nicoletta , Posteraro Brunella , Sanguinetti Maurizio , Lanzone Antonio , Scambia Giovanni , Vento Giovanni
Published: July 2022

The newborn’s microbiota composition at birth seems to be influenced by maternal microbiota. Maternal vaginal microbiota can be a determining factor of spontaneous Preterm Birth (SPPTB), the leading cause of perinatal mortality. The aim of the study is to investigate the likelihood of a causal relationship between the maternal vaginal microbiota composition and neonatal lung and intestinal microbiota profile at birth, in cases of SPPTB. The association between the lung and/or meconium microbiota with the subsequent development of bronchopulmonary dysplasia (BPD) was also investigated. Maternal vaginal swabs, newborns’ bronchoalveolar lavage fluid (BALF) (1st, 3rd, 7th day of life) and first meconium samples were collected from 20 women and 23 preterm newborns with gestational age ≤ 30 weeks (12 = SPPTB; 11 = Medically Indicated Preterm Birth–MIPTB). All the samples were analyzed for culture examination and for microbiota profiling using metagenomic analysis based on the Next Generation Sequencing (NGS) technique of the bacterial 16S rRNA gene amplicons. No significant differences in alpha e beta diversity were found between the neonatal BALF samples of SPPTB group and the MIPTB group. The vaginal microbiota of mothers with SPPTB showed a significant difference in alpha diversity with a decrease in Lactobacillus and an increase in Proteobacteria abundance. No association was found between BALF and meconium microbiota with the development of BPD. Vaginal colonization by Ureaplasma bacteria was associated with increased risk of both SPPTB and newborns’ BPD occurrence. In conclusion, an increase in α-diversity values and a consequent fall in Lactobacillus in vaginal environment could be associated to a higher risk of SPPTB. We could identify neither a specific neonatal lung or meconium microbiota profiles in preterm infants born by SPPTB nor a microbiota at birth suggestive of subsequent BPD development. Although a strict match has not been revealed between microbiota of SPPTB mother-infant couples, a relationship cannot be excluded. To figure out the reciprocal influence of the maternal-neonatal microbiota and its potential role in the pathogenesis of SPPTB and BPD further research is needed.
Thyroid cancer in children: A multicenter international study highlighting clinical features and surgical outcomes of primary and secondary tumors
Authors: Martucci Cristina , Crocoli Alessandro , De Pasquale Maria Debora , Spinelli Claudio , Strambi Silvia , Brazzarola Paolo , Morelli Eleonora , Cassiani Jessica , Mancera Juliana , Luengas Juan Pablo , Lobos Pablo , Liberto Daniel , Astori Estefanìa , Sarnacki Sabine , Couloigner Vincent , Simon François , Lambert Cassandre , Abib Simone de Campos Vieira , Cervantes Onivaldo , Caran Eliana , Delgado Lindman Diana , Jones Matthew O. , Shukla Rajeev , Losty Paul D. , Inserra Alessandro
Published: July 2022

Background:

Thyroid gland malignancies are rare in pediatric patients (0.7% of tumors); only 1.8% are observed in patients aged <20 years, with a higher prevalence recorded in women and adolescents. Risk factors include genetic syndromes, MEN disorders, autoimmune diseases, and exposure to ionizing radiation. Radiotherapy is also associated with an increased risk of secondary thyroid cancer. This study describes the clinical features and surgical outcomes of primary and secondary thyroid tumors in pediatric patients.

Methods

Institutional data were collected from eight international surgical oncology centers for pediatric patients with thyroid cancer between 2000 and 2020. Statistical analyses were performed using the GraphPad Prism software.

Results

Among 255 total cases of thyroid cancer, only 13 (5.1%) were secondary tumors. Primary thyroid malignancies were more likely to be multifocal in origin (odds ratio [OR] 1.993, 95% confidence interval [CI].7466–5.132, p = 0.2323), have bilateral glandular location (OR 2.847, 95% CI.6835–12.68, p = 0.2648), and be metastatic at first diagnosis (OR 1.259, 95% CI.3267–5.696, p > 0.999). Secondary tumors showed a higher incidence of disease relapse (OR 1.556, 95% CI.4579-5.57, p = 0.4525) and surgical complications (OR 2.042, 95% CI 0.7917–5.221, p = 0.1614), including hypoparathyroidism and recurrent laryngeal nerve injury. The overall survival (OS) was 99% at 1 year and 97% after 10 years. No EFS differences were evident between the primary and secondary tumors (chi-square 0.7307, p = 0.39026).

