bluuebunny/crossref_metadata_2025 huggingface dataset:
Robust Assessment of EEG Connectivity Patterns in Mild Cognitive Impairment and Alzheimer's Disease
Authors: Clark Ruaridh A. , Smith Keith , Escudero Javier , Ibáñez Agustín , Parra Mario A.
Published: July 2022

The prevalence of dementia, including Alzheimer's disease (AD), is on the rise globally with screening and intervention of particular importance and benefit to those with limited access to healthcare. Electroencephalogram (EEG) is an inexpensive, scalable, and portable brain imaging technology that could deliver AD screening to those without local tertiary healthcare infrastructure. We study EEG recordings of subjects with sporadic mild cognitive impairment (MCI) and prodromal familial, early-onset, AD for the same working memory tasks using high- and low-density EEG, respectively. A challenge in detecting electrophysiological changes from EEG recordings is that noise and volume conduction effects are common and disruptive. It is known that the imaginary part of coherency (iCOH) can generate functional connectivity networks that mitigate against volume conduction, while also erasing true instantaneous activity (zero or π-phase). We aim to expose topological differences in these iCOH connectivity networks using a global network measure, eigenvector alignment (EA), shown to be robust to network alterations that emulate the erasure of connectivities by iCOH. Alignments assessed by EA capture the relationship between a pair of EEG channels from the similarity of their connectivity patterns. Significant alignments—from comparison with random null models—are seen to be consistent across frequency ranges (delta, theta, alpha, and beta) for the working memory tasks, where consistency of iCOH connectivities is also noted. For high-density EEG recordings, stark differences in the control and sporadic MCI results are observed with the control group demonstrating far more consistent alignments. Differences between the control and pre-dementia groupings are detected for significant correlation and iCOH connectivities, but only EA suggests a notable difference in network topology when comparing between subjects with sporadic MCI and prodromal familial AD. The consistency of alignments, across frequency ranges, provides a measure of confidence in EA's detection of topological structure, an important aspect that marks this approach as a promising direction for developing a reliable test for early onset AD.
Diabetic Striatopathy Complicated With Acute Ischemic Stroke: A Case Report
Authors: Huang Xiao , Qi Junli , Li Yiding , Li Jianhui , Yang Meng-Ge
Published: July 2022

Diabetic striatopathy (DS) is a rare complication secondary to hyperglycemia, featured by the choreiform movements and reversible striatal abnormalities on neuroimaging. Several studies have described the clinical characteristics of DS, however, the simultaneous occurrence of DS and acute ischemic stroke (AIS) in the striatum has not been reported. Herein, we report a 68-year-old man with uncontrolled type 2 diabetes who experienced the progressive involuntary movement of the right upper and lower limbs for 10 days. We initially considered this patient as an AIS with hemorrhage in the left basal ganglia and adjacent area because his brain magnetic resonance imaging (MRI) showed hyperintensity on fluid-attenuated inversion recovery (FLAIR) and diffusion-weighted imaging (DWI) images, as well as slight T1-hyperintensity around T1-hypointensity. However, his symptoms worsen persistently, which was inconsistent with neuroimaging findings. Further computed tomography (CT) scan revealed an extensive hyper-density and focal low-density in the left striatum, suggesting the diagnosis of DS and AIS. His symptoms were in complete remission after 2 months of glucose control. However, striatal hyperintensity on T1 images was significantly increased compared to the initial images, which disappeared 18 months later. Additionally, DWI hyperintensity on infarction lesions disappeared, while softening lesions and gliosis were observed on the follow-up MRI images. Therefore, we finally diagnosed the patient as DS complicated with AIS. This report highlights that DS and AIS could occur simultaneously in the striatum after hyperglycemia, which is easily misdiagnosed as AIS with hemorrhage and requires clinicians to pay more attention to avoid misdiagnosis and delayed treatment.
Children’s Neural Sensitivity to Prosodic Features of Natural Speech and Its Significance to Speech Development in Cochlear Implanted Children
Authors: Chen Yuebo , Luo Qinqin , Liang Maojin , Gao Leyan , Yang Jingwen , Feng Ruiyan , Liu Jiahao , Qiu Guoxin , Li Yi , Zheng Yiqing , Lu Shuo
Published: July 2022

Catchy utterances, such as proverbs, verses, and nursery rhymes (i.e., “No pain, no gain” in English), contain strong-prosodic (SP) features and are child-friendly in repeating and memorizing; yet the way those prosodic features encoded by neural activity and their influence on speech development in children are still largely unknown. Using functional near-infrared spectroscopy (fNIRS), this study investigated the cortical responses to the perception of natural speech sentences with strong/weak-prosodic (SP/WP) features and evaluated the speech communication ability in 21 pre-lingually deaf children with cochlear implantation (CI) and 25 normal hearing (NH) children. A comprehensive evaluation of speech communication ability was conducted on all the participants to explore the potential correlations between neural activities and children’s speech development. The SP information evoked right-lateralized cortical responses across a broad brain network in NH children and facilitated the early integration of linguistic information, highlighting children’s neural sensitivity to natural SP sentences. In contrast, children with CI showed significantly weaker cortical activation and characteristic deficits in speech perception with SP features, suggesting hearing loss at the early age of life, causing significantly impaired sensitivity to prosodic features of sentences. Importantly, the level of neural sensitivity to SP sentences was significantly related to the speech behaviors of all children participants. These findings demonstrate the significance of speech prosodic features in children’s speech development.
BDNF Alleviates Microglial Inhibition and Stereotypic Behaviors in a Mouse Model of Obsessive-Compulsive Disorder
Authors: Luo Yuchong , Chen Xiao , Wei Chunren , Zhang Hongyang , Zhang Lingyi , Han Lu , Sun Ke , Li Boxing , Wen Shenglin
Published: July 2022

Obsessive-compulsive disorder (OCD) is a severe mental illness characterized by obsessions and compulsions. However, its underlying mechanisms remain to be elucidated. Recent studies have suggested that neuroimmune dysregulation is involved in the pathogenesis of OCD. To investigate the role of microglia in this disorder, we established a pharmacological mouse model by using the serotonin (5-HT) 1A/1B receptor agonist RU24969 to mimic monoamine dysregulation in OCD, and we examined the morphological and functional alterations of microglia in this model. We found that RU24969 treatment led to compulsive circling behavior in mice. Strikingly, we found that the density and mobility of microglia in the prelimbic cortex were much lower in RU24969-treated mice than in control mice. Moreover, the expression of cytokines and chemokines, including BDNF, IL-1β, IL-6, TNFα, CD80, CD86, MHC-I, and MHC-II, also decreased in RU24969-treated mice. Importantly, we found that injection of BDNF or induction of BDNF expression by trehalose completely reversed microglial dysfunction and reduced stereotypic behavior. These results indicate that microglial dysfunction is closely related to stereotypic behaviors in our mouse model of OCD and that BDNF could be an effective treatment for stereotypic behaviors.
Mesenchymal Stem Cell-Derived Exosomal MiRNAs Promote M2 Macrophages Polarization: Therapeutic Opportunities for Spinal Cord Injury
Authors: Liang Ze-Yan , Xu Xiong-Jie , Rao Jian , Yang Zhe-Lun , Wang Chun-Hua , Chen Chun-Mei
Published: July 2022

Spinal cord injury (SCI) is an enormous public health concern affecting approximately 250,000–500,000 people worldwide each year. It is mostly irreversible considering the limitations of currently available treatments, and its prevention and management have been the prime focus of many studies. Mesenchymal stem cell (MSC) transplantation is one of the most promising treatments for SCI. The role of MSCs in SCI has been studied extensively, and MSCs have been shown to have many limitations. Moreover, the therapeutic effects of MSCs are more likely related to paracrine effects. In SCIs, macrophages from peripheral sources differentiate into M1 macrophages, promoting inflammation and aggravating neuronal damage; however, studies have shown that MSC-derived exosomes can induce the polarization of macrophages from the M1 to the M2 phenotype, thereby promoting nerve function recovery in patients with SCI. In this review, we discussed the research progress of MSC-derived exosomal miRNAs in promoting M2 macrophage differentiation in the SCI, and introduced some exosomal miRNAs that can regulate the differentiation of M2 macrophages in non-SCI; it is hoped that the regulatory role of these exosome-derived miRNAs can be confirmed in SCI.
Characterization, Hypoglycemic Activity, and Antioxidant Activity of Methanol Extracts From Amomum tsao-ko: in vitro and in vivo Studies
Authors: Xie Libin , Yu Dan , Li Yanan , Ju Huidong , Chen Jia , Hu Lianxia , Yu Longquan
Published: July 2022

The dried fruit of Amomum tsao-ko is well-known as a spice as well as a Chinese traditional herb. This study aimed to identify the bioactive constituents in the powder of methanol extract from Amomum tsao-ko (PMEAT) and to evaluate the hypoglycemic and antioxidant effects of PMEAT, in vitro and in vivo. We identified 36 phytochemicals in PMEAT by employing HPLC-MS/MS. PMEAT solution was found to have potent α-glucosidase-inhibiting activity (IC50, 0.145 mg/mL) in vitro, twice as strong as that of acarbose (IC50, 0.273 mg/mL). To investigate the hypoglycemic activity of PMEAT in vivo, we studied the impact of low-dose PMEAT (the addition of 100 mg/kg PMEAT to the mice diet) and high-dose PMEAT (200 mg/kg PMEAT addition) treatments in STZ-induced diabetic mice. After 6 weeks of intervention, significantly decreased fasting blood glucose (FBG) (p < 0.05), significantly decreased area under the curve (AUC) of the oral glucose tolerance test (p < 0.05), significantly decreased HOMA-IR (p < 0.05), and significantly increased HOMA-β (p < 0.05) were observed in the high-dose PMEAT group. Moreover, we performed an antioxidant activity experiment in vitro. The results showed that PMEAT had a strong ability to scavenge DPPH (IC50, 0.044 mg/mL) as well as ABTS free radicals (IC50, 0.040 mg/mL). In an animal experiment conducted on oxidative damage mice model which was induced by D-glucose and a high-fat diet, we observed significantly increased dismutase (SOD) (p < 0.01), glutathione (GSH) (p < 0.01), and glutathione peroxidase (GSH-Px) (p < 0.01) and significantly reduced malondialdehyde (MDA) and 8-ISO-prostaglandin-PGF2α (8-ISO-PGF2α), after treatment with PMEAT for 90 days. In conclusion, this study reveals the therapeutic potential of Amomum tsao-ko for the treatment of diabetes and helps us discover new antioxidant candidates from natural sources.
Healthy Eating Index-2015 and Predicted 10-Year Cardiovascular Disease Risk, as Well as Heart Age
Authors: Zhang Yinyin , Lu Cong , Li Xinyu , Fan Yameng , Li Jiaqiao , Liu Yamei , Yu Yan , Zhou Long
Published: July 2022

Background and Aims

Dietary factor plays an important role in the prevention of cardiovascular disease (CVD). The healthy eating index-2015 (HEI-2015), an indicator of the overall dietary quality, has been introduced to reflect adherence to the 2015–2020 Dietary Guidelines for Americans (DGA). This study aims to explore the associations of the HEI-2015 with predicted 10-year CVD risk and heart age among United States adults aged 30–74 years old using data from the National Health and Nutrition Examination Survey (NHANES) 2011–2014.

Methods and Results

We conducted a cross-sectional analysis among 6,614 participants aged 30–74 years old. The HEI-2015 scores were calculated from 2-days 24-h dietary recall interviews. The 10-year CVD risk and heart age were derived from the sex-specific Framingham general cardiovascular disease risk score. We defined high cardiovascular disease risk as a predicted 10-year cardiovascular disease risk of > 20%. Multiple linear regression and binary logistic regression models were used to investigate the associations of the HEI-2015 with predicted 10-year CVD risk and heart age. Compared with participants in the lowest HEI-2015 quartile, those in the highest quartile had lower predicted 10-year CVD risk (β = −2.37, 95% CI: −3.09 to –1.65, P < 0.0001), lower heart age (β = −2.63, 95% CI: −3.29 to –1.96, P < 0.0001) and lower odds for high risk of CVD (OR = 0.62, 95% CI: 0.49 to 0.80, P-trend < 0.0001) after adjusting for multiple covariates.

Conclusion

Higher adherence to the 2015–2020 Dietary Guidelines for Americans is associated with lower predicted 10-year cardiovascular disease risk and lower heart age among United States adults.
Resistin as a Systemic Inflammation-Related Biomarker for Sarcopenia in Patients With Chronic Obstructive Pulmonary Disease
Authors: Gao Jinghan , Deng Mingming , Li Yanxia , Yin Yan , Zhou Xiaoming , Zhang Qin , Hou Gang
Published: July 2022

Background

Sarcopenia is common in patients with chronic obstructive pulmonary disease (COPD) and is mainly caused by systemic inflammation. Resistin acts as a proinflammatory cytokine and is involved in the activation of multiple inflammatory signaling pathways. The aim of this study was to determine the relationship between resistin levels and systemic inflammation and to assess the clinical value of circulating resistin for sarcopenia in patients with COPD.

Methods

In this prospective observational study, we enrolled 235 patients with COPD who were divided into development and validation sets. The definition of sarcopenia followed the guidelines from the Asian Working Group for Sarcopenia. Serum concentrations of resistin and TNF-α were measured using an enzyme-linked immunosorbent assay (ELISA).

Results

In this study, higher serum resistin levels were significantly associated with lower skeletal muscle mass and muscular strength. The serum resistin levels in patients with sarcopenia were significantly higher than those in patients without sarcopenia. The serum resistin level had positive correlations with the serum TNF-α level (r = 0.250, p = 0.007). The predictive efficacy of the serum resistin level (AUC: 0.828) for sarcopenia was superior to that of the serum TNF-α level (AUC: 0.621). The cutoff point (7.138 ng/ml) for the serum resistin level was validated in the validation set (AUC: 0.818).

Conclusions

Serum resistin levels were associated with systemic inflammation and can be used accurately and easily to predict sarcopenia in patients with COPD.
Antitumor Potential and Structure Characterization of Polysaccharides From Lagotis brevituba Maxim in the Tibetan Plateau
Authors: Gong Ruixue , Cao Weiguo , Huang Haijun , Yu Bao , Chen Huan , Tao Wei , Luorong Quji , Luo Juan , Zhang Dan
Published: July 2022

This study purified two polysaccharides (LBMPs) from Lagotis brevituba Maxim in several steps. The chemical structure of LBMP-2 was determined by HPGPC, FT-IR, IC, 1H and 13C NMR, AFM, SEM, and TEM. The results show that LBMP-2 was mainly composed of GalA, and the Mw of LBMP-2 is 23.799 kDa. In addition, the antioxidant activity, and the antitumor activity in vitro and in vivo were studied. LBMP-2 has excellent antioxidant and antitumor capacity. The inhibition of tumor cell proliferation in vitro may result in the inhibition of aerobic respiration and glycolysis. Tumor growth inhibition in vivo may inhibit the expression of AMPK in tumors and enhance spleen function. Compared with conventional chemotherapy drug cyclophosphamide, LBMP-2 is less harmful to the body and safer. Therefore, LBMP-2 provides a potential source of antitumor drugs.
A Systematic Review and Meta-Analysis of Studies Comparing Concurrent Chemoradiotherapy With Radiotherapy Alone in the Treatment of Stage II Nasopharyngeal Carcinoma
Authors: Xu Yao-Can , Chen Kai-Hua , Liang Zhong-Guo , Zhu Xiao-Dong
Published: July 2022

Purpose

The role of concurrent chemoradiotherapy (CCRT) in stage II nasopharyngeal carcinoma (NPC) is still controversial. Our objective is to evaluate the value of concurrent chemotherapy in stage II NPC receiving radiotherapy (RT).

Methods

We searched the PubMed, Embase, and Scopus databases for studies comparing CCRT versus RT alone in stage II NPC with survival outcomes and toxicities, including locoregional recurrence-free survival (LRFS), metastasis-free survival (DMFS), progression-free survival (PFS), overall survival (OS), and grade 3–4 acute toxicities. The hazard ratios (HRs) of survival outcomes and risk ratios (RRs) of toxicities were extracted for meta-analysis. Subgroup analysis for stage N1 patients was performed to further explore whether these populations can earn benefits from concurrent chemotherapy.

Results

Nine eligible studies with a total of 4,092 patients were included. CCRT was associated with a better OS (HR = 0.61, 95% CI 0.44–0.82), LRFS (HR = 0.62, 95% CI 0.50–0.78), and PFS (HR = 0.65, 95% CI 0.54–0.79), but with similar DMFS (HR = 0.81, 95% CI = 0.46–1.45) compared with two-dimensional RT (2DRT) alone. However, CCRT showed no survival benefit in terms of OS (HR = 0.84, 95% CI 0.62–1.15), LRFS (HR = 0.85, 95% CI 0.54–1.34), DMFS (HR = 0.96, 95% CI 0.60–1.54), and PFS (HR = 0.96, 95% CI 0.66–1.37) compared with intensity-modulated RT (IMRT) alone. Subgroup analyses indicated that CCRT had similar OS (HR = 1.04, 95% CI 0.37–2.96), LRFS (HR = 0.70, 95% CI 0.34–1.45), DMFS (HR = 1.03, 95% CI 0.53–2.00), and PFS (HR = 1.04, 95% CI 0.58–1.88) in the stage N1 populations. Meanwhile, compared to RT alone, CCRT significantly increased the incidence of grade 3–4 leukopenia (RR = 4.00, 95% CI 2.29–6.97), mucositis (RR = 1.43, 95% CI 1.16–1.77), and gastrointestinal reactions (RR = 8.76, 95% CI 2.63–29.12). No significant differences of grade 3–4 toxicity in thrombocytopenia (RR = 3.45, 95% CI 0.85–13.94) was found between the two groups.

Conclusion

For unselected patients with stage II NPC, CCRT was superior to 2DRT alone with better LRFS, PFS, and OS, while adding concurrent chemotherapy to IMRT did not significantly improve survival but exacerbated acute toxicities.

Systematic Review Registration

https://www.crd.york.ac.uk/PROSPERO/, identifier CRD42022318253.
A Pituitary Carcinoma Patient With Cerebrospinal Fluid Dissemination Showing a Good Response to Temozolomide Combined With Whole-Brain and Spinal Cord Radiotherapy: A Case Report and Literature Review
Authors: Du Peng , Wu Xuefan , Lv Kun , Xiong Ji , Geng Daoying
Published: July 2022

Pituitary carcinoma (PC) is extremely rare, with its incidence only accounting for 0.1%-0.2% of pituitary tumor (PT). Existing histological features, including invasiveness, cellular pleomorphism, nuclear atypia, mitosis, necrosis, etc., can be observed in pituitary adenoma (PA), invasive PA (IPA) and PC. Invasion is not the basis for the diagnosis of PC. The diagnosis of PC is often determined after the metastases are found, hence early diagnosis is extraordinarily difficult. Owing to the conventional treatment for PC may not be effective, a large portion of patients survived less than one year after diagnosis. Therefore, it is of great significance to find an efficacious treatment for PC. We report a rare case of sparsely granulated somatotroph carcinoma with cerebrospinal fluid dissemination showing a favorable treatment response to temozolomide (TMZ) combined with whole-brain and spinal cord radiotherapy.
Association of Cell Death Markers With Tumor Immune Cell Infiltrates After Chemo-Radiation in Cervical Cancer
Authors: Oltean Teodora , Lippens Lien , Lemeire Kelly , De Tender Caroline , Vuylsteke Marnik , Denys Hannelore , Vandecasteele Katrien , Vandenabeele Peter , Adjemian Sandy
Published: July 2022

Irradiation induces distinct cellular responses such as apoptosis, necroptosis, iron-dependent cell death (a feature of ferroptosis), senescence, and mitotic catastrophe. Several of these outcomes are immunostimulatory and may represent a potential for immunogenic type of cell death (ICD) induced by radiotherapy triggering abscopal effects. The purpose of this study is to determine whether intra-tumoral ICD markers can serve as biomarkers for the prediction of patient’s outcomes defined as the metastasis status and survival over a 5-year period. Thirty-eight patients with locally advanced cervical cancer, treated with neoadjuvant chemoradiotherapy using cisplatin were included in this study. Pre-treatment tumor biopsy and post-treatment hysterectomy samples were stained for cell death markers and danger associated molecular patterns (DAMPs): cleaved caspase-3 (apoptosis), phosphorylated mixed lineage kinase domain like pseudokinase (pMLKL; necroptosis), glutathione peroxidase 4 (GPX4; ferroptosis) and 4-hydroxy-2-noneal (4-HNE; ferroptosis), high mobility group box 1 (HMGB1) and calreticulin. Although these markers could not predict the patient’s outcome in terms of relapse or survival, many significantly correlated with immune cell infiltration. For instance, inducing ferroptosis post-treatment seems to negatively impact immune cell recruitment. Measuring ICD markers could reflect the impact of treatment on the tumor microenvironment with regard to immune cell recruitment and infiltration.

One Sentence Summary

Cell death readouts during neoadjuvant chemoradiation in cervical cancer
Impact of the Types and Relative Quantities of IGHV Gene Mutations in Predicting Prognosis of Patients With Chronic Lymphocytic Leukemia
Authors: Kaufman Matthew , Yan Xiao-Jie , Li Wentian , Ghia Emanuela M. , Langerak Anton W. , Rassenti Laura Z. , Belessi Chrysoula , Kay Neil E. , Davi Frederic , Byrd John C. , Pospisilova Sarka , Brown Jennifer R. , Catherwood Mark , Davis Zadie , Oscier David , Montillo Marco , Trentin Livio , Rosenquist Richard , Ghia Paolo , Barrientos Jacqueline C. , Kolitz Jonathan E. , Allen Steven L. , Rai Kanti R. , Stamatopoulos Kostas , Kipps Thomas J. , Neuberg Donna , Chiorazzi Nicholas
Published: July 2022

Patients with CLL with mutated IGHV genes (M-CLL) have better outcomes than patients with unmutated IGHVs (U-CLL). Since U-CLL usually express immunoglobulins (IGs) that are more autoreactive and more effectively transduce signals to leukemic B cells, B-cell receptor (BCR) signaling is likely at the heart of the worse outcomes of CLL cases without/few IGHV mutations. A corollary of this conclusion is that M-CLL follow less aggressive clinical courses because somatic IGHV mutations have altered BCR structures and no longer bind stimulatory (auto)antigens and so cannot deliver trophic signals to leukemic B cells. However, the latter assumption has not been confirmed in a large patient cohort. We tried to address the latter by measuring the relative numbers of replacement (R) mutations that lead to non-conservative amino acid changes (Rnc) to the combined numbers of conservative (Rc) and silent (S) amino acid R mutations that likely do not or cannot change amino acids, “(S+Rc) to Rnc IGHV mutation ratio”. When comparing time-to-first-treatment (TTFT) of patients with (S+Rc)/Rnc ≤ 1 and >1, TTFTs were similar, even after matching groups for equal numbers of samples and identical numbers of mutations per sample. Thus, BCR structural change might not be the main reason for better outcomes for M-CLL. Since the total number of IGHV mutations associated better with longer TTFT, better clinical courses appear due to the biologic state of a B cell having undergone many stimulatory events leading to IGHV mutations. Analyses of larger patient cohorts will be needed to definitively answer this question.
A Practical Nomogram and Risk Stratification System Predicting the Cancer-Specific Survival for Patients With Advanced Hepatocellular Carcinoma
Authors: Yang Dashuai , Su Yang , Zhao Fangrui , Chen Chen , Zhao Kailiang , Xiong Xiangyun , Ding Youming
Published: July 2022

Background

Hepatocellular carcinoma (HCC) has the highest cancer-related mortality rate. This study aims to create a nomogram to predict the cancer-specific survival (CSS) in patients with advanced hepatocellular carcinoma.

Methods

Patients diagnosed with advanced HCC (AJCC stage III and IV) during 1975 to 2018 were obtained from the Surveillance, Epidemiology, and End Results (SEER) database. Qualified patents were randomized into training cohort and validation cohort at a ratio of 7:3. The results of univariate and multivariate Cox regression analyses were used to construct the nomogram. Consistency index (C-index), area under the time-dependent receiver operating characteristic (ROC) curve [time-dependent area under the curve (AUC)], and calibration plots were used to identify and calibrate the nomogram. The net reclassification index (NRI), integrated discrimination improvement (IDI), and C-index, and decision curve analysis DCA were adopted to compare the nomogram’s clinical utility with the AJCC criteria.

Results

The 3,103 patients with advanced hepatocellular carcinoma were selected (the training cohort: 2,175 patients and the validation cohort: 928 patients). The C-index in both training cohort and validation cohort were greater than 0.7. The AUC for ROC in the training cohort was 0.781, 0.771, and 0.791 at 1, 2, and 3 years CSS, respectively. Calibration plots showed good consistency between actual observations and the 1-, 2-, and 3-year CSS predicted by the nomogram. The 1-, 2-, and 3-year NRI were 0.77, 0.46, and 0.48, respectively. The 1-, 2-, and 3-year IDI values were 0.16, 0.15, and 0.12 (P < 0.001), respectively. DCA curves in both the training and validation cohorts demonstrated that the nomogram showed better predicted 1-, 2-, and 3-year CSS probabilities than AJCC criteria.

Conclusions

This study established a practical nomogram for predicting CSS in patients with advanced HCC and a risk stratification system that provided an applicable tool for clinical management.
Ewing’s Sarcoma of the Breast in a Young Woman: A Case Report and Review of the Literature
Authors: Papi Simona , Combi Francesca , Segattini Silvia , Accogli Silvia , Palma Enza , Gambini Anna , Andreotti Alessia , Luppi Gabriele , Tazzioli Giovanni
Published: July 2022

Ewing’s Sarcoma Family Tumors (ESFT) include classic Ewing’s sarcoma of bone, extra-skeletal Ewing’s sarcoma (EES), malignant small cell tumor of the chest wall (Askin tumor), and soft tissue-based Peripheral Primitive Neuroectodermal tumors (pPNET). The t(11;22)(q24;q12) translocation is associated with 85% of tumors and leads to EWS-FLI-1 (Ewing’s Sarcoma–Friend Leukemia Integration-1) formation. This is a potent transforming gene that encodes a chimeric protein that plays a role in the genesis of Ewing’s Sarcoma and Primitive Neuroectodermal Tumors. The breast location of ESFT remains exceptional. The prognosis is among the poorest of all subtypes of breast cancer and even poorer than other extraosseous Ewing’s sarcomas. We describe the case report of a 23-year-old patient with a growing breast lump, who required an accurate and challenging diagnostic estimation and who ultimately resulted in a peripheral primary neuroectodermal tumor (pPNET). Through this case description and a brief narrative review of the literature, we aim to highlight the rarity of ESFT located in the breast. Histopathological confirmation is mandatory for all growing masses of the breast to reach a conclusive diagnosis and plan the correct treatment. Patients with rare diagnoses should always be centralized in breast units, conducting multidisciplinary meetings and, when necessary, the diagnosis should be shared through wider national or international registries.
Case Report: Malignant Brain Tumors in Siblings With MSH6 Mutations
Authors: Wu Di , Chen Qingshan , Chen Jian
Published: July 2022

Background

Familial brain tumor incidences are low. Identifying the genetic alterations of familial brain tumors can help better understand the pathogenesis and make therapy regimens for these tumors.

Case Presentation

An elder female and a younger male were diagnosed with brain tumors at the age of 10 and 5, respectively. Whole-genome sequencing analysis of the two patients’ blood, primary brain tumor tissues, and their parents’ blood samples was performed, which revealed that the two tumor samples harbored extremely high somatic mutation loads. Additionally, we observed pigmentation on the male patient’s skin.

Conclusion

Germline, biallelic mutation of MSH6—a gene related to DNA mismatch repair whose defect will result in constitutional mismatch repair deficiency (CMMRD)—is causal for the brain tumors of these two siblings.
“Sandwich” Strategy to Intensify EGFR Blockade by Concurrent Tyrosine Kinase Inhibitor and Monoclonal Antibody Treatment in Highly Selected Patients
Authors: Zhang Guoqing , Yan Beibei , Guo Yanan , Yang Hang , Li Jindong
Published: July 2022

EGFR TKIs are not curative, and targeted resistance inevitably results in therapeutic failure. Additionally, there are numerous uncommon EGFR mutations that are insensitive to EGFR TKIs, and there is a lack of clinical strategies to overcome these limitations. EGFR TKI and mAbs target EGFR at different sites, and a combination regimen for delaying/preventing resistance to targeted therapy or obtaining more intensive inhibition for uncommon mutations at cellular, animal and human levels has been explored. This review critically focuses on a combination strategy for uncommon EGFR mutation-positive NSCLC, and discuss the preclinical data, clinical implications, limitations and future prospects of the combination strategy.
DHW-208, A Novel Phosphatidylinositol 3-Kinase (PI3K) Inhibitor, Has Anti-Hepatocellular Carcinoma Activity Through Promoting Apoptosis and Inhibiting Angiogenesis
Authors: Wang Shu , Wu Yuting , Liu Mingyue , Zhao Qingchun , Jian Lingyan
Published: July 2022

Hepatocellular carcinoma (HCC) is one of the most common tumors worldwide with high prevalence and lethality. Due to insidious onset and lack of early symptoms, most HCC patients are diagnosed at advanced stages without adequate methods but systemic therapies. PI3K/AKT/mTOR signaling pathway plays a crucial role in the progression and development of HCC. Aberrant activation of PI3K/AKT/mTOR pathway is involved in diverse biological processes, including cell proliferation, apoptosis, migration, invasion and angiogenesis. Therefore, the development of PI3K-targeted inhibitors is of great significance for the treatment of HCC. DHW-208 is a novel 4-aminoquinazoline derivative pan-PI3K inhibitor. This study aimed to assess the therapeutic efficacy of DHW-208 in HCC and investigate its underlying mechanism. DHW-208 could inhibit the proliferation, migration, invasion and angiogenesis of HCC through the PI3K/AKT/mTOR signaling pathway in vitro. Consistent with the in vitro results, in vivo studies demonstrated that DHW-208 elicits an antitumor effect by inhibiting the PI3K/AKT/mTOR-signaling pathway with a high degree of safety in HCC. Therefore, DHW-208 is a candidate compound to be developed as a small molecule PI3K inhibitor for the treatment of HCC, and our study provides a certain theoretical basis for the treatment of HCC and the development of PI3K inhibitors.
Solamargine Inhibits the Development of Hypopharyngeal Squamous Cell Carcinoma by Decreasing LncRNA HOXA11-As Expression
Authors: Meng Ying , Jin Mengli , Yuan Dai , Zhao Yicheng , Kong Xiangri , Guo Xuerui , Wang Xingye , Hou Juan , Wang Bingmei , Song Wu , Tang Yong
Published: July 2022

Hypopharyngeal squamous cell carcinoma (HSCC) is one of the high mortality cancers with a poor prognosis, which is driving the development of new chemotherapeutic agents. We identified the anticancer effects of a natural compound, solamargine (SM), on FaDU cells and explored its mechanism in terms of non-coding RNA. It was observed that SM inhibited the proliferation of FaDU cells with an IC50 of 5.17 μM. High-throughput sequencing data revealed that lncRNA HOXA11-AS was significantly downregulated in cells co-incubated with SM. Further assays demonstrated that SM-induced downregulation of lncRNA HOXA11-AS showed important implications for apoptosis. Given the properties of HOXA11-AS as a miR-155 sponge, we further confirmed that SM upregulated the expression of miR-155 in FaDU cells. C-Myc is a transcription factor that regulates cell differentiation and apoptosis, whose mRNA is considered to be targeted by miR-155. We showed that c-Myc expression was downregulated by SM and accompanied by increased apoptosis, which was consistent with the findings of transcriptome sequencing. Furthermore, SM administration suppressed xenograft tumor growth in a xenograft mouse model in vivo. In the light of the aforementioned findings, our results suggested that SM downregulated the expression of HOXA11-AS, which in turn induces apoptosis by downregulating c-Myc in FaDU, providing evidence for the anticancer effect of SM on HSCC and uncovering the effect of SM on non-coding RNAs as, at least partly, a mechanism of action.
Comprehensive Analysis of the Aberrance and Functional Significance of Ferroptosis in Gastric Cancer
Authors: Xiao Jun , Zheng Lingyan , Liu Jingfeng
Published: July 2022

Objective: Ferroptosis is a type of iron-dependent necrosis related to cancer. Nevertheless, the features of ferroptosis in gastric cancer (GC) remain poorly understood. This study conducted a systematic analysis of ferroptosis regulators in GC.

Methods: We gathered five GC cohorts, namely, TCGA-STAD, GSE84437, GSE62254, GSE26901, and GSE15459. Unsupervised clustering analysis was adopted to cluster GC patients into different ferroptosis subtypes based on ferroptosis regulators. Immune cell infiltration and hallmark pathway activity were estimated via ssGSEA. The ferroptosis index was developed with the PCA computational method. Response to chemotherapy agents and small molecular compounds was inferred via GDSC, CTRP, and PRISM projects. Two anti-PD-1 therapy cohorts were gathered and the potential of FPI in predicting immune response was assessed.

Results: Expression profiles, genetic mutations, DNA methylation, prognostic implications, and drug sensitivity of ferroptosis regulators were characterized in GC. Three ferroptosis subtypes were clustered with distinct prognosis, hallmark pathway activity, and tumor-infiltrating immune cells. Ferroptosis levels were quantified based on the expression of prognostic ferroptosis-related signatures. The significant relationships between FPI and clinicopathological characteristics were observed. Furthermore, high FPI was in relation to poor prognosis, inflamed tumor microenvironment (TME) as well as high sensitivity to chemotherapy agents (docetaxel and cisplatin), and CTRP- and PRISM-derived compounds. Also, FPI acted as a promising predictor of immune response.

Conclusion: Collectively, our findings identified a novel ferroptosis-based subtype classification of GC, and revealed the potential of ferroptosis in forming TME diversity and complexity, and guiding individualized treatment.
Reduning Attenuates LPS-Induced Human Unmilical Vein Endothelial Cells (HUVECs) Apoptosis Through PI3K-AKT Signaling Pathway
Authors: Wang Ziyi , Wang Xuesong , Guo Zhe , Liao Haiyan , Chai Yan , Wang Ziwen , Wang Zhong
Published: July 2022

The molecular mechanism of Reduning (RDN) in the treatment of sepsis was analyzed based on network pharmacology. The system pharmacology method was administered to search the active ingredients and targets of RDN, identify the sepsis-related genes, and determine the targets of RDN in the treatment of sepsis. Cytoscape was used to build a “drug component-target” network to screen key compounds. A protein-protein interaction (PPI) network was constructed using STRING, and core targets were revealed through topological analysis. 404 shared targets of RDN and sepsis were introduced into DAVID Bioinformatics Resources 6.8 for GO and KEGG enrichment analysis to predict their possible signaling pathways and explore their molecular mechanisms. GO enrichment analysis highlighted that they were largely related to protein phosphorylation, inflammatory reaction, and positive regulation of mitogen-activated protein kinase (MAPK) cascade. KEGG enrichment analysis outlined that they were enriched in PI3K-AKT signaling pathway, calcium signaling pathway, rhoptry-associated protein 1 (Rap1) signaling pathway, and advanced glycation end products and receptors for advanced glycation end products (AGE-RAGE) signaling pathway. Molecular biological validation results exposed that RDN could significantly improve the protein expression of p-AKT and p-PI3K, alleviate apoptosis-related proteins expression level and decrease apoptosis rate in LPS-induced HUVECs. In conclusion, it was illustrated that RDN could considerably constrain LPS-induced apoptosis by activating the PI3K-AKT signaling pathway, which advocated a basis for fundamental mechanism research and clinical application of RDN in the treatment of sepsis.
Nanostructured Lipid Carrier-Based Delivery of Pioglitazone for Treatment of Type 2 Diabetes
Authors: Ilyas Umair , Asif Muhammad , Wang Minglian , Altaf Reem , Zafar Hajra , Faran Ashraf Baig Mirza Muhammad , Paiva-Santos Ana Cláudia , Abbas Muhammad
Published: July 2022

Pioglitazone (PGZ) is utilized as a therapeutic agent in the management of (type 2) diabetes to control blood glucose levels. The existing research work was intended to make and optimize PGZ-containing NLCs (nanostructured lipid carriers). The fabricated nanostructured lipid carrier preparation was optimized by using different concentrations of the surfactants (Tween 80 and Span 80) and solid lipid (Compritol® 888 ATO) and liquid lipid (Labrasol®) while keeping the concentration of drug (PGZ), and co-surfactants (poloxamer 188) the same. The optimized NLC formulation (PGZ-NLCs) was further assessed for physical and chemical characterization, in vitro PGZ release, and stability studies. The optimized PGZ-NLCs have shown an average diameter of 150.4 nm, EE of 92.53%, PDI value of 0.076, and zeta-potential of −29.1 mV, correspondingly. The DSC thermal analysis and XRD diffractograms had not presented the spectrum of PGZ, confirming the comprehensive encapsulation of PGZ in the lipid core. PGZ-NLCs showed significantly extended release (51% in 24 h) compared to the unformulated PGZ. Our study findings confirmed that PGZ-NLCs can be a promising drug delivery system for the treatment of type 2 diabetes.
Convergent Morphological Evolution in Silene Sect. Italicae (Caryophyllaceae) in the Mediterranean Basin
Authors: Naciri Yamama , Toprak Zeynep , Prentice Honor C. , Hugot Laetitia , Troia Angelo , Burgarella Concetta , Gradaille Josep Lluis , Jeanmonod Daniel
Published: July 2022

Recent divergence can obscure species boundaries among closely related taxa. Silene section Italicae (Caryophyllaceae) has been taxonomically controversial, with about 30 species described. We investigate species delimitation within this section using 500 specimens sequenced for one nuclear and two plastid markers. Despite the use of a small number of genes, the large number of sequenced samples allowed confident delimitation of 50% of the species. The delimitation of other species (e.g., Silene nemoralis, S. nodulosa and S. andryalifolia) was more challenging. We confirmed that seven of the ten chasmophyte species in the section are not related to each other but are, instead, genetically closer to geographically nearby species belonging to Italicae yet growing in open habitats. Adaptation to chasmophytic habitats therefore appears to have occurred independently, as a result of convergent evolution within the group. Species from the Western Mediterranean Basin showed more conflicting species boundaries than species from the Eastern Mediterranean Basin, where there are fewer but better-delimited species. Significant positive correlations were found between an estimation of the effective population size of the taxa and their extent of occurrence (EOO) or area of occupancy (AOO), and negative but non-significant correlations between the former and the posterior probability (PP) of the corresponding clades. These correlations might suggest a lower impact of incomplete lineage sorting in species with low effective population sizes and small distributional ranges compared with that in species inhabiting large areas. Finally, we confirmed that S. italica and S. nemoralis are distinct species, that S. nemoralis might furthermore include two different species and that S. velutina from Corsica and S. hicesiae from the Lipari Islands are sister species.
Transgressive Potential Prediction and Optimal Cross Design of Seed Protein Content in the Northeast China Soybean Population Based on Full Exploration of the QTL-Allele System
Authors: Feng Weidan , Fu Lianshun , Fu Mengmeng , Sang Ziqian , Wang Yanping , Wang Lei , Ren Haixiang , Du Weiguang , Hao Xiaoshuai , Sun Lei , Zhang Jiaoping , Wang Wubin , Xing Guangnan , He Jianbo , Gai Junyi
Published: July 2022

Northeast China is a major soybean production region in China. A representative sample of the Northeast China soybean germplasm population (NECSGP) composed of 361 accessions was evaluated for their seed protein content (SPC) in Tieling, Northeast China. This SPC varied greatly, with a mean SPC of 40.77%, ranging from 36.60 to 46.07%, but it was lower than that of the Chinese soybean landrace population (43.10%, ranging from 37.51 to 50.46%). The SPC increased slightly from 40.32–40.97% in the old maturity groups (MG, MGIII + II + I) to 40.93–41.58% in the new MGs (MG0 + 00 + 000). The restricted two-stage multi-locus genome-wide association study (RTM-GWAS) with 15,501 SNP linkage-disequilibrium block (SNPLDB) markers identified 73 SPC quantitative trait loci (QTLs) with 273 alleles, explaining 71.70% of the phenotypic variation, wherein 28 QTLs were new ones. The evolutionary changes of QTL-allele structures from old MGs to new MGs were analyzed, and 97.79% of the alleles in new MGs were inherited from the old MGs and 2.21% were new. The small amount of new positive allele emergence and possible recombination between alleles might explain the slight SPC increase in the new MGs. The prediction of recombination potentials in the SPC of all the possible crosses indicated that the mean of SPC overall crosses was 43.29% (+2.52%) and the maximum was 50.00% (+9.23%) in the SPC, and the maximum transgressive potential was 3.93%, suggesting that SPC breeding potentials do exist in the NECSGP. A total of 120 candidate genes were annotated and functionally classified into 13 categories, indicating that SPC is a complex trait conferred by a gene network.
Sclerospora graminicola Suppresses Plant Defense Responses by Disrupting Chlorophyll Biosynthesis and Photosynthesis in Foxtail Millet
Authors: Zhang Baojun , Liu Xu , Sun Yurong , Xu Lin , Ren Zhixian , Zhao Yaofei , Han Yuanhuai
Published: July 2022

Downy mildew of foxtail millet is an important oomycete disease caused by Sclerospora graminicola, affecting the yield and quality of the crop. Foxtail millet infected with S. graminicola exhibit symptoms of leaf yellowing and leaf cracking. To uncover the pathogenic mechanism of this disease, we explored the effects on chlorophyll synthesis and photosynthesis of foxtail millet leaves infected by S. graminicola. An elite foxtail millet variety, JG21, susceptible to S. graminicola, was used as for this study. S. graminicola inhibited chlorophyll synthesis and caused loose mesophyll cell arrangement. In addition, some cells were severely vacuolated in S. graminicola-infected foxtail millet leaves at the early stages of infection. S. graminicola could invade the mesophyll cells through haustoria which destroyed the chloroplast structure at the middle stages of infection causing significant accumulation of osmiophilic particles (OPs) and disintegrated chloroplast grana lamellae. Furthermore, foxtail millet leaves split longitudinally at the later stages of infection. Chlorophyll and carotenoid contents in infected leaves decreased significantly compared with those in the control. Net photosynthetic rate (Pn) of leaves and stomatal conductance showed a downward trend, and intercellular carbon dioxide concentrations increased significantly following the infection with S. graminicola. A total of 1,618 differentially expressed genes (DEGs) were detected between the control group and the treatment groups using RNA sequencing (RNA-Seq) among S1–S5 stages. DEGs associated with “photosynthesis” and “light reaction” were enriched. Gene expression patterns showed that 91.3% of 23 genes related to chlorophyll synthesis and photosynthesis, were significantly down-regulated than the control during S1–S5 stages. Based on the gene expression dataset, weighed gene co-expression network analysis (WGCNA) with 19 gene co-expression modules related to photosynthesis revealed six hub genes related to chlorophyll synthesis, which were suppressed during infection. The results suggest that infection of S. graminicola led to weak chlorophyll synthesis and rapid chloroplasts disappearance in foxtail millet. The defense responses and resistance of foxtail millet to S. graminicola were inhibited because chloroplast structure and function were destroyed in leaves, and the sexual reproduction in S. graminicola could be completed rapidly.
Identification and Comprehensive Genome-Wide Analysis of Glutathione S-Transferase Gene Family in Sweet Cherry (Prunus avium) and Their Expression Profiling Reveals a Likely Role in Anthocyanin Accumulation
Authors: Sabir Irfan Ali , Manzoor Muhammad Aamir , Shah Iftikhar Hussain , Liu Xunju , Jiu Songtao , Wang Jiyuan , Alam Pravej , Abdullah Muhammad , Zhang Caixi
Published: July 2022

Glutathione S-transferases (GSTs) in plants are multipurpose enzymes that are involved in growth and development and anthocyanins transportation. However, members of the GST gene family were not identified in sweet cherry (Prunus avium). To identify the GST genes in sweet cherry, a genome-wide analysis was conducted. In this study, we identified 67 GST genes in P. avium genome and nomenclature according to chromosomal distribution. Phylogenetic tree analysis revealed that PavGST genes were classified into seven chief subfamily: TCHQD, Theta, Phi, Zeta, Lambda, DHAR, and Tau. The majority of the PavGST genes had a relatively well-maintained exon–intron and motif arrangement within the same group, according to gene structure and motif analyses. Gene structure (introns-exons) and conserved motif analysis revealed that the majority of the PavGST genes showed a relatively well-maintained motif and exons–introns configuration within the same group. The chromosomal localization, GO enrichment annotation, subcellular localization, syntenic relationship, Ka/Ks analysis, and molecular characteristics were accomplished using various bioinformatics tools. Mode of gene duplication showed that dispersed duplication might play a key role in the expansion of PavGST gene family. Promoter regions of PavGST genes contain numerous cis-regulatory components, which are involved in multiple stress responses, such as abiotic stress and phytohormones responsive factors. Furthermore, the expression profile of sweet cherry PavGSTs showed significant results under LED treatment. Our findings provide the groundwork for future research into induced LED anthocyanin and antioxidants deposition in sweet cherries.