bluuebunny/crossref_metadata_2025 huggingface dataset:
Microbial Enzymatic Synthesis of Amikacin Analogs With Antibacterial Activity Against Multidrug-Resistant Pathogens
Authors: Ban Yeon Hee , Song Myoung Chong , Jeong Joong Ho , Kwun Min Seok , Kim Chang Rae , Ryu Hwi So , Kim Eunji , Park Je Won , Lee Dong Gun , Yoon Yeo Joon
Published: September 2021

With the constant emergence of multidrug-resistant gram-negative bacteria, interest in the development of new aminoglycoside (AG) antibiotics for clinical use has increased. The regioselective modification of AG scaffolds could be an efficient approach for the development of new antibiotics with improved therapeutic potency. We enzymatically synthesized three amikacin analogs containing structural modifications in the amino groups and evaluated their antibacterial activity and cytotoxicity. Among them, 6′-N-acyl-3″-N-methylated analogs showed improved antibacterial activity against the multidrug-resistant gram-negative bacteria tested, while exhibiting reduced in vitro nephrotoxicity compared to amikacin. This study demonstrated that the modifications of the 6′-amino group as well as the 3″-amino group have noteworthy advantages for circumventing the AG-resistance mechanism. The regiospecific enzymatic modification could be exploited to develop novel antibacterial agents with improved pharmacological potential.
Characterization and Identification of a Novel Torovirus Associated With Recombinant Bovine Torovirus From Tibetan Antelope in Qinghai-Tibet Plateau of China
Authors: Dai Xiaoyi , Lu Shan , Shang Guobao , Zhu Wentao , Yang Jing , Liu Liyun , Xu Jianguo
Published: September 2021

Toroviruses (ToVs) are enteric pathogens and comprise three species, equine torovirus (EToV), bovine torovirus (BToV), and porcine torovirus (PToV). In this study, a novel torovirus (antelope torovirus, AToV) was discovered from fecal samples of Tibetan antelopes (Pantholops hodgsonii) with viral loads of 2.10×109 to 1.76×1010 copies/g. The genome of AToV is 28,438 nucleotides (nt) in length encoding six open reading frames (ORFs) with 11 conserved domains in pp1ab and a putative slippery sequence (14171UUUAAAC14177) in the overlapping region of ORF1a and ORF1b. Phylogenetic analysis illustrated strains of AToV form a unique clade within ToVs and comparative analysis showed AToV share relatively low sequence identity with other ToVs in six ORFs (68.2–91.6% nucleotide identity). These data suggested that AToV represents a novel and distinct species of ToVs. Based on the M genes, evolutionary analysis with BEAST of AToV and other ToVs led to a most recent common ancestor estimate of 366years ago. Remarkably, recombination analysis revealed AToV was the unknown parental ToV that once involving in the recombinant events of HE genes of two Dutch strains of BToV (B150 and B155), which indicated that AToV occurred cross-species transmission and existed both in the Netherlands and China. This study revealed a novel torovirus, a natural reservoir host (Tibetan antelope) of toroviruses for the first time, and appealed to further related studies to better understand the diversity of toroviruses.
Evaluating a Memory Clinic Using the RE-AIM Model. The Experience of the “Memory and Neuropsychiatry Clinic” in Hospital Del Salvador, Chile
Authors: Leon Tomas , Castro Loreto , Mascayano Franco , Lawlor Brian , Slachevsky Andrea
Published: September 2021

The development of healthcare services for dementia is key to improving access to care and post-diagnostic support for people living with dementia. Memory Units have emerged as a new healthcare service composed of multidisciplinary teams with the goal of improving diagnosis and/or management of dementia patients. The main objective of this study was to describe and evaluate the Reach and Effectiveness of a Memory Unit in a public hospital in Chile, using the RE-AIM model, a multi-component model that allows for the evaluation of the implementation of ongoing healthcare programs. Regarding “R” (Reach): from March 2018 up to June 2019, a total of 510 patients were referred and assessed. Most patients came from primary care (51.9%) and from outpatient services at the Hospital Salvador (39.2%), particularly from the Neurology (63.3%) and Psychiatry (16.0%) departments. We estimated that our Memory Unit assessed 5.39% of all of the dementia patients living in the area of referral. With respect to “E” (Effectiveness): 419 patients are still being followed up at the Memory Unit. Ninety-one patients (18%) were discharged. Of these, 55 (66%) were referred to primary healthcare, 28 (31%) to other outpatient services, 9 (10%) to a specialized mental healthcare center, and 9 (10%) to a daycare center. Due to the short period of time that the Memory Unit has been operating, no other RE-AIM dimensions could be evaluated at this juncture. To our knowledge, this is the first implementation study of a Memory Unit in Latin America, and the first using the RE-AIM model. Although cultural differences worldwide might play a role in the lack of international guidelines, the publication of the experience of the first year of this unit in Chile could inform new countries about this process. Ongoing challenges include continuing to collect data to complement the RE-AIM evaluation and developing a protocol that can be adopted elsewhere in Chile and Latin America. Further studies are needed to assess the benefits of a Memory Unit in comparison to regular care and to develop a model that assures continuity and coordination of care for people with dementia.
Progressive Stroke Caused by Neurosyphilis With Concentric Enhancement in the Internal Cerebral Artery on High-Resolution Magnetic Resonance Imaging: A Case Report
Authors: Zhang Kejia , Chu Fengna , Wang Chao , Shi Mingchao , Yang Yi
Published: September 2021

Background: Neurosyphilis can initially present as a stroke. However, the general management strategy for stroke may not be effective for this condition. Intracranial vessel wall imaging indicating arteritis can help differentiate neurosyphilis from other causes of stroke.

Case presentation: A 59-year-old Chinese woman presented with an acute infarct in the left basal ganglia and multiple stenoses in the bilateral middle cerebral arteries, anterior cerebral artery, and basilar artery, which aggravated twice, despite antiplatelet treatment. High-resolution magnetic resonance imaging (HR-MRI) suggested concentric enhancement in the left middle cerebral artery. Treponema pallidum test results were positive, suggesting neurosyphilis.

Conclusions: HR-MRI provides valuable information regarding arteritis, which is helpful in differentiating neurosyphilis from other causes of stroke. Antiplatelet medication should be used judiciously for neurosyphilis-related stroke.
Development and Validation of a Patient-Reported Outcome Scale for Tension-Type Headache
Authors: Huang Jinke , Guo Weichi , Li Hui , Xie Runsheng , Shen Min , Wang Huimin
Published: September 2021

Objective: To validate a patient-reported outcome (PRO) measure for patients with tension-type headache (TTH).

Methods: Literature analysis, interview, and group discussion were performed to develop an initial TTH-PRO. Thereafter, the initial scale was pre-evaluation in a small range of patients with TTH, and the expert panel made necessary adjustments based on the content feedback. The clinical test was carried out by using the adjusted initial scale. Based on the test results, the items were screened by the method of classical test theory to form the final scale, and the performance evaluation indicators such as validity, reliability, and responsiveness of the final scale were tested.

Results: The final formed TTH-PRO scale contained three domains, six dimensions, and 30 items. The split-half reliability, Cronbach's α coefficients, and construct validity of the scale were acceptable, as was feasibility. The responsiveness in the physiological domain was fair, but the overall responsiveness still needed further clinical validation.

Conclusions:The TTH-PRO scale has been developed with extensive patient input and demonstrates evidence for reliability and validity. It is complementary to existing evaluation indicators of TTH, emphasizing the patient's experience. Further studies are needed to optimize its items and to verify its clinical applicability for population in more regions and countries.
Endovascular Treatment With and Without Intravenous Thrombolysis in Large Vessel Occlusions Stroke: A Systematic Review and Meta-Analysis
Authors: Li Shuo , Liu Dan-Dan , Lu Guo , Liu Yun , Zhou Jun-Shan , Deng Qi-Wen , Yan Fu-Ling
Published: September 2021

Background: Previous studies have shown conflicting results about the benefits of pretreatment with intravenous thrombolysis before endovascular treatment (EVT) in patients with acute ischemic stroke (AIS) with large vessel occlusions (LVOs). This study aimed to investigate the clinical efficacy and safety of EVT alone vs. bridging therapy (BT) in patients with AIS with LVOs.

Methods: A systematic review with meta-analysis of all available studies comparing clinical outcomes between BT and EVT alone was conducted by searching the National Center for Biotechnology Information/National Library of Medicine PubMed and Web of Science databases for relevant literature from database inception to October 20, 2020.

Results: A total of 93 studies enrolling 45,190 patients were included in the present analysis. In both unadjusted and adjusted analyses, BT was associated with a higher likelihood of 90-day good outcome (crude odds ratio [cOR] 1.361, 95% confidence interval [CI] 1.234–1.502 and adjusted OR [aOR] 1.369, 95% CI 1.217–1.540) and successful reperfusion (cOR 1.271, 95% CI 1.149–1.406 and aOR 1.267, 95% CI 1.095–1.465) and lower odds of 90-day mortality (cOR 0.619, 95% CI 0.560–0.684 and aOR 0.718, 95% CI 0.594–0.868) than EVT alone. The two groups did not differ in the occurrence of symptomatic intracranial hemorrhage (sICH) (cOR 1.062, 95% CI 0.915–1.232 and aOR 1.20, 95% CI 0.95–1.47), 24-h early recovery (cOR 1.306, 95% CI 0.906–1.881 and aOR 1.46, 95% CI 0.46–2.19), and number of thrombectomy device passes ≤ 2 (aOR 1.466, 95% CI 0.983–2.185) after sensitivity analyses and adjustment for publication bias.

Conclusions: BT provides more benefits than EVT alone in terms of clinical functional outcomes without compromising safety in AIS patients with LVOs.
Bibliometric Analysis of Studies on Neuropathic Pain Associated With Depression or Anxiety Published From 2000 to 2020
Authors: Li Kai-Li-Mi , Chen Yu-Meng , Wang Xue-Qiang , Hu Hao-Yu
Published: September 2021

Objective: Neuropathic pain (NP) associated with depression or anxiety is highly prevalent in clinical practice. Publications about NP associated with depression or anxiety increased exponentially from 2000 to 2020. However, studies that applied the bibliometric method in analyzing global scientific research about NP associated with depression or anxiety are rare. This work used the bibliometric method to analyze the publications on NP associated with depression or anxiety between 2000 and 2020.

Method: Publications from 2000 and 2020 were identified from the Thomson Reuters Web of Science (WoS) database. We employed CiteSpace V to conduct the bibliometric study.

Results: A total of 915 articles or reviews were obtained from the WoS database. The number of publications has increased over the last two decades. The USA was the most productive among countries or regions in the field. According to the burst key words, neuroinflammation, hippocampus, safety, and modulation were the hot global research issues in the domain.

Conclusion: Publications about NP associated with depression or anxiety have remarkably increased from 2000 to 2020. These historical opinions about NP associated with depression or anxiety could be an important practical basis for further research into potential development trends.
Cerebroventricular Microinjections of MPTP on Adult Zebrafish Induces Dopaminergic Neuronal Death, Mitochondrial Fragmentation, and Sensorimotor Impairments
Authors: Kalyn Michael , Ekker Marc
Published: September 2021

Mitochondria are dynamic organelles that mediate the energetic supply to cells and mitigate oxidative stress through the intricate balance of fission and fusion. Mitochondrial dysfunction is a prominent feature within Parkinson disease (PD) etiologies. To date, there have been conflicting studies of neurotoxin impact on dopaminergic cell death, mitochondrial function and behavioral impairment using adult zebrafish. Here, we performed cerebroventricular microinjections (CVMIs) of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on adult transgenic zebrafish that resulted in significant reductions in dopaminergic neurons within the telencephalon and olfactory bulbs (OB) of Tg(dat:eGFP) fish. Visualization of mCherry and mitochondrial gene expression analysis in Tg(dat:tom20 MLS:mCherry) fish reveal that MPTP induces mitochondrial fragmentation in dopaminergic neurons and the activation of the pink1/parkin pathway involved mitophagy. Moreover, the loss of dopaminergic neurons translated into a transient locomotor and olfactory phenotype. Taken together, these data can contribute to a better understanding of the mitochondrial impact on dopaminergic survivability.
Pharmacological Rescue of the Brain Cortex Phenotype of Tbx1 Mouse Mutants: Significance for 22q11.2 Deletion Syndrome
Authors: Favicchia Ilaria , Flore Gemma , Cioffi Sara , Lania Gabriella , Baldini Antonio , Illingworth Elizabeth
Published: September 2021

Objectives

Tbx1 mutant mice are a widely used model of 22q11.2 deletion syndrome (22q11.2DS) because they manifest a broad spectrum of physical and behavioral abnormalities that is similar to that found in 22q11.2DS patients. In Tbx1 mutants, brain abnormalities include changes in cortical cytoarchitecture, hypothesized to be caused by the precocious differentiation of cortical progenitors. The objectives of this research are to identify drugs that have efficacy against the brain phenotype, and through a phenotypic rescue approach, gain insights into the pathogenetic mechanisms underlying Tbx1 haploinsufficiency.

Experimental Approach

Disease model: Tbx1 heterozygous and homozygous embryos. We tested the ability of two FDA-approved drugs, the LSD1 inhibitor Tranylcypromine and Vitamin B12, to rescue the Tbx1 mutant cortical phenotype. Both drugs have proven efficacy against the cardiovascular phenotype, albeit at a much reduced level compared to the rescue achieved in the brain.

Methods

In situ hybridization and immunostaining of histological brain sections using a subset of molecular markers that label specific cortical regions or cell types. Appropriate quantification and statistical analysis of gene and protein expression were applied to identify cortical abnormalities and to determine the level of phenotypic rescue achieved.

Results

Cortical abnormalities observed in Tbx1 mutant embryos were fully rescued by both drugs. Intriguingly, rescue was obtained with both drugs in Tbx1 homozygous mutants, indicating that they function through mechanisms that do not depend upon Tbx1 function. This was particularly surprising for Vitamin B12, which was identified through its ability to increase Tbx1 gene expression.

Conclusion

To our knowledge, this is only the second example of drugs to be identified that ameliorate phenotypes caused by the mutation of a single gene from the 22q11.2 homologous region of the mouse genome. This one drug-one gene approach might be important because there is evidence that the brain phenotype in 22q11.2DS patients is multigenic in origin, unlike the physical phenotypes, which are overwhelmingly attributable to Tbx1 haploinsufficiency. Therefore, effective treatments will likely involve the use of multiple drugs that are targeted to the function of specific genes within the deleted region.
Dynamic Changes in the Levels of Amyloid-β42 Species in the Brain and Periphery of APP/PS1 Mice and Their Significance for Alzheimer’s Disease
Authors: Zhang Liding , Yang Changwen , Li Yanqing , Niu Shiqi , Liang Xiaohan , Zhang Zhihong , Luo Qingming , Luo Haiming
Published: September 2021

Although amyloid-β42 (Aβ42) has been used as one of the core biomarkers for Alzheimer’s disease (AD) diagnosis, the dynamic changes of its different forms in the brain, blood, and even intestines and its correlation with the progression of AD disease remain obscure. Herein, we screened Aβ42-specific preferred antibody pairs 1F12/1F12 and 1F12/2C6 to accurately detect Aβ42 types using sandwich ELISA, including total Aβ42, Aβ42 oligomers (Aβ42Os), and Aβ42 monomers (Aβ42Ms). The levels of Aβ42 species in the brain, blood, and intestines of different aged APP/PS1 mice were quantified to study their correlation with AD progression. Total Aβ42 levels in the blood were not correlated with AD progression, but Aβ42Ms level in the blood of 9-month-old APP/PS1 mice was significantly reduced, and Aβ42Os level in the brain was significantly elevated compared to 3-month-old APP/PS1, demonstrating that the levels of Aβ42Ms and Aβ42Os in the blood and brain were correlated with AD progression. Interestingly, in 9-month-old APP/PS1 mice, the level of Aβ42 in the intestine was higher than that in 3-month-old APP/PS1 mice, indicating that the increased level of Aβ42 in the gastrointestinal organs may also be related to the progression of AD. Meanwhile, changes in the gut microbiota composition of APP/PS1 mice with age were also observed. Therefore, the increase in Aβ derived from intestinal tissues and changes in microbiome composition can be used as a potential early diagnosis tool for AD, and further used as an indicator of drug intervention to reduce brain amyloid.
Hippocampal CA1 Neurons Represent Positive Feedback During the Learning Process of an Associative Memory Task
Authors: Takamiya Shogo , Shiotani Kazuki , Ohnuki Tomoya , Osako Yuma , Tanisumi Yuta , Yuki Shoko , Manabe Hiroyuki , Hirokawa Junya , Sakurai Yoshio
Published: September 2021

The hippocampus is crucial for forming associations between environmental stimuli. However, it is unclear how neural activities of hippocampal neurons dynamically change during the learning process. To address this question, we developed an associative memory task for rats with auditory stimuli. In this task, the rats were required to associate tone pitches (high and low) and ports (right and left) to obtain a reward. We recorded the firing activity of neurons in rats hippocampal CA1 during the learning process of the task. As a result, many hippocampal CA1 neurons increased their firing rates when the rats received a reward after choosing either the left or right port. We referred to these cells as “reward-direction cells.” Furthermore, the proportion of the reward-direction cells increased in the middle-stage of learning but decreased after the completion of learning. This result suggests that the activity of reward-direction cells might serve as “positive feedback” signal that facilitates the formation of associations between tone pitches and port choice.
Adolescent's Willingness to Adopt a More Plant-Based Diet: A Theory-Based Interview Study
Authors: Havermans Remco C. , Rutten Geert , Bartelet Dimona
Published: September 2021

A plant-based diet is more sustainable, and research suggests that adolescents obtain health benefits from adopting a more plant-based diet (e.g., improved weight control, increased cardiovascular health). However, it is still unclear what factors promote/hinder their intention to attain such a dietary habit. The aim of the present study was to examine factors affecting adolescents' willingness to consume more plant-based foods. In a theory-based interview study, using the Reasoned Action Approach as framework, adolescents were interviewed concerning their reasons for their (un)willingness to adopt a more plant-based diet. A total of 11 adolescents (15/16 years old; 7 girls, 4 boys) were recruited and interviewed at two secondary schools in the Dutch Province of Limburg, the Netherlands. None of the interviewees reported being vegan/vegetarian/flexitarian. The interviewed adolescents overall expressed little interest in adopting a more plant-based diet. They appeared to have little knowledge of what would comprise a more plant-based diet and showed a lack of awareness of the benefits for personal and planet health. Further, most participants indicated lacking skills to prepare plant-based meals. Despite that, they felt confident they would be able to consume a much more plant-based diet for a definite period. Most importantly, the low intention to consume more plant-based food options was explained by the perceived (or expected) poor taste of these foods. We conclude that education on the plant-based diet (i.e., increasing awareness of the benefits, and skills to procure or prepare a plant-based meal) might increase both knowledge and plant-based food familiarity. The latter being important as food familiarity is key in promoting its acceptance.
Bioelectric Impedance Analysis Test Improves the Detection of Prostate Cancer in Biopsy Candidates: A Multifeature Decision Support System
Authors: Bartoletti Riccardo , Greco Alberto , Di Vico Tommaso , Durante Jacopo , Ficarra Vincenzo , Scilingo Enzo Pasquale , Valenza Gaetano
Published: September 2021

Prostate cancer (PCa) gold-standard diagnosis relies on prostate biopsy, which is currently overly recommended since other available noninvasive tools such as prostate-specific antigen (PSA) multiparametric MRI (mMRI) showed low diagnostic accuracy or high costs, respectively. The aim of the study was to determine the accuracy of a novel Bioelectric Impedance Analysis (BIA) test endorectal probe for the selection of patients candidate to prostate biopsy and in particular the clinical value of three different parameters such as resistance (R), reactance (Xc), and phase angle (PA) degree. One-hundred twenty-three consecutive candidates to prostate biopsy and 40 healthy volunteers were enrolled. PSA and PSA density (PSAD) determinations, Digital Rectal Examination (DRE), and the novel BIA test were analyzed in patients and controls. A 16-core prostate biopsy was performed after a mMRI test. The study endpoints were to determine accuracy of BIA test in comparison with PSA, PSAD levels, and mMRI and obtain prostate cancer (PCa) prediction by BIA test. The Mann-Whitney U-test, the Wilkoxon rank test, and the Holm-Bonferroni’s method were adopted for statistical analyses, and a computational approach was also applied to differentiate patients with PCa from those with benign disease. Combined PSA, PSAD, DRE, and trans-rectal ultrasound test failed to discern patients with PCa from those with benign disease (62.86% accuracy). mMRI PIRADS ≥3 showed a sensitivity of 83% and a specificity of 59%. The accuracy in discerning PCa increased up to 75% by BIA test (sensitivity 63.33% and specificity 83.75%). The novel finger probe BIA test is a cheap and reliable test that may help to improve clinical multifeature noninvasive diagnosis for PCa and reduce unnecessary biopsies.
Role of MRI-Based Functional Imaging in Improving the Therapeutic Index of Radiotherapy in Cancer Treatment
Authors: Li Mei , Zhang Qin , Yang Kaixuan
Published: September 2021

Advances in radiation technology, such as intensity-modulated radiation therapy (IMRT), have largely enabled a biological dose escalation of the target volume (TV) and reduce the dose to adjacent tissues or organs at risk (OARs). However, the risk of radiation-induced injury increases as more radiation dose utilized during radiation therapy (RT), which predominantly limits further increases in TV dose distribution and reduces the local control rate. Thus, the accurate target delineation is crucial. Recently, technological improvements for precise target delineation have obtained more attention in the field of RT. The addition of functional imaging to RT can provide a more accurate anatomy of the tumor and normal tissues (such as location and size), along with biological information that aids to optimize the therapeutic index (TI) of RT. In this review, we discuss the application of some common MRI-based functional imaging techniques in clinical practice. In addition, we summarize the main challenges and prospects of these imaging technologies, expecting more inspiring developments and more productive research paths in the near future.
Prognostic Score for De Novo Metastatic Breast Cancer With Liver Metastasis and Its Predictive Value of Locoregional Treatment Benefit
Authors: Ji Lei , Fan Lei , Zhu Xiuzhi , Gao Yu , Wang Zhonghua
Published: September 2021

Background

There is a significant survival difference and lack of effective treatment among breast cancer patients with liver metastasis. This present study aimed to construct a novel prognostic score for predicting the prognosis and locoregional treatment benefit of de novo metastatic breast cancer with liver metastasis (BCLM).

Methods

In total, 2,398 eligible patients between 2010 and 2016 were selected from the Surveillance, Epidemiology, and End Results (SEER) database. They were assigned to the training set including 1,662 patients (2010–2014) and validation set comprising 736 patients (2015–2016) depending on the time of diagnosis. The prognostic score was based on regression coefficients in the multivariate Cox regression analysis. And then, patients were stratified into low-, intermediate-, and high-risk groups by the prognostic score. The discrimination and calibration of prognostic score were evaluated using time-dependent receiver operating characteristic (ROC) curves analysis and calibration curves, respectively. Subgroup analysis was performed to evaluate locoregional surgery and chemotherapy benefit in different risk groups.

Results

Age, race, insurance and marital status, T stage, pathological grade, molecular subtypes, and extrahepatic metastasis were identified as independent prognostic variables in the prognostic score. The prognostic score showed high discrimination power with an area under the curve (AUC) of 0.77 and 0.72 and excellent agreement suggested by calibration plots in the training and validation sets, respectively. Intermediate-risk [hazard ratio (HR) 2.39, 95% confidence interval (CI) 2.09–2.73, P<0.001] and high-risk groups (HR 4.88; 95% CI 4.13–5.76; P<0.001) had significantly worse prognosis in comparison with the low-risk group. The median overall survival (OS) in three prognostic groups were 44, 18, and 7 months, with a 3-year survival rate of 56, 23, and 7%, respectively. Apart from the high-risk group (HR 0.79; 95% CI 0.56–1.10; P=0.157), the low-risk (HR 0.64; 95% CI 0.49–0.84; P=0.001) and intermediate-risk groups (HR 0.68; 95% CI 0.55–0.85; P=0.001) could benefit from the surgery of primary site, while chemotherapy improved prognosis in all risk groups.

Conclusions

A prognostic score was developed to accurately predict the prognosis of de novo BCLM patients. Moreover, it may be useful for further subdividing them into different risk groups and helping guide clinicians in treatment decisions.
Patterns of Recurrence and Survival Rate After Complete Resection of Pathological Stage N2 Small-Cell Lung Cancer
Authors: Yu Lian , Xu Jianlin , Qiao Rong , Zhong Hua , Han Baohui , Zhong Runbo
Published: September 2021

The benefits of surgical resection for patients with stage N2 limited-disease small-cell lung cancer (LD-SCLC) remain controversial. This retrospective study analyzed the survival and recurrence patterns of the patients diagnosed with pathological N2 (p-N2) LD-SCLC after radical resection. A total of 171 p-N2 LD-SCLC patients who underwent radical pulmonary resection and systematic lymphadenectomies at Shanghai Chest Hospital from July 2005 to June 2015 were enrolled. The influence of the mediastinal lymph node status (single or multiple nodes, single- or multiple-station) on the survival and recurrence patterns was retrospectively analyzed. The main recurrence sites were outside the chest cavity (54.8%) and hematogenous metastasis (67.4%). The bone and liver as initial recurrence sites had a poor prognosis, with a median overall survival (OS) of 13.100 months and 11.900 months, respectively. The median disease-free survival (DFS) of patients diagnosed with single and multiple p-N2 after surgery were 19.233 and 9.367 months (P = 0.001), and the median OS were 43.033 and 17.100 months (P < 0.001), respectively. In conclusion, recurrence occurred in the form of hematogenous metastasis mostly in the extra-thoracic part. Interestingly, patients diagnosed with single p-N2 benefited from radical resection. Surgery may be a treatment option regardless of the T stage if N2 SCLC with a single metastatic lymph node can be identified preoperatively.
Biological Role and Clinical Implications of microRNAs in BRCA Mutation Carriers
Authors: Tommasi Chiara , Pellegrino Benedetta , Boggiani Daniela , Sikokis Angelica , Michiara Maria , Uliana Vera , Bortesi Beatrice , Bonatti Francesco , Mozzoni Paola , Pinelli Silvana , Squadrilli Anna , Viani Maria Vittoria , Cassi Diana , Maglietta Giuseppe , Meleti Marco , Musolino Antonino
Published: September 2021

Women with pathogenic germline mutations in BRCA1 and BRCA2 genes have an increased risk to develop breast and ovarian cancer. There is, however, a high interpersonal variability in the modality and timing of tumor onset in those subjects, thus suggesting a potential role of other individual’s genetic, epigenetic, and environmental risk factors in modulating the penetrance of BRCA mutations. MicroRNAs (miRNAs) are small noncoding RNAs that can modulate the expression of several genes involved in cancer initiation and progression. MiRNAs are dysregulated at all stages of breast cancer and although they are accessible and evaluable, a standardized method for miRNA assessment is needed to ensure comparable data analysis and accuracy of results. The aim of this review was to highlight the role of miRNAs as potential biological markers for BRCA mutation carriers. In particular, biological and clinical implications of a link between lifestyle and nutritional modifiable factors, miRNA expression and germline BRCA1 and BRCA2 mutations are discussed with the knowledge of the best available scientific evidence.
Enhanced CT-Based Radiomics to Predict Micropapillary Pattern Within Lung Invasive Adenocarcinoma
Authors: Xu Yunyu , Ji Wenbin , Hou Liqiao , Lin Shuangxiang , Shi Yangyang , Zhou Chao , Meng Yinnan , Wang Wei , Chen Xiaofeng , Wang Meihao , Yang Haihua
Published: September 2021

Objective

We aimed to investigate whether enhanced CT-based radiomics can predict micropapillary pattern (MPP) of lung invasive adenocarcinoma (IAC) in the pre-op phase and to develop an individual diagnostic predictive model for MPP in IAC.

Methods

170 patients who underwent complete resection for pathologically confirmed lung IAC were included in our study. Of these 121 were used as a training cohort and the other 49 as a test cohort. Clinical features and enhanced CT images were collected and assessed. Quantitative CT analysis was performed based on feature types including first order, shape, gray-level co-occurrence matrix-based, gray-level size zone matrix-based, gray-level run length matrix-based, gray-level dependence matrix-based, neighboring gray tone difference matrix-based features and transform types including Log, wavelet and local binary pattern. Receiver operating characteristic (ROC) and area under the curve (AUC) were used to value the ability to identify the lung IAC with MPP using these characteristics.

Results

Using quantitative CT analysis, one thousand three hundred and seventeen radiomics features were deciphered from R (https://www.r-project.org/). Then these radiomic features were decreased to 14 features after dimension reduction using the least absolute shrinkage and selection operator (LASSO) method in R. After correlation analysis, 5 key features were obtained and used as signatures for predicting MPP within IAC. The individualized prediction model which included age, smoking, family tumor history and radiomics signature had better identification (AUC=0.739) in comparison with the model consisting only of radiomics features (AUC=0.722). DeLong test showed that the difference in AUC between the two models was statistically significant (P<0.01). Compared with the simple radiomics model, the more comprehensive individual prediction model has better prediction performance.

Conclusion

The use of radiomics approach is of great value in the diagnosis of tumors by non-invasive means. The individualized prediction model in the study, when incorporated with age, smoking and radiomics signature, had effective predictive performance of lung IAC with MPP lesions. The combination of imaging features and clinical features can provide additional diagnostic value to identify the micropapillary pattern in IAC and can affect clinical diagnosis and treatment.
The Association of Aberrant Expression of FGF1 and mTOR-S6K1 in Colorectal Cancer
Authors: Duan Tinghui , Zhou Diyuan , Yao Yizhou , Shao Xinyu
Published: September 2021

Colorectal cancer (CRC) is one of the most frequent malignant neoplasms worldwide, and the effect of treatments is limited. Fibroblast growth factor 1 (FGF1) has been involved in a wide variety of several malignant diseases and takes part in the tumorigenesis of CRC. However, the function and mechanism of FGF1 in CRC remains elusive. In this study, the results indicated that FGF1 is elevated in CRC tissues and linked with poor prognosis (P < 0.001). In subgroup analysis of FGF1 in CRC, regardless of any clinic-factors except gender, high level FGF1 expression was associated with markedly shorter survival (P < 0.05). In addition, the expression of p-S6K1 and FGF1 was not associated in normal tissue (P = 0.781), but their expression was closely related in tumor tissue (P = 0.010). The oncogenic role of FGF1 was determined using in vitro and in vivo functional assays. FGF1 depletion inhibited the proliferation and migration of CRC cells in vitro and vivo. FGF1 was also significantly correlated with mTOR-S6K1 pathway on the gene and protein levels (P < 0.05). In conclusion, FGF1 acts as a tumor activator in CRC, and against FGF1 may provide a new visual field on treating CRC, especially for mTORC1-targeted resistant patients.
Downregulation of GNA15 Inhibits Cell Proliferation via P38 MAPK Pathway and Correlates with Prognosis of Adult Acute Myeloid Leukemia With Normal Karyotype
Authors: Li Mengya , Liu Yu , Liu Yajun , Yang Lu , Xu Yan , Wang Weiqiong , Jiang Zhongxing , Liu Yanfang , Wang Shujuan , Wang Chong
Published: September 2021

Background

The prognosis of acute myeloid leukemia (AML) with a normal karyotype is highly heterogonous, and the current risk stratification is still insufficient to differentiate patients from high-risk to standard-risk. Changes in some genetic profiles may contribute to the poor prognosis of AML. Although the prognostic value of G protein subunit alpha 15 (GNA15) in AML has been reported based on the GEO (Gene Expression Omnibus) database, the prognostic significance of GNA15 has not been verified in clinical samples. The biological functions of GNA15 in AML development remain open to investigation. This study explored the clinical significance, biological effects and molecular mechanism of GNA15 in AML.

Methods

Reverse transcription-quantitative polymerase chain reaction (RT-qPCR) was used to detect the mRNA expression level of GNA15 in blasts of bone marrow specimens from 154 newly diagnosed adult AML patients and 26 healthy volunteers. AML cell lines, Kasumi-1 and SKNO-1, were used for lentiviral transfection. Cell Counting Kit-8 (CCK8) and colony formation assays were used to determine cell proliferation. Cell cycle and apoptosis were analyzed by flow cytometry. The relevant signaling pathways were evaluated by Western blot. The Log-Rank test and Kaplan-Meier were used to evaluate survival rate, and the Cox regression model was used to analyze multivariate analysis. Xenograft tumor mouse model was used for in vivo experiments.

Results

The expression of GNA15 in adult AML was significantly higher than that in healthy individuals. Subjects with high GNA15 expression showed lower overall survival and relapse-free survival in adult AML with normal karyotype. High GNA15 expression was independently correlated with a worse prognosis in multivariate analysis. Knockdown of GNA15 inhibited cell proliferation and cell cycle progression, and induced cell apoptosis in AML cells. GNA15-knockdown induced down-regulation of p-P38 MAPK and its downstream p-MAPKAPK2 and p-CREB. Rescue assays confirmed that P38 MAPK signaling pathway was involved in the inhibition of proliferation mediated by GNA15 knockdown.

Conclusions

In summary, GNA15 was highly expressed in adult AML, and high GNA15 expression was independently correlated with a worse prognosis in adult AML with normal karyotype. Knockdown of GNA15 inhibited the proliferation of AML regulated by the P38 MAPK signaling pathway. Therefore, GNA15 may serve as a potential prognostic marker and a therapeutic target for AML in the future.
Overexpression of Circular RNA circ_0013587 Reverses Erlotinib Resistance in Pancreatic Cancer Cells Through Regulating the miR-1227/E-Cadherin Pathway
Authors: Xu Huiting , Chen Runzhi , Shen Qian , Yang Dongmei , Peng Hui , Tong Jin , Fu Qiang
Published: September 2021

Background

Erlotinib, a small-molecule epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor, demonstrated therapeutic efficacy against pancreatic cancer. However, acquired resistance to erlotinib in pancreatic cancer is widely observed, and the exact mechanisms have not been fully explored until now. We examined the role of circular RNA circ_0013587 in the acquired resistance to erlotinib in pancreatic cancer cells and explored the underlying mechanisms.

Methods

We selected erlotinib-resistant pancreatic cancer cells from the AsPC-1 cell line. The expression of circ_0013587 was examined by qRT-PCR assays. The effects of circ_0013587 on pancreatic cancer cell proliferation, invasion, and erlotinib resistance were assessed by cell functional assays. Bioinformatic analysis and dual-luciferase reporter assays identified circ_0013587 and E-cadherin as direct targets of miR-1227. Mouse xenograft models were employed to investigate the function of circ_0013587 in erlotinib resistance of tumors in vivo.

Results

Circ_0013587 expression was significantly reduced in erlotinib-resistant AsPC-1 cells. We found that increasing circ_0013587 levels in erlotinib-resistant AsPC-1 cells re-sensitized them, whereas reducing circ_0013587 levels in erlotinib-sensitive AsPC-1 cells made them resistant. Mechanically, circ_0013587 released E-cadherin from the suppression of miR-1227, leading to E-cadherin up-regulation. Rescue assays highlighted that circ_0013587 reversed erlotinib resistance in pancreatic cancer cells by increasing E-cadherin levels through reducing the expression of miR-1227. Furthermore, circ_0013587 overexpression sensitized erlotinib-resistant AsPC-1 cells to erlotinib in xenograft models.

Conclusions

Our results demonstrated that down-regulation of circ_0013587 contributes to acquired resistance to erlotinib in pancreatic cancer cells through mediating the miR-1227/E-cadherin pathway and that circ_0013587 is a potential target molecular to overcome erlotinib resistance.
Case Report: EBV Chronic Infection and Lymphoproliferation in Four APDS Patients: The Challenge of Proper Characterization, Therapy, and Follow-Up
Authors: Rivalta Beatrice , Amodio Donato , Milito Cinzia , Chiriaco Maria , Di Cesare Silvia , Giancotta Carmela , Conti Francesca , Santilli Veronica , Pacillo Lucia , Cifaldi Cristina , Desimio Maria Giovanna , Doria Margherita , Quinti Isabella , De Vito Rita , Di Matteo Gigliola , Finocchi Andrea , Palma Paolo , Trizzino Antonino , Tommasini Alberto , Cancrini Caterina
Published: September 2021

Activated PI3K-kinase Delta Syndrome (APDS) is an autosomal-dominant primary immunodeficiency (PID) caused by the constitutive activation of the PI3Kδ kinase. The consequent hyperactivation of the PI3K-Akt-mTOR pathway leads to an impaired T- and B-cells differentiation and function, causing progressive lymphopenia, hypogammaglobulinemia and hyper IgM. Patients with APDS show recurrent sinopulmonary and chronic herpes virus infections, immune dysregulation manifestations, including cytopenia, arthritis, inflammatory enteropathy, and a predisposition to persistent non-neoplastic splenomegaly/lymphoproliferation and lymphoma. The recurrence of the lymphoproliferative disorder and the difficulties in the proper definition of malignancy on histological examination represents the main challenge in the clinical management of APDS patients, since a prompt and correct diagnosis is needed to avoid major complications. Targeted therapies with PI3Kδ-Akt-mTOR pathway pharmacologic inhibitors (i.e., Rapamycin, Theophylline, PI3K inhibitors) represent a good therapeutic strategy. They can also be used as bridge therapies when HSCT is required in order to control refractory symptoms. Indeed, treated patients showed a good tolerance, improved immunologic phenotype and reduced incidence/severity of immune dysregulation manifestations. Here, we describe our experience in the management of four patients, one male affected with APDS1 (P1) and the other three, a male and two females, with APDS2 (P2, P3, P4) presenting with chronic EBV replication, recurrent episodes of immune dysregulation manifestations and lymphomas. These cases highlighted the importance of a tailored and close follow-up, including serial endoscopic and lymph nodes biopsies control to detect a prompt and correct diagnosis and offer the best therapeutic strategy.
Case Report: Diffuse Polymicrogyria Associated With a Novel ADGRG1 Variant
Authors: Carneiro Fábio , Duarte Júlia , Laranjeira Francisco , Barbosa-Gouveia Sofia , Couce María-Luz , Fonseca Maria José
Published: September 2021

Pathogenic variants of the ADGRG1 gene are associated with bilateral frontoparietal polymicrogyria, defined radiologically by polymicrogyria with an anterior-posterior gradient, pontine and cerebellar hypoplasia and patchy white matter abnormalities. We report a novel homozygous ADGRG1 variant with atypical features. The patient presented at 8 months of age with motor delay, esotropia, hypotonia with hyporeflexia and subsequently developed refractory epilepsy. At the last assessment, aged 12 years, head control, sitting and language were not acquired. Magnetic resonance imaging revealed diffuse polymicrogyria with relative sparing of the anterior temporal lobes, without an anterior-posterior gradient, diffuse hypomyelination and pontine and cerebellar hypoplasia. A panel targeting brain morphogenesis defects yielded an unreported homozygous ADGRG1 nonsense variant (dbSNP rs746634404), present in the heterozygous state in both parents. We report a novel ADGRG1 variant associated with diffuse polymicrogyria without an identifiable anterior-posterior gradient, diffuse hypomyelination and a severe motor and cognitive phenotype. Our case highlights the phenotypic diversity of ADGRG1 pathogenic variants and the clinico-anatomical overlap between recognized polymicrogyria syndromes.
Early Prediction of Tacrolimus-Induced Tubular Toxicity in Pediatric Refractory Nephrotic Syndrome Using Machine Learning
Authors: Mo Xiaolan , Chen Xiujuan , Ieong Chifong , Gao Xia , Li Yingjie , Liao Xin , Yang Huabin , Li Huiyi , He Fan , He Yanling , Chen Yilu , Liang Huiying , Huang Min , Li Jiali
Published: September 2021

Background and Aims: Tacrolimus(TAC)-induced nephrotoxicity, which has a large individual variation, may lead to treatment failure or even the end-stage renal disease. However, there is still a lack of effective models for the early prediction of TAC-induced nephrotoxicity, especially in nephrotic syndrome(NS). We aimed to develop and validate a predictive model of TAC-induced tubular toxicity in children with NS using machine learning based on comprehensive clinical and genetic variables.

Materials and Methods: A retrospective cohort of 218 children with NS admitted between June 2013 and December 2018 was used to establish the models, and 11 children were prospectively enrolled for external validation. We screened 47 clinical features and 244 genetic variables. The changes in urine N- acetyl- β-D- glucosaminidase(NAG) levels before and after administration was used as an indicator of renal tubular toxicity.

Results: Five machine learning algorithms, including extreme gradient boosting (XGBoost), gradient boosting decision tree (GBDT), extremely random trees (ET), random forest (RF), and logistic regression (LR) were used for model generation and validation. Four genetic variables, including TRPC6 rs3824934_GG, HSD11B1 rs846910_AG, MAP2K6 rs17823202_GG, and SCARB2 rs6823680_CC were incorporated into the final model. The XGBoost model has the best performance: sensitivity 75%, specificity 77.8%, accuracy 77.3%, and AUC 78.9%.

Conclusion: A pre-administration model with good performance for predicting TAC-induced nephrotoxicity in NS was developed and validated using machine learning based on genetic factors. Physicians can estimate the possibility of nephrotoxicity in NS patients using this simple and accurate model to optimize treatment regimen before administration or to intervene in time after administration to avoid kidney damage.
Cardio- and Cerebrovascular Outcomes of Postoperative Acute Kidney Injury in Noncardiac Surgical Patients With Hypertension
Authors: Guangyu Yan , Jingfeng Lou , Xing Liu , Hong Yuan , Yao Lu
Published: September 2021

Background: The cardiovascular and cerebrovascular risk of postoperative acute kidney injury (AKI) in surgical patients is poorly described, especially in the hypertensive population.

Methods: We conducted a retrospective cohort study among all hypertensive patients who underwent elective noncardiac surgery from January 1st, 2012 to August 1st, 2017 at the Third Xiangya Hospital. The primary outcomes were fatal stroke and fatal myocardial infarction (MI). The secondary outcomes were all-cause mortality.

Results: The postoperative cumulative mortality within 3 months, 6 months, 1 year, 2 years, and 5 years were 1.27, 1.48, 2.15, 2.15, and 5.36%, for fatal stroke, and 2.05, 2.27, 2.70, 3.37, and 5.61% for fatal MI, respectively, in patients with postoperative AKI. Compared with non-AKI patients, those with postoperative AKI had a significantly higher risk of fatal stroke and fatal MI within 3 months [hazard ratio (HR): 5.49 (95% CI: 1.88−16.00) and 11.82 (95% CI: 4.56−30.62), respectively], 6 months [HR: 3.58 (95% CI: 1.43−8.97) and 9.23 (95% CI: 3.89−21.90), respectively], 1 year [HR: 3.64 (95% CI: 1.63−8.10) and 5.14 (95% CI: 2.50−10.57), respectively], 2 years [HR: 2.21 (95% CI: 1.03−4.72) and 3.06 (95% CI: 1.66−5.64), respectively], and 5 years [HR: 2.27 (95% CI: 1.30−3.98) and 1.98 (95% CI: 1.16−3.20), respectively]. In subgroup analysis of perioperative blood pressure (BP) lowering administration, postoperative AKI was significantly associated with 1-year and 5-year risk of fatal stroke [HR: 9.46 (95% CI: 2.85−31.40) and 3.88 (95% CI: 1.67−9.01), respectively] in patients with ACEI/ARB, and MI [HR: 6.62 (95% CI: 2.23−19.62) and 2.44 (95% CI: 1.22−4.90), respectively] in patients with CCB.

Conclusion: Hypertensive patients with postoperative AKI have a significantly higher risk of fatal stroke and fatal MI, as well as all-cause mortality, within 5 years after elective noncardiac surgery. In patients with perioperative administration of ACEI/ARB and CCB, postoperative AKI was significantly associated with higher risk of fatal stroke and MI, respectively.