bluuebunny/crossref_metadata_2025 huggingface dataset:
Postoperative Concurrent Chemoradiotherapy for Locally Advanced Thoracic Esophageal Squamous Cell Carcinoma: A Phase II Clinical Trial
Authors: Li Hui , Gu Dayong , Du Mingyu , Zhou Guoren , Zhang Zhi , Ye Jinjun
Published: June 2022

Background

This study aims to investigate the efficacy and safety of postoperative intensity-modulated radiotherapy (IMRT) covering partial regional lymph node areas combined with chemotherapy for locally advanced thoracic esophageal squamous cell carcinoma patients.

Methods

This was a single-center, single-arm phase II clinical trial that began in 2014. Patients who underwent radical transthoracic resection within 3 months and were histologically confirmed esophageal squamous cell carcinoma (pT3-4 or N+, M0 determined according to AJCC Guidelines, Edition 7) were recruited. Postoperative radiotherapy was performed with a total dose of 50.4Gy in 28 fractions using IMRT. Clinical target volumes (CTVs) included tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes. Synchronous chemotherapy for 2 cycles (paclitaxel 150mg/m2, day1; Cisplatin 25mg/m2, day1-3; every 4 weeks), followed by 2 cycles of consolidation chemotherapy with the same regimen. The primary endpoint was the 2-year local control rate, and the secondary endpoints were overall survival (OS) and adverse events (AEs).

Results

A total of 75 eligible patients were included from 2014 to 2017. The 2-year LRFS rate, as the primary endpoint, was 73.3%. The 1-year and 3-year OS rates were 88.0% and 68.0%, respectively. Local recurrence occurred in 13/75 (17.4%) patients, of which 2.7% (2/75) were extra-target lymph nodes. Grade 4 adverse events reported in this study included 10 cases (13.3%) of neutropenia, 1 case (1.3%) of anemia, and 2 cases (2.7%) of thrombocytopenia, without toxic-related deaths. Almost all (96%) patients completed the entire postoperative radiotherapy course, and 62 (82.7%) patients completed at least 2 cycles of chemotherapy.

Conclusion

Postoperative IMRT (clinical target volume including tumor bed, anastomosis, bilateral supraclavicular region, and superior mediastinal lymph nodes) combined with synchronous chemotherapy in patients with locally advanced thoracic esophageal squamous cell carcinoma was well tolerated, with a high local control rate and a low probability of recurrence outside the irradiation field.

Clinical Trial Registration

https://clinicaltrials.gov/ChiCTR1900022689.
Survival Benefit of Surgical Resection for Pancreatic Neuroendocrine Tumors With Oligometastatic Liver Metastasis: A Retrospective and Propensity Score-Matching Analysis
Authors: Yang Zhen , Liang Jie , Leng Kaiming , Shi Guangjun
Published: June 2022

Background

Pancreatic neuroendocrine tumors (PanNETs) are a heterogeneous group of pancreatic malignancies. Surgical resection is the only curative treatment option for patients with localized PanNETs, yet the role of cancer-directed surgery (CDS) in the setting of oligometastatic liver metastasis remains a controversy.

Methods

All patients diagnosed with PanNETs and liver-only metastasis from 2010 to 2018 were identified from the SEER database. The biases of baseline characteristics between CDS and no-CDS cohorts were reduced by the propensity score-matching (PSM) method, and the prognostic role of CDS was estimated using the Kaplan–Meier method and Cox regression models. Logistic regression analysis was utilized to identify factors associated with patients who underwent CDS.

Results

A total of 1,270 PanNET patients with oligometastatic liver metastasis were included and analyzed. Of these patients, 283 (22.3%) patients underwent CDS of the primary tumor, while the remaining 987 (77.7%) did not. The OS and CSS were significantly better in the CDS cohort regardless of the propensity score analysis. Multivariate analysis revealed that age, tumor differentiation, tumor location, and lymph node status were significantly associated with patients who were more likely to receive CDS.

Conclusion

Our study demonstrated that CDS was associated with survival benefits in selected patients with PanNETs and liver-only metastasis based on a large population database.
The Prognostic and Clinical Value of Tumor-Associated Macrophages in Patients With Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Wang Changjun , Lin Yan , Zhu Hanjiang , Zhou Yidong , Mao Feng , Huang Xin , Sun Qiang , Li Chenggang
Published: June 2022

Background

The prognostic and clinical value of tumor-associated macrophages (TAMs) in patients with breast cancer (BCa) remains unclear. We conducted the current meta-analysis to systematically evaluate the association of CD68+ and CD163+ TAM density with the prognosis and clinicopathologic features of BCa patients.

Methods

Searches of Web of Science, PubMed, and EMBASE databases were performed up to January 31, 2022. The meta-analysis was conducted using hazard risks (HRs) and 95% confidence intervals (CIs) for survival data including overall survival (OS), disease-free survival (DFS), and BCa specific survival. Sensitivity and meta-regression analyses were also conducted to identify the robustness of the pooled estimates.

Results

Our literature search identified relevant articles involving a total of 8,496 patients from 32 included studies. Our analysis indicates that a high CD68+ TAM density in the tumor stoma was significantly linked with poor OS (HR 2.46, 95% CI, 1.83–3.31, P<0.001) and shorter DFS (HR 1.77, 95% CI, 1.08–2.89, P=0.02) compared to low CD68+ TAM density. A significant association was also found in the tumor nest. Analysis of CD163+ TAM density showed similar results (all P<0.001). Notably, the pooled analysis with multivariate-adjusted HRs for OS and DFS also found that a high TAM density was significantly related to poorer outcomes for BCa patients (all P<0.05). In addition, BCa patients with high TAM density were more likely to have larger tumors, no vascular invasion, and positive estrogen receptor expression (all P<0.05).

Conclusion

This meta-analysis indicates that a high CD68+ and CD163+ TAM density is associated with poor OS and shorter DFS in BCa patients. Further clinical studies and in vivo experiments are needed to elucidate the underlying mechanism of TAMs.

Systematic Review Registration

https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42022304853, identifier CRD42022304853.
From Transcriptomics, Metabolomics to Functional Studies: Extracellular ATP Induces TGF-β-Like Epithelial Mesenchymal Transition in Lung Cancer Cells
Authors: Evers Maria , Song Jingwen , Shriwas Pratik , Greenbaum Harrison S. , Chen Xiaozhuo
Published: June 2022

We and others previously showed that extracellular ATP (eATP) is implicated in epithelial mesenchymal transition (EMT). However, the mechanisms by which eATP induces EMT and ATP’s relationship to TGF-β, a well-known EMT inducer, are largely unclear. Also, eATP-induced EMT has never been studied at transcriptomic and metabolomics levels. Based on our previous studies, we hypothesized that eATP acts as a specific inducer and regulator of EMT at all levels in cancer cells. RNAseq and metabolomics analyses were performed on human non-small cell lung cancer (NSCLC) A549 cells treated with either eATP or TGF-β. Bio-functional assays, such as invasion, intracellular ATP, cell proliferation, cytoskeleton remodeling, and others were conducted in NSCLC A549 and H1299 cells to validate changes observed from RNAseq and metabolomics studies. In the RNAseq study, eATP significantly enriched expressions of genes involved in EMT similarly to TGF-β after 2 and 6 hours of treatment. Samples treated with eATP for 2 hours share 131 upregulated EMT genes with those of TGF-β treated samples, and 42 genes at 6 hours treatment. Eleven genes, with known or unknown functions in EMT, are significantly upregulated by both inducers at both time points, have been identified. BLOC1S6, one of the 11 genes, was selected for further study. eATP induced numerous EMT-related changes in metabolic pathways, including cytoskeleton rearrangement, glycolysis, glutaminolysis, ROS, and individual metabolic changes similar to those induced by TGF-β. Functional bioassays verified the findings from RNAseq and metabolomics that eATP EMT-like changes in A549 and H1299 cells similarly to TGF-β. BLOC1S6 was found to be implicated in EMT. In these studies, eATP-induced EMT, at all levels examined, is similar but non-identical to that induced by TGF-β, and functions in such a way that exogenous addition of TGF-β is unnecessary for the induction. The study of BLOC1S6 further verified its potential roles in EMT and the RNAseq analysis results. All these strongly indicate that eATP is a multi-functional and multi-locational inducer and regulator of EMT, changing our thinking on how EMT is induced and regulated and pointing to new directions for inhibiting EMT in cancer.
Multiphasic CT-Based Radiomics Analysis for the Differentiation of Benign and Malignant Parotid Tumors
Authors: Yu Qiang , Wang Anran , Gu Jinming , Li Quanjiang , Ning Youquan , Peng Juan , Lv Fajin , Zhang Xiaodi
Published: June 2022

Objective

This study aims to investigate the value of machine learning models based on clinical-radiological features and multiphasic CT radiomics features in the differentiation of benign parotid tumors (BPTs) and malignant parotid tumors (MPTs).

Methods

This retrospective study included 312 patients (205 cases of BPTs and 107 cases of MPTs) who underwent multiphasic enhanced CT examinations, which were randomly divided into training (N = 218) and test (N = 94) sets. The radiomics features were extracted from the plain, arterial, and venous phases. The synthetic minority oversampling technique was used to balance minority class samples in the training set. Feature selection methods were done using the least absolute shrinkage and selection operator (LASSO), mutual information (MI), and recursive feature extraction (RFE). Two machine learning classifiers, support vector machine (SVM), and logistic regression (LR), were then combined in pairs with three feature selection methods to build different radiomics models. Meanwhile, the prediction performances of different radiomics models based on single phase (plain, arterial, and venous phase) and multiphase (three-phase combination) were compared to determine which model construction method and phase were more discriminative. In addition, clinical models based on clinical-radiological features and combined models integrating radiomics features and clinical-radiological features were established. The prediction performances of the different models were evaluated by the area under the receiver operating characteristic (ROC) curve (AUC) and the drawing of calibration curves.

Results

Among the 24 established radiomics models composed of four different phases, three feature selection methods, and two machine learning classifiers, the LASSO-SVM model based on a three-phase combination had the optimal prediction performance with AUC (0.936 [95% CI = 0.866, 0.976]), sensitivity (0.78), specificity (0.90), and accuracy (0.86) in the test set, and its prediction performance was significantly better than with the clinical model based on LR (AUC = 0.781, p = 0.012). In the test set, the combined model based on LR had a lower AUC than the optimal radiomics model (AUC = 0.933 vs. 0.936), but no statistically significant difference (p = 0.888).

Conclusion

Multiphasic CT-based radiomics analysis showed a machine learning model based on clinical-radiological features and radiomics features has the potential to provide a valuable tool for discriminating benign from malignant parotid tumors.
FBXO9 Mediates the Cancer-Promoting Effects of ZNF143 by Degrading FBXW7 and Facilitates Drug Resistance in Hepatocellular Carcinoma
Authors: Wang Zhenyu , Chen Xiaoxia , Zhou Lianer , Zhao Xinge , Ge Chao , Zhao Fangyu , Xie Haiyang , Chen Taoyang , Tian Hua , Li Hong , Li Jinjun
Published: June 2022

F-box proteins are critical for malignancy because they control the turnover of key proteins that govern multiple cellular processes. F-box protein 9 (FBXO9) belongs to the F-box protein family and exhibits oncogenic properties in hematological malignancies. However, the function and molecular mechanism of FBXO9 in hepatocellular carcinoma (HCC) remain unclear. Here, we report that FBXO9 was remarkably overexpressed in HCC. Loss- and gain-of-function experiments showed that FBXO9 facilitates HCC cell proliferation and metastasis both in vitro and in vivo. Mechanistically, as a direct upstream transcription factor, FBXO9 is regulated by zinc finger protein 143 (ZNF143) and accelerates tumor growth and metastasis by targeting the F-box and WD repeat domain containing 7 (FBXW7) for ubiquitination and degradation. Additionally, we found that with FBXO9 knockdown, HCC cells were more sensitive to treatment with lenvatinib and sorafenib. In summary, our results demonstrate that a ZNF143-FBXO9-FBXW7 signaling regulatory axis may be involved in tumor progression in HCC, and suggest that FBXO9 could be a potential biomarker and therapeutic target for HCC.
Next-Generation Sequencing Analysis of Gastric Cancer Identifies the Leukemia Inhibitory Factor Receptor as a Driving Factor in Gastric Cancer Progression and as a Predictor of Poor Prognosis
Authors: Di Giorgio Cristina , Marchianò Silvia , Marino Elisabetta , Biagioli Michele , Roselli Rosalinda , Bordoni Martina , Bellini Rachele , Urbani Ginevra , Zampella Angela , Distrutti Eleonora , Donini Annibale , Graziosi Luigina , Fiorucci Stefano
Published: June 2022

Gastric cancer (GC) is the third cause of cancer-related mortality worldwide. Nevertheless, because GC screening programs are not cost-effective, most patients receive diagnosis in the advanced stages, when surgical options are limited. Peritoneal dissemination occurs in approximately one-third of patients with GC at the diagnosis and is a strong predictor of poor outcome. Despite the clinical relevance, biological and molecular mechanisms underlying the development of peritoneal metastasis in GC remain poorly defined. Here, we report results of a high-throughput sequencing of transcriptome expression in paired samples of non-neoplastic and neoplastic gastric samples from 31 patients with GC with or without peritoneal carcinomatosis. The RNA-seq analysis led to the discovery of a group of highly upregulated or downregulated genes, including the leukemia inhibitory factor receptor (LIFR) and one cut domain family member 2 (ONECUT2) that were differentially modulated in patients with peritoneal disease in comparison with patients without peritoneal involvement. Both LIFR and ONECUT2 predicted survival at univariate statistical analysis. LIFR and its major ligand LIF belong to the interleukin-6 (IL-6) cytokine family and have a central role in immune system regulation, carcinogenesis, and dissemination in several human cancers. To confirm the mechanistic role of the LIF/LIFR pathway in promoting GC progression, GC cell lines were challenged in vitro with LIF and a LIFR inhibitor. Among several GC cell lines, MKN45 cells displayed the higher expression of the receptor, and their exposure to LIF promotes a concentration-dependent proliferation and epithelial–mesenchymal transition (EMT), as shown by modulation of relative expression of E-cadherin/vimentin along with JAK and STAT3 phosphorylation and acquisition of a migratory phenotype. Furthermore, exposure to LIF promoted the adhesion of MKN45 cells to the peritoneum in an ex vivo assay. These effects were reversed by the pharmacological blockade of LIFR signaling. Together, these data suggest that LIFR might have a major role in promoting disease progression and peritoneal dissemination in patients with GC and that development of LIF/LIFR inhibitors might have a role in the treatment of GC.
Secondary Brain Injury Following Neonatal Intraventricular Hemorrhage: The Role of the Ciliated Ependyma
Authors: Dawes William
Published: June 2022

Intraventricular hemorrhage is recognized as a leading cause of hydrocephalus in the developed world and a key determinant of neurodevelopmental outcome following premature birth. Even in the absence of haemorrhagic infarction or posthaemorrhagic hydrocephalus, there is increasing evidence of neuropsychiatric and neurodevelopmental sequelae. The pathophysiology underlying this injury is thought to be due to a primary destructive and secondary developmental insult, but the exact mechanisms remain elusive and this has resulted in a paucity of therapeutic interventions. The presence of blood within the cerebrospinal fluid results in the loss of the delicate neurohumoral gradient within the developing brain, adversely impacting on the tightly regulated temporal and spatial control of cell proliferation and migration of the neural stem progenitor cells within the subventricular zone. In addition, haemolysis of the erythrocytes, associated with the release of clotting factors and leucocytes into the cerebrospinal (CSF), results in a toxic and inflammatory CSF microenvironment which is harmful to the periventricular tissues, resulting in damage and denudation of the multiciliated ependymal cells which line the choroid plexus and ventricular system. The ependyma plays a critical role in the developing brain and beyond, acting as both a protector and gatekeeper to the underlying parenchyma, controlling influx and efflux across the CSF to brain interstitial fluid interface. In this review I explore the hypothesis that damage and denudation of the ependymal layer at this critical juncture in the developing brain, seen following IVH, may adversely impact on the brain microenvironment, exposing the underlying periventricular tissues to toxic and inflammatory CSF, further exacerbating disordered activity within the subventricular zone (SVZ). By understanding the impact that intraventricular hemorrhage has on the microenvironment within the CSF, and the consequences that this has on the multiciliated ependymal cells which line the neuraxis, we can begin to develop and test novel therapeutic interventions to mitigate damage and reduce the associated morbidity.
Effect of Invasive Mechanical Ventilation at Birth on Lung Function Later in Childhood
Authors: Di Filippo Paola , Dodi Giulia , Di Pillo Sabrina , Chiarelli Francesco , Attanasi Marina
Published: June 2022

Background

Despite recent neonatal care improvements, mechanical ventilation still remains a major cause of lung injury and inflammation. There is growing literature on short- and long-term respiratory outcomes in infants born prematurely in the post-surfactant era, but the exclusive role of mechanical ventilation at birth in lung function impairment is still unclear. The aim of this study was to assess the effect of neonatal mechanical ventilation on lung function parameters in children born ≤ 32 weeks of gestational age at 11 years of age.

Materials and Methods

In total, 55 ex-preterm children born between January 1, 2006 and December 31, 2007 were enrolled at 11 years of age. Neonatal information was obtained from medical records. Information about family and personal clinical history was collected by questionnaires. At 11 years of age, we measured spirometry parameters, lung volumes, diffusing lung capacity, and fractional exhaled nitric oxide. In addition, an allergy evaluation by skin prick test and eosinophil blood count were performed. A multivariable linear or logistic regression analysis was performed to examine the associations of mechanical ventilation with respiratory outcomes, adjusting for confounders (maternal smoking during pregnancy, gestational age, surfactant replacement therapy, and BMI).

Results

No difference in lung function evaluation between ventilated and unventilated children were found. No association was also found between mechanical ventilation with lung function parameters.

Conclusion

Mechanical ventilation for a short period at birth in preterm children was not associated with lung function impairment at 11 years of age in our study sample. It remains to define if ventilation may have a short-term effect on lung function, not evident at 11 years of age.
Elastic Stable Intramedullary Nailing and Temporary External Fixation for the Treatment of Unstable Femoral Shaft Fractures in Children Aged 5-11 Years Old: A Retrospective Study of 28 Cases
Authors: Lu Yunan , Canavese Federico , Lin Ran , Chen Jinchen , Chen Yibin , Huang Yuling , