bluuebunny/crossref_metadata_2025 huggingface dataset:
ArcR contributes to tolerance to fluoroquinolone antibiotics by regulating katA in Staphylococcus aureus
Authors: Fu Tongtong , Fan Zheng , Li Yujie , Li Zhoufei , Du Bing , Liu Shiyu , Cui Xiaohu , Zhang Rui , Zhao Hanqing , Feng Yanling , Xue Guanhua , Cui Jinghua , Yan Chao , Gan Lin , Feng Junxia , Xu Ziying , Yu Zihui , Tian Ziyan , Ding Zanbo , Chen Jinfeng , Chen Yujie , Yuan Jing
Published: February 2023

Staphylococcus aureus is an opportunistic pathogen that shows a unique ability to quickly respond to a variety of antibiotics. The Crp/Fnr family transcriptional regulator ArcR controls expression of arginine deiminase pathway genes arcABDC, which enable the utilization of arginine as an energy source for cell growth under anaerobic conditions. However, ArcR shares low overall similarity with other Crp/Fnr family proteins, suggesting that they differ in the response to environmental stress. In this study, MIC and survival assays were performed to determine the role of ArcR in antibiotic resistance and tolerance. The results showed that deletion of arcR reduced tolerance of S.aureus to fluoroquinolone antibiotics, mainly through a defect in the response to oxidative stress. In ΔarcR mutant, the expression of the major catalase gene katA was downregulated, and katA overexpression restored bacterial resistance to oxidative stress and antibiotics. We showed that ArcR directly regulated katA transcription by binding to the promoter region of katA. Therefore, our results revealed the contribution of ArcR in bacterial tolerance to oxidative stress and subsequently to fluoroquinolones antibiotics. This study added our understanding on the role of Crp/Fnr family in bacterial susceptibility to antibiotics.
Seasonal differences in intestinal flora are related to rats’ intestinal water metabolism
Authors: Li Jing , Sun Yike , Wang Ruochong , Ma Shuran , Shi Lei , Wang Kai , Zhang Hairong , Wang Tong , Liu Leilei
Published: February 2023

Many studies have reported obvious seasonal differences in the intestinal flora of rats, and this stable distribution of the seasonal flora helps in maintaining the normal physiological function of the host. However, the mechanism underlying these seasonal differences in intestinal flora remains unclear. To explore the correlation among seasonal factors and intestinal water metabolism and intestinal flora, 20 Sprague Dawley (SD) rats were divided into spring, summer, autumn, and winter groups. The environment for the four seasons was simulated using the Balanced Temperature and Humidity Control system. The intestinal water metabolism was evaluated by determining the intestinal transmission function, fecal water content, water content of colonic tissue, and the colonic expression levels of AQP3, AQP4, and AQP8. The composition and relative abundance of intestinal microflora in rats in each season were assessed through 16S rDNA amplifier sequencing, and the relationship between the dominant flora and intestinal water metabolism in each season was analyzed using Spearman correlation analysis. The high temperature and humidity season could lead to an increase in intestinal water metabolism and intestinal water content in rats, whereas the low temperature and humidity season could lead to a decrease, which was closely related to the change in microflora. To explore the molecular mechanism of seasonal changes in intestinal water metabolism, the concentration of colonic 5-HT, VIP, cAMP, and PKA associated with intestinal water metabolism in rats were also examined. Seasonal changes could affect the concentration of colonic 5-HT and VIP in rats, and then regulate AQPs through cAMP/PKA pathway to affect the intestinal water metabolism. These results suggest that seasonal factors affect the level of intestinal water metabolism in rats and result in seasonal differences in intestinal flora.
Bacteriocin production enhancing mechanism of Lactiplantibacillus paraplantarum RX-8 response to Wickerhamomyces anomalus Y-5 by transcriptomic and proteomic analyses
Authors: Nie Rong , Zhu Zekang , Qi Yanwei , Wang Zhao , Sun Haoxuan , Liu Guorong
Published: February 2023

Plantaricin is a kind of bacteriocin with broad-spectrum antibacterial activity on several food pathogens and spoilage microorganisms, showing potential in biopreservation applications. However, the low yield of plantaricin limits its industrialization. In this study, it was found that the co-culture of Wickerhamomyces anomalus Y-5 and Lactiplantibacillus paraplantarum RX-8 could enhance plantaricin production. To investigate the response of L. paraplantarum RX-8 facing W. anomalus Y-5 and understand the mechanisms activated when increasing plantaricin yield, comparative transcriptomic and proteomic analyses of L. paraplantarum RX-8 were performed in mono-culture and co-culture. The results showed that different genes and proteins in the phosphotransferase system (PTS) were improved and enhanced the uptake of certain sugars; the key enzyme activity in glycolysis was increased with the promotion of energy production; arginine biosynthesis was downregulated to increase glutamate mechanism and then promoted plantaricin yield; and the expression of several genes/proteins related to purine metabolism was downregulated and those related to pyrimidine metabolism was upregulated. Meanwhile, the increase of plantaricin synthesis by upregulation of plnABCDEF cluster expression under co-culture indicated that the PlnA-mediated quorum sensing (QS) system took part in the response mechanism of L. paraplantarum RX-8. However, the absence of AI-2 did not influence the inducing effect on plantaricin production. Mannose, galactose, and glutamate were critical metabolites and significantly simulate plantaricin production (p < 0.05). In summary, the findings provided new insights into the interaction between bacteriocin-inducing and bacteriocin-producing microorganisms, which may serve as a basis for further research into the detailed mechanism.
Development of Candida autochthonous starter for cigar fermentation via dissecting the microbiome
Authors: Jia Yun , Liu Yuanfa , Hu Wanrong , Cai Wen , Zheng Zhaojun , Luo Cheng , Li Dongliang
Published: February 2023

Introduction

The main goal of tobacco fermentation technology is to minimize the alkaloid content while improving flavor substance content.

Methods

This study revealed the microbial community structure and their metabolic functions during cigar leaf fermentation by high-throughput sequencing and correlation analysis, and evaluated the fermentation performance of functional microbes based on in vitro isolation and bioaugmentation fermentation.

Results

The relative abundance of Staphylococcus and Aspergillus increased first but then decreased during the fermentation, and would occupy the dominant position of bacterial and fungal communities, respectively, on the 21st day. Correlation analysis predicted that Aspergillus, Staphylococcus and Filobasidium could contribute to the formation of saccharide compounds, Bacillus might have degradation effects on nitrogenous substances. In particular, Candida, as a co-occurring taxa and biomarker in the later stage of fermentation, could not only degrade nitrogenous substrates and synthesize flavor substances, but also contribute to maintaining the stability of microbial community. Moreover, based on in vitro isolation and bioaugmentation inoculation, it was found that Candida parapsilosis and Candida metapsilosis could significantly reduce the alkaloids content and increase the content of flavor components in tobacco leaves.

Discussion

This study found and validated the critical role of Candida in the fermentation of cigar tobacco leaves through high-throughput sequencing and bioaugmentation inoculation, which would help guide the development of microbial starters and directional regulation of cigar tobacco quality.
Biological synthesis of ursodeoxycholic acid
Authors: Song Peng , Zhang Xue , Feng Wei , Xu Wei , Wu Chaoyun , Xie Shaoqing , Yu Sisi , Fu Rongzhao
Published: February 2023

Ursodeoxycholic acid (UDCA) is a fundamental treatment drug for numerous hepatobiliary diseases that also has adjuvant therapeutic effects on certain cancers and neurological diseases. Chemical UDCA synthesis is environmentally unfriendly with low yields. Biological UDCA synthesis by free-enzyme catalysis or whole-cell synthesis using inexpensive and readily available chenodeoxycholic acid (CDCA), cholic acid (CA), or lithocholic acid (LCA) as substrates is being developed. The free enzyme-catalyzed one-pot, one-step/two-step method uses hydroxysteroid dehydrogenase (HSDH); whole-cell synthesis, mainly uses engineered bacteria (mainly Escherichia coli) expressing the relevant HSDHs. To further develop these methods, HSDHs with specific coenzyme dependence, high enzyme activity, good stability, and high substrate loading concentration, P450 monooxygenase with C-7 hydroxylation activity and engineered strain harboring HSDHs must be exploited.
Intestinal microbiota changes pre- and post-fecal microbiota transplantation for treatment of recurrent Clostridioides difficile infection among Iranian patients with concurrent inflammatory bowel disease
Authors: Gholam-Mostafaei Fahimeh Sadat , Azimirad Masoumeh , Naseri Kaveh , Nabavi-Rad Ali , Asadzadeh Aghdaei Hamid , Shahrokh Shabnam , Ebrahimi Daryani Nasser , Yadegar Abbas , Zali Mohammad Reza
Published: February 2023

Introduction

Patients with inflammatory bowel disease (IBD) are at a greater risk for the recurrence of Clostridioides difficile infection (rCDI) that is triggered by intestinal microbiota dysbiosis. Fecal microbiota transplantation (FMT) has emerged as a highly effective therapeutic option for this complication. However, little is known about the impact of FMT on intestinal microbiota alterations in rCDI patients suffering from IBD. In this study, we aimed to investigate post-FMT intestinal microbiota alterations in Iranian rCDI patients with underlying IBD.

Methods

A total of 21 fecal samples were collected including 14 samples pre- and post-FMT and 7 samples from healthy donors. Microbial analysis was performed by quantitative real-time PCR (RT-qPCR) assay targeting the 16S rRNA gene. The pre-FMT profile and composition of the fecal microbiota were compared to the microbial changes of samples collected 28 days after FMT.

Results and discussion

Overall, the fecal microbiota profile of recipients was more similar to donor samples after the transplantation. We observed a significant increase in the relative abundance of Bacteroidetes post-FMT, compared to the pre-FMT microbial profile. Furthermore, there were remarkable differences between the microbial profile of pre-FMT, post-FMT, and healthy donor samples by PCoA analysis based on the ordination distance. This study demonstrates FMT as a safe and effective approach to restore the indigenous composition of the intestinal microbiota in rCDI patients and ultimately results in the treatment of concurrent IBD.
Small target detection with remote sensing images based on an improved YOLOv5 algorithm
Authors: Pei Wenjing , Shi Zhanhao , Gong Kai
Published: February 2023

Introduction

Small target detection with remote sensing images is a challenging topic due to the small size of the targets, complex, and fuzzy backgrounds.

Methods

In this study, a new detection algorithm is proposed based on the YOLOv5s algorithm for small target detection. The data enhancement strategy based on the mosaic operation is applied to expand the remote image training sets so as to diversify the datasets. First, the lightweight and stable feature extraction module (LSM) and C3 modules are combined to form the feature extraction module, called as LCB module, to extract more features in the remote sensing images. Multi-scale feature fusion is realized based on the Res 2 unit, Dres 2, and Spatial Pyramid Pooling Small (SPPS) models, so that the receptive field can be increased to obtain more multi-scale global information based on Dres2 and retain the obtained feature information of the small targets accordingly. Furthermore, the input size and output size of the network are increased and set in different scales considering the relatively less target features in the remote images. Besides, the Efficient Intersection over Union (EIoU) loss is used as the loss function to increase the training convergence velocity of the model and improve the accurate regression of the model.

Results and discussion

The DIOR-VAS and Visdrone2019 datasets are selected in the experiments, while the ablation and comparison experiments are performed with five popular target detection algorithms to verify the effectiveness of the proposed small target detection method.
Radiomics and machine learning applied to STIR sequence for prediction of quantitative parameters in facioscapulohumeral disease
Authors: Colelli Giulia , Barzaghi Leonardo , Paoletti Matteo , Monforte Mauro , Bergsland Niels , Manco Giulia , Deligianni Xeni , Santini Francesco , Ricci Enzo , Tasca Giorgio , Mira Antonietta , Figini Silvia , Pichiecchio Anna
Published: February 2023

Purpose

Quantitative Muscle MRI (qMRI) is a valuable and non-invasive tool to assess disease involvement and progression in neuromuscular disorders being able to detect even subtle changes in muscle pathology. The aim of this study is to evaluate the feasibility of using a conventional short-tau inversion recovery (STIR) sequence to predict fat fraction (FF) and water T2 (wT2) in skeletal muscle introducing a radiomic workflow with standardized feature extraction combined with machine learning algorithms.

Methods

Twenty-five patients with facioscapulohumeral muscular dystrophy (FSHD) were scanned at calf level using conventional STIR sequence and qMRI techniques. We applied and compared three different radiomics workflows (WF1, WF2, WF3), combined with seven Machine Learning regression algorithms (linear, ridge and lasso regression, tree, random forest, k-nearest neighbor and support vector machine), on conventional STIR images to predict FF and wT2 for six calf muscles.

Results

The combination of WF3 and K-nearest neighbor resulted to be the best predictor model of qMRI parameters with a mean absolute error about ± 5ppfor FF and ± 1.8msfor wT2.

Conclusion

This pilot study demonstrated the possibility to predict qMRI parameters in a cohort of FSHD subjects starting from conventional STIR sequence.
Comparison of a direct aspiration first pass technique vs. stent retriever thrombectomy for the treatment of acute large vessel occlusion stroke in the anterior circulation with atrial fibrillation
Authors: Fan Hongxing , Li Zhenhui , Li Yi , Tan Yanping , Mao Zhenlin , Liu Qian , Zhu Youfeng
Published: February 2023

Objectives

The stent retriever thrombectomy (SRT) and a direct aspiration first-pass technique (ADAPT) are the two main mechanical thrombectomy (MT) techniques for acute ischemic stroke. Few data are available for comparing the therapeutic effects associated with the two mechanical thrombectomy techniques in acute ischemic stroke with atrial fibrillation. The purpose of this study was to compare the efficacy and safety of both techniques for the treatment of acute large vessel occlusion stroke in the anterior circulation with atrial fibrillation.

Methods

Retrospective analysis was performed in stroke patients with atrial fibrillation admitted to Guangzhou Red Cross Hospital from January 2018 to June 2022 who received mechanical thrombectomy by either SRT or ADAPT. Comparisons were made with regards to the initial traits, course of therapy, effectiveness indicators, and complications of these individuals. The primary outcome is recanalization rate.

Results

In this study, after screening 431 patients, 92 eligible patients, with 48 patients received SRT and 44 patients received ADAPT, were included. There was no significant difference in the recanalization rate between the two groups (SRT 87.5% vs. ADAPT 84.1%, P = 0.639). Compared with SRT, patients in ADAPT group had a shorter puncture to recanalization time [33.5 min (27.0–59.5) vs. 50.5 min (31.5–91.5), P = 0.009], a higher first pass success recanalization rate (54.5 vs. 33.3%, p = 0.040), and a higher rate of patients with improvement of NIHSS scores ≥4 at discharge (84.1 vs. 56.3%, P = 0.004). However, distal embolization occurred more frequently in the ADAPT group than that in SRT group (50.0 vs. 22.9%, P = 0.007). There was no significant difference between the two groups in the 3-month mRS score, symptomatic cerebral hemorrhage, or mortality.

Conclusions

Compared with SRT, ADAPT has similar recanalization rate for the treatment of acute large vessel occlusion stroke in the anterior circulation with atrial fibrillation. However, ADAPT might be more effective in terms of shorter puncture to recanalization time and higher first pass success recanalization rate. Further studies are needed for confirming our results.
Anticholinergics: A potential option for preventing posttraumatic epilepsy
Authors: Sanabria Viviam , Romariz Simone , Braga Matheus , Foresti Maira Licia , Naffah-Mazzacoratti Maria da Graça , Mello Luiz Eugênio , Longo Beatriz M.
Published: February 2023

Interest in the use of anticholinergics to prevent the development of epilepsy after traumatic brain injury (TBI) has grown since recent basic studies have shown their effectiveness in modifying the epileptogenic process. These studies demonstrated that treatment with anticholinergics, in the acute phase after brain injury, decreases seizure frequency, and severity, and the number of spontaneous recurrent seizures (SRS). Therefore, anticholinergics may reduce the risk of developing posttraumatic epilepsy (PTE). In this brief review, we summarize the role of the cholinergic system in epilepsy and the key findings from using anticholinergic drugs to prevent PTE in animal models and new clinical trial protocols. Furthermore, we discuss why treatment with anticholinergics is more likely to prevent PTE than treatment for other epilepsies.
Ischemic stroke prediction of patients with carotid atherosclerotic stenosis via multi-modality fused network
Authors: Lv Peng , Yang Jing , Wang Jiacheng , Guo Yi , Tang Qiying , Magnier Baptiste , Lin Jiang , Zhou Jianjun
Published: February 2023

Carotid atherosclerotic stenosis of the carotid artery is an important cause of ischemic cerebrovascular disease. The aim of this study was to predict the presence or absence of clinical symptoms in unknown patients by studying the existence or lack of symptoms of patients with carotid atherosclerotic stenosis. First, a deep neural network prediction model based on brain MRI imaging data of patients with multiple modalities is constructed; it uses the multi-modality features extracted from the neural network as inputs and the incidence of diagnosis as output to train the model. Then, a machine learning-based classification algorithm is developed to utilize the clinical features for comparison and evaluation. The experimental results showed that the deep learning model using imaging data could better predict the clinical symptom classification of patients. As part of preventive medicine, this study could help patients with carotid atherosclerosis narrowing to prepare for stroke prevention based on the prediction results.
Invasion characteristics and clinical significance of tumor-associated macrophages in gastrointestinal Krukenberg tumors
Authors: Huang Zigao , Li Baojia , Qin Haiquan , Mo Xianwei
Published: February 2023

Background

Tumor-associated macrophages (TAMs) have been used as potential drug targets in preclinical research and clinical trials of various cancers. However, their distribution in Krukenberg tumors (KTs) remains unclear. We investigated the expression and prognostic value of TAMs in patients with gastrointestinal cancer with KTs.

Methods

The infiltration of various types of TAMs was detected in surgical tissues of 35 patients with KTs using immunohistochemical staining. The level of infiltration of TAMs in tumor nests (TN), tumor stroma (TS), and invasive margin (IM) areas was evaluated. The Kaplan–Meier method and univariate/multivariate Cox regression risk models were used to analyze the relationship between the degree of TAMs invasion and overall survival (OS) and progression-free survival (PFS).

Results

The distribution of TAMs exhibited spatial heterogeneity between TN, TS, and IM regions in primary tumor (PT) and KT tissues. TAMs infiltrated in the TN had greater prognostic value and were barely influenced by preoperative neoadjuvant therapy, despite similar grades of invasion in PT and KT tissues. Moreover, the number of CD68+ TAMs in TN of KT tissues was an independent risk factor affecting patient OS, whereas tumor resection scope might be an independent risk factor affecting patient PFS.

Conclusions

In view of the close relationship between TAMs, the tumor microenvironment and patient prognosis, targeting TAMs combined with chemotherapy is expected to become a new approach for the treatment of patients with KTs.
Single progesterone receptor-positive phenotype has the similar clinicopathological features and outcome as triple-negative subtype in metastatic breast cancer
Authors: Luo Yunbo , Pu Hongyu , Li Fangwei , Qian Shuangqiang , Chen Jingtai , Zhao Xiaobo , Hou Lingmi
Published: February 2023

Objective

The same clinicopathological features and prognosis have been reported between single progesterone receptor-positive (sPR-positive) and triple-negative phenotype in early-stage breast cancer, but such similarity has not been studied in metastatic breast cancer (MBC). Therefore, the purpose of this study was to estimate the difference between sPR-positive phenotype and other phenotypes in MBC.

Methods

Patients with HER-2-negative MBC were selected from the Surveillance, Epidemiology and End Results database. Pearson’s χ2 test was used to compare the difference of clinicopathologic factors between sPR-positive phenotype and other phenotypes. Univariate and multivariate analyses were performed to evaluate the effects of hormone receptor (HoR) phenotypes and other clinicopathologic factors on the cancer-specific survival (CSS) and overall survival (OS).

Results

Overall, 10877 patients including 7060 patients (64.9%) with double HoR-positive (dHoR-positive), 1533 patients (14.1%) with single estrogen receptor-positive (sER-positive), 126 patients (1.2%) with sPR-positive and 2158 patients (19.8%) with double HoR-negative (dHoR-negative) were analyzed. The patients with sPR-positive or dHoR-negative were more likely to be younger, higher grade and tumor stage, visceral and brain metastasis than ER-positive phenotypes (P<0.001). MBC with sPR-positive had the similar CSS (HR: 1.135, 95%CI: 0.909-1.417, P=2.623) and OS (HR: 1.141, 95%CI: 0.921-1.413, P=0.229) as dHoR-negative, but worse outcome than ER-positive phenotypes. Chemotherapy significantly improved the survival for MBC, especially for sPR-positive MBC (CSS, HR: 0.39, 95%CI: 0.213-0.714, P=0.002; OS, HR: 0.366, 95%CI: 0.203-0.662, P=0.001).

Conclusions

Patients with sPR-positive and triple-negative have similar biological behavior and prognosis in MBC. Chemotherapy may be a preferred recommendation for MBC with sPR-positive.
Development and validation of an MRI-radiomics nomogram for the prognosis of pancreatic ductal adenocarcinoma
Authors: Xu Xinsen , Qu Jiaqi , Zhang Yijue , Qian Xiaohua , Chen Tao , Liu Yingbin
Published: February 2023

Objective

To develop and validate an MRI-radiomics nomogram for the prognosis of pancreatic ductal adenocarcinoma (PDAC).

Background

“Radiomics” enables the investigation of huge amounts of radiological features in parallel by extracting high-throughput imaging data. MRI provides better tissue contrast with no ionizing radiation for PDAC.

Methods

There were 78 PDAC patients enrolled in this study. In total, there were 386 radiomics features extracted from MRI scan, which were screened by the least absolute shrinkage and selection operator algorithm to develop a risk score. Cox multivariate regression analysis was applied to develop the radiomics-based nomogram. The performance was assessed by discrimination and calibration.

Results

The radiomics-based risk-score was significantly associated with PDAC overall survival (OS) (P < 0.05). With respect to survival prediction, integrating the risk score, clinical data and TNM information into the nomogram exhibited better performance than the TNM staging system, radiomics model and clinical model. In addition, the nomogram showed fine discrimination and calibration.

Conclusions

The radiomics nomogram incorporating the radiomics data, clinical data and TNM information exhibited precise survival prediction for PDAC, which may help accelerate personalized precision treatment.

Clinical trial registration

clinicaltrials.gov, identifier NCT05313854.
Development and validation of a mutation-based model to predict immunotherapeutic efficacy in NSCLC
Authors: He Ping , Liu Jie , Xu Qingyuan , Ma Huaijun , Niu Beifang , Huang Gang , Wu Wei
Published: February 2023

Background

Immunotherapy has become increasingly important in the perioperative period of non-small-cell lung cancer (NSCLC). In this study, we intended to develop a mutation-based model to predict the therapeutic effificacy of immune checkpoint inhibitors (ICIs) in patients with NSCLC.

Methods

Random Forest (RF) classifiers were generated to identify tumor gene mutated features associated with immunotherapy outcomes. Then the best classifier with the highest accuracy served for the development of the predictive model. The correlations of some reported biomarkers with the model were analyzed, such as TMB, PD-(L)1, KEAP1-driven co-mutations, and immune subtypes. The training cohort and validation cohorts performed survival analyses to estimate the predictive efficiency independently.

Results

An 18-gene set was selected using random forest (RF) classififiers. A predictive model was developed based on the number of mutant genes among the candidate genes, and patients were divided into the MT group (mutant gene ≥ 2) and WT group (mutant gene < 2). The MT group (N = 54) had better overall survival (OS) compared to the WT group (N = 290); the median OS was not reached vs. nine months (P < 0.0001, AUC = 0.73). The robust predictive performance was confifirmed in three validation cohorts, with an AUC of 0.70, 0.57, and 0.64 (P < 0.05). The MT group was characterized by high tumor neoantigen burden (TNB), increased immune infifiltration cells such as CD8 T and macrophage cells, and upregulated immune checkpoint molecules, suggesting potential biological advantages in ICIs therapy.

Conclusions

The predictive model could precisely predict the immunotherapeutic efficacy in NSCLC based on the mutant genes within the model. Furthermore, some immune-related features and cell expression could support robust efficiency.
Early calcitonin levels in medullary thyroid carcinoma: Prognostic role in patients without distant metastases at diagnosis
Authors: Sparano Clotilde , Adornato Virginia , Puccioni Matteo , Zago Elena , Perigli Giuliano , Badii Benedetta , Santoro Roberto , Maggi Mario , Petrone Luisa
Published: February 2023

Introduction

Calcitonin is the most specific marker for medullary thyroid carcinoma, thus, low detectable calcitonin values after surgery can conceal persistent disease. The present study aimed to explore the prognostic role of pre-operative and early calcitonin levels in patients without distant metastases at diagnosis.

Methods

A retrospective cohort of patients suffering from medullary thyroid carcinoma was considered (N=55). The final disease status, i.e. complete response (undetectable calcitonin levels and negative radiological assessments) or persistent disease (detectable calcitonin levels and/or positive radiological assessments), was deduced from the last available follow-up. Pre-operative and early calcitonin levels (i.e. six months after surgery) have been correlated to several clinical and histological features, according to the final disease status.

Results

Persistent disease patients showed higher pre-operative and early calcitonin values (p=0.028 and p<0.001, respectively), compared to complete response sub-cohort. Cox-regression models show that early detectable calcitonin increases up to 18-fold the risk of persistent disease, independently from tumour size and pre-operative calcitonin levels (p=0.006). Of note, when considering only patients who finally developed distant metastasis, ROC curve analysis shows that an early calcitonin level ≥16 pg/ml predicts the final disease status with a sensitivity of 89% and a specificity of 82% (AUC=0.911, CI95%: 0.819-1000, p<0.001).

Conclusion

Calcitonin levels six months after surgery represents an easy and effective predictor of persistent disease for medullary thyroid carcinoma without distant metastasis at diagnosis.
Case report: ATIC-ALK fusion in infant-type hemispheric glioma and response to lorlatinib
Authors: Shahab Shubin W. , Schniederjan Matthew , Vega Jose Velazquez , Little Stephen , Reisner Andrew , MacDonald Tobey , Aguilera Dolly
Published: February 2023

Introduction

Infant type hemispheric gliomas are a rare tumor with unique molecular characteristics. In many cases these harbor mutations in receptor tyrosine kinase pathways and respond to targeted therapy. Here we describe the case of an infant with this type of tumor with a novel ATIC-ALK fusion that has responded dramatically to the ALK inhibitor lorlatinib, despite being refractory to standard chemotherapy.

Case description

The infant was initially treated with standard chemotherapy and found to have an ATIC-ALK fusion. When surveillance imaging revealed progressive disease, the patient was switched to the ALK-inhibitor lorlatinib at 47 mg/m2/day. The patient demonstrated a significant clinical and radiographic response to the ALK inhibitor lorlatinib after just 3 months of treatment and a near complete response by 6 months of therapy.

Conclusion

The ALK inhibitor lorlatinib is an effective targeted therapy in infant type hemispheric glioma patients harboring ATIC-ALK fusion.
A promising new cancer marker: Long noncoding RNA EGFR-AS1
Authors: Zhu Danhua , Ouyang Xiaoxi , Zhang Yanhong , Yu Xiaopeng , Su Kunkai , Li Lanjuan
Published: February 2023

Cancer consists of a group of diseases with the salient properties of an uncontrolled cell cycle, metastasis, and evasion of the immune response, mainly driven by the genomic instability of somatic cells and the physicochemical environment. Long noncoding RNAs (lncRNAs) are defined as noncoding RNAs with a length of more than 200 nucleotides. LncRNA dysregulation participates in diverse disease types and is tightly associated with patient clinical features, such as age, disease stage, and prognosis. In addition, an increasing number of lncRNAs have been confirmed to regulate a series of biological and pathological processes through numerous mechanisms. The lncRNA epidermal growth factor receptor antisense RNA 1 (EGFR-AS1) was recently discovered to be aberrantly expressed in many types of diseases, particularly in cancers. A high level of EGFR-AS1 was demonstrated to correlate with multiple patient clinical characteristics. More importantly, EGFR-AS1 was found to be involved in the mediation of various cellular activities, including cell proliferation, invasion, migration, chemosensitivity, and stemness. Therefore, EGFR-AS1 is a promising marker for cancer management. In this review, we introduce the expression profile, molecular mechanisms, biological functions, and clinical value of EGFR-AS1 in cancers.
Case report: Expansion of phenotypic and genotypic data in TENM3-related syndrome: Report of two cases
Authors: Lu Fen , Xu Xin , Zheng Bixia , Wang Chunli , Zhou Wei , Tang Jian , Zhao Xiaoke
Published: February 2023

Biallelic TENM3 variants were recently reported to cause non-syndromic microphthalmia with coloboma-9 (MCOPCB9) and microphthalmia and/or coloboma with developmental delay (MCOPS15). To date, only eight syndromic and non-syndromic microphthalmia cases with recessive TENM3 variants have been reported. Herein, we report two unrelated new cases with biallelic variants in TENM3, widening the molecular and clinical spectrum. Regarding patient 1, WES revealed compound heterozygous variants in the TENM3 gene: c.3847_3855del; p.Leu1283_Ser1285del and c.3698_3699insA; p.Thr1233Thrfs*20 in the index patient, who was presenting with bilateral microphthalmia, congenital cataract, microcephaly, and global developmental delay. Regarding patient 2, compound missense heterozygous variants in the TENM3 gene were identified: c.941C > T; p.Ala314Val and c.6464T > C; p.Leu2155Pro in the 3-year-old boy, who presented with congenital esotropia, speech delay, and motor developmental delay. The clinical features of these two cases revealed high concordance with the previously reported cases, including microphthalmia and developmental delay. The presence of microcephaly in our patient potentially expands the neurologic phenotype associated with loss of function variants in TENM3, as microcephaly has not previously been described. Furthermore, we present evidence that missense variants in TENM3 are associated with similar, but milder, ocular features.
Chinese herbal injection for cardio-cerebrovascular disease: Overview and challenges
Authors: Huajuan Jiang , Xulong Huang , Bin Xian , Yue Wang , Yongfeng Zhou , Chaoxiang Ren , Jin Pei
Published: February 2023

Cardio-cerebrovascular diseases are the leading cause of death worldwide and there is currently no optimal treatment plan. Chinese herbal medicine injection (CHI) is obtained by combining traditional Chinese medicine (TCM) theory and modern production technology. It retains some characteristics of TCM while adding injection characteristics. CHI has played an important role in the treatment of critical diseases, especially cardio-cerebrovascular diseases, and has shown unique therapeutic advantages. TCMs that promote blood circulation and remove blood stasis, such as Salvia miltiorrhiza, Carthami flos, Panax notoginseng, and Chuanxiong rhizoma, account for a large proportion of CHIs of cardio-cerebrovascular disease. CHI is used to treat cardio-cerebrovascular diseases and has potential pharmacological activities such as anti-platelet aggregation, anti-inflammatory, anti-fibrosis, and anti-apoptosis. However, CHIs have changed the traditional method of administering TCMs, and the drugs directly enter the bloodstream, which may produce new pharmacological effects or adverse reactions. This article summarizes the clinical application, pharmacological effects, and mechanism of action of different varieties of CHIs commonly used in the treatment of cardio-cerebrovascular diseases, analyzes the causes of adverse reactions, and proposes suggestions for rational drug use and pharmaceutical care methods to provide a reference for the rational application of CHIs for cardio-cerebrovascular diseases.
Quality of life associated with immunosuppressant treatment adherence in liver transplant recipients: A cross-sectional study
Authors: Shafiekhani Mojtaba , Shahabinezhad Farbod , Tavakoli Zahra , Tarakmeh Tahereh , Haem Elham , Sari Negar , Nasirabadi Shohreh , Dehghani Masoud
Published: February 2023

Purpose: Transplanted organ survival after solid organ transplantation highly correlates with the adherence levels of the patients to their immunosuppressive drugs. On the other hand, one of the main goals of liver transplantation is to increase the overall quality of life (QOL) for the patient. This study is aimed to analyze the relationship between adherence and QOL in adult liver transplant recipients of the biggest liver transplant center in Asia.

Methods: All of the included patients were older than 18 years and at least 6 months had passed from their liver transplantation. The adherence level was measured with BAASIS method and the QOL was assessed by SF-36 questionnaire in real-time interviews. The relationship between adherence and different aspects of QOL in addition to qualitative and quantitative influential factors on these two outcomes was calculated with statistical analysis.

Results: Among the 122 included patients, 41% of the were categorized in the non-adherent group. The most important reasons for non-adherence in these patients included forgetfulness (62%), lack of medication (12%), financial problems for drug supply (9%), and side effects (2%). According to the results of the multivariate linear regression model, rejection was the only influential factor in the occurrence of non-adherence among patients (OR = 8.226 CI (1.404-48.196)). The overall mean QOL score of patients was reported 51.09 ± 21.86. The lowest is given to social functioning, while mental health has achieved the highest score. The mean QOL scores in different dimensions in patients with adherence were higher than non-adherents, which was only significant in mental health (p-value = 0.01). Additionally, in total scores related to Physical Composite Score (PSC) and Mental Composite Score (MCS), the mean MSC scores in adherent patients were significantly higher than non-adherent patients (p-value: 0.02). Although adherent patients have an overall greater QOL, the only meaningful effect on QOL total score was from income level.

Conclusion: The overall QoL score has been in all parameters higher in the adherent group compared with non-adherent patients. The difference in QoL was most meaningfully significant in mental composite score among other parameters of QoL.
Molluskicidal nanoemulsion of Neomitranthes obscura (DC.) N. Silveira for schistosomiasis control
Authors: Rangel Leonardo da Silva , Paiva Machado Francisco , Amaral Raquel , Cláudia Rodrigues Da Silva Ana , Santos Marcelo Guerra , Albuquerque Dos Santos José Augusto , Lidmar Von Ranke Natalia , Rodrigues Carlos Rangel , Rocha Leandro , Faria Robson Xavier
Published: February 2023

Schistosomiasis is caused by the parasite Schistosoma mansoni, which uses mollusks of the Biomphalaria genus as intermediate hosts. In 2020, approximately 241 million people worldwide underwent treatment for schistosomiasis. For this reason, the World Health Organization encourages research on alternative molluskicides based on plant species. The objective of this work was to investigate Neomitranthes obscura essential oil from leaf chemical composition and its essential oil nanoemulsion activity on intermediate hosts of schistosomiasis Biomphalaria glabrata control. The major chemical components of the Neomitranthes obscura essential oil were zonarene, seline-3,7(11)-diene, β-selinene, and α-selinene. The nanoemulsion tested using 24-well plate methodology showed lethality and juvenile mollusks with LC90 values of 53.9 and 25.0 ppm after 48 h, respectively, and on their spawning with an LC90 of 66.2 ppm after 48 h. Additionally, the nanoemulsion exhibited an LC90 value against the infective form of the parasite Schistosoma mansoni of 11.5 ppm after 4 h. This pharmaceutical formulation acted inhibiting the acetylcholinesterase activity and was not toxic for Mellanoides sp. This result suggests the use of this nanoformulation as a promising alternative in the control of Biomphalaria glabrata and the transmission of schistosomiasis.
Cell surface GRP78 regulates TGFβ1-mediated profibrotic responses via TSP1 in diabetic kidney disease
Authors: Trink Jackie , Ahmed Usman , O’Neil Kian , Li Renzhong , Gao Bo , Krepinsky Joan C.
Published: February 2023

Introduction: Diabetic kidney disease (DKD) is the leading cause of kidney failure in North America, characterized by glomerular accumulation of extracellular matrix (ECM) proteins. High glucose (HG) induction of glomerular mesangial cell (MC) profibrotic responses plays a central role in its pathogenesis. We previously showed that the endoplasmic reticulum resident GRP78 translocates to the cell surface in response to HG, where it mediates Akt activation and downstream profibrotic responses in MC. Transforming growth factor β1 (TGFβ1) is recognized as a central mediator of HG-induced profibrotic responses, but whether its activation is regulated by cell surface GRP78 (csGRP78) is unknown. TGFβ1 is stored in the ECM in a latent form, requiring release for biological activity. The matrix glycoprotein thrombospondin 1 (TSP1), known to be increased in DKD and by HG in MC, is an important factor in TGFβ1 activation. Here we determined whether csGRP78 regulates TSP1 expression and thereby TGFβ1 activation by HG.

Methods: Primary mouse MC were used. TSP1 and TGFβ1 were assessed using standard molecular biology techniques. Inhibitors of csGRP78 were: 1) vaspin, 2) the C-terminal targeting antibody C38, 3) siRNA downregulation of its transport co-chaperone MTJ-1 to prevent GRP78 translocation to the cell surface, and 4) prevention of csGRP78 activation by its ligand, active α2-macroglobulin (α2M*), with the neutralizing antibody Fα2M or an inhibitory peptide.

Results: TSP1 transcript and promoter activity were increased by HG, as were cellular and ECM TSP1, and these required PI3K/Akt activity. Inhibition of csGRP78 prevented HG-induced TSP1 upregulation and deposition into the ECM. The HG-induced increase in active TGFβ1 in the medium was also inhibited, which was associated with reduced intracellular Smad3 activation and signaling. Overexpression of csGRP78 increased TSP-1, and this was further augmented in HG.

Discussion: These data support an important role for csGRP78 in regulating HG-induced TSP1 transcriptional induction via PI3K/Akt signaling. Functionally, this enables TGFβ1 activation in response to HG, with consequent increase in ECM proteins. Means of inhibiting csGRP78 signaling represent a novel approach to preventing fibrosis in DKD.
A novel prognostic scoring model based on copper homeostasis and cuproptosis which indicates changes in tumor microenvironment and affects treatment response
Authors: Ma Yun-Long , Yang Ya-Fei , Wang Han-Chao , Yang Chun-Cheng , Yan Lun-Jie , Ding Zi-Niu , Tian Bao-Wen , Liu Hui , Xue Jun-Shuai , Han Cheng-Long , Tan Si-Yu , Hong Jian-Guo , Yan Yu-Chuan , Mao Xin-Cheng , Wang Dong-Xu , Li Tao
Published: February 2023

Background: Intracellular copper homeostasis requires a complex system. It has shown considerable prospects for intervening in the tumor microenvironment (TME) by regulating copper homeostasis and provoking cuproptosis. Their relationship with hepatocellular carcinoma (HCC) remains elusive.

Methods: In TCGA and ICGC datasets, LASSO and multivariate Cox regression were applied to obtain the signature on the basis of genes associated with copper homeostasis and cuproptosis. Bioinformatic tools were utilized to reveal if the signature was correlated with HCC characteristics. Single-cell RNA sequencing data analysis identified differences in tumor and T cells’ pathway activity and intercellular communication of immune-related cells. Real-time qPCR analysis was conducted to measure the genes’ expression in HCC and adjacent normal tissue from 21 patients. CCK8 assay, scratch assay, transwell, and colony formation were conducted to reveal the effect of genes on in vitro cell proliferation, invasion, migration, and colony formation.

Results: We constructed a five-gene scoring system in relation to copper homeostasis and cuproptosis. The high-risk score indicated poor clinical prognosis, enhanced tumor malignancy, and immune-suppressive tumor microenvironment. The T cell activity was markedly reduced in high-risk single-cell samples. The high-risk HCC patients had a better expectation of ICB response and reactivity to anti-PD-1 therapy. A total of 156 drugs were identified as potential signature-related drugs for HCC treatment, and most were sensitive to high-risk patients. Novel ligand-receptor pairs such as FASLG, CCL, CD40, IL2, and IFN-Ⅱ signaling pathways were revealed as cellular communication bridges, which may cause differences in TME and immune function. All crucial genes were differentially expressed between HCC and paired adjacent normal tissue. Model-constructed genes affected the phosphorylation of mTOR and AKT in both Huh7 and Hep3B cells. Knockdown of ZCRB1 impaired the proliferation, invasion, migration, and colony formation in HCC cell lines.

Conclusion: We obtained a prognostic scoring system to forecast the TME changes and assist in choosing therapy strategies for HCC patients. In this study, we combined copper homeostasis and cuproptosis to show the overall potential risk of copper-related biological processes in HCC for the first time.
Hypoxia-ameliorated photothermal manganese dioxide nanoplatform for reversing doxorubicin resistance
Authors: Chen Zhenzhen , Liu Zhihong , Zhang Qian , Huang Sheng , Zhang Zaizhong , Feng Xianquan , Zeng Lingjun , Lin Ding , Wang Lie , Song Hongtao
Published: February 2023

Drug resistance is a huge hurdle in tumor therapy. Tumor hypoxia contributes to chemotherapy resistance by inducing the hypoxia-inducible factor-1α (HIF-1α) pathway. To reduce tumor hypoxia, novel approaches have been devised, providing significant importance to reverse therapeutic resistance and improve the effectiveness of antitumor therapies. Herein, the nanosystem of bovine serum albumin (BSA)-templated manganese dioxide (MnO2) nanoparticles (BSA/MnO2 NPs) loaded with doxorubicin (DOX) (DOX-BSA/MnO2 NPs) developed in our previous report was further explored for their physicochemical properties and capacity to reverse DOX resistance because of their excellent photothermal and tumor microenvironment (TME) response effects. The DOX-BSA/MnO2 NPs showed good biocompatibility and hemocompatibility. Meanwhile, DOX-BSA/MnO2 NPs could greatly affect DOX pharmacokinetic properties, with prolonged circulation time and reduced cardiotoxicity, besides enhancing accumulation at tumor sites. DOX-BSA/MnO2 NPs can interact with H2O2 and H+ in TME to form oxygen and exhibit excellent photothermal effect to further alleviate hypoxia due to MnO2, reversing DOX resistance by down-regulating HIF-1α expression and significantly improving the antitumor efficiency in DOX-resistant human breast carcinoma cell line (MCF-7/ADR) tumor model. The hypoxia-ameliorated photothermal MnO2 platform is a promising strategy for revering DOX resistance.
Functional selectivity of EM-2 analogs at the mu-opioid receptor
Authors: Piekielna-Ciesielska Justyna , Malfacini Davide , Djeujo Francine Medjiofack , Marconato Chantal , Wtorek Karol , Calo’ Girolamo , Janecka Anna
Published: February 2023

The mu opioid receptor agonists are the most efficacious pain controlling agents but their use is accompanied by severe side effects. More recent developments indicate that some ligands can differentially activate receptor downstream pathways, possibly allowing for dissociation of analgesia mediated through the G protein from the opioid-related side effects mediated by β-arrestin pathway. In an effort to identify such biased ligands, here we present a series of thirteen endomorphin-2 (EM-2) analogs with modifications in positions 1, 2, and/or 3. All obtained analogs behaved as mu receptor selective agonists in calcium mobilization assay carried out on cells expressing opioid receptors and chimeric G proteins. A Bioluminescence Resonance Energy Transfer (BRET) approach was employed to determine the ability of analogs to promote the interaction of the mu opioid receptor with G protein or β-arrestin 2. Nearly half of the developed analogs showed strong bias towards G protein, in addition four compounds were nearly inactive towards β-arrestin 2 recruitment while blocking the propensity of EM-2 to evoke mu-β-arrestin 2 interaction. The data presented here contribute to our understanding of EM-2 interaction with the mu opioid receptor and of the transductional propagation of the signal. In addition, the generation of potent and selective mu receptor agonists strongly biased towards G protein provides the scientific community with novel tools to investigate the in vivo consequences of biased agonism at this receptor.