Conclusions

This multicenter study demonstrated excellent survival in pediatric thyroid malignancies. Secondary tumors exhibited greater disease relapse (15.8 vs. 10.5%) and a higher incidence of surgical complications (36.8 vs. 22.2%).
Abdominal massage alleviates functional diarrhea in immature rats via modulation of intestinal microbiota and tight junction protein
Authors: Huang Yanyi , Ma Qing , He Jingxin , Liang Xingshan , Mai Qingxin , Luo Huifang , Hu Jingyi , Song Yang
Published: July 2022

Functional diarrhea (FD) is a common type of chronic diarrhea in children. Recurrent diarrhea can negatively impact children's quality of life and raise healthcare costs significantly. However, conventional treatments are ineffective and limited. Moreover, children with chronic conditions have poor medication compliance. Therefore, non-pharmacological and complementary treatments are urgently needed. In China, abdominal massage is widely used to treat diarrhea in children. Numerous clinical studies have verified its usefulness in treating gastrointestinal disorders as well. Nevertheless, its intrinsic mechanisms are still unclear, and the impact of massage direction on treatment effects has received less attention. In our study, we found that FD was not associated with pathogen infection. A dysbiosis of the intestinal microbiota and disruption of the intestinal barrier are most likely to cause FD. Moreover, this study also substantiates that abdominal massage can mitigate functional diarrhea by altering the intestinal microbiota structure and decreasing the number of bacteria that damage intestinal mucosal barriers. The reduction of Ruminococcus_torques_group and Clostridium_innocuum_group at the genus level potentially mediated the beneficial effects of abdominal massage on alleviating diarrhea. Furthermore, massaging from two different directions, clockwise (CW) and counter-clockwise (CCW) massage, would not significantly influence the effect of the massage on intestinal microbiota or tight junction proteins. In summary, abdominal massage is an effective complementary therapy for children suffering from functional diarrhea.
Effect of Acid Suppressants on Non–Helicobacter pylori Helicobacters Within Parietal Cells
Authors: Nakamura Masahiko , Murasato Futa , Øverby Anders , Kodama Yosuke , Michimae Hirofumi , Sasaki Kazuki , Flahou Bram , Haesebrouck Freddy , Murayama Somay Y. , Takahashi Shinichi , Uchida Masayuki , Suzuki Hidekazu , Matsui Hidenori
Published: July 2022

We investigated the effect of increased pH induced by acid suppressants on the viability of non–Helicobacter pylori helicobacters (NHPHs) within parietal cell intracellular canaliculi and fundic glandular lumina by immunohistochemistry, electron microscopy, quantitative PCR, urea breath tests, and using a bilayer culture system. Three months before the experiment, mice were infected with the NHPH H. suis and then treated with famotidine (2 mg/kg body weight [BW], once daily), lansoprazole (30 mg/kg BW, once daily), or vonoprazan (20 mg/kg BW, once daily) for 3 days. Immunohistochemical studies using the TUNEL method, quantitative PCR analysis, and urea breath tests were performed. PCR analysis showed a decrease in the NHPH quantity after vonoprazan treatment. Urea breath tests revealed a significant decrease in the NHPH urease activity after vonoprazan, lansoprazole, and famotidine treatments for 3 days; however, 4 days after the treatment, urease activity reversed to the pretreatment level for each treatment group. Electron microscopy revealed an increase in the damaged NHPH after vonoprazan treatment. The TUNEL method revealed apoptotic NHPH within parietal cells after vonoprazan treatment. The bilayer culture results demonstrated that NHPH moved more quickly at a pH of 4.0 than at a pH of 3.0, 5.0, and 6.5, and electron microscopy revealed a change from the spiral form to the coccoid form under near-neutral pH conditions. We thus proposed that acid suppressants, especially vonoprazan, induce NHPH damage by altering pH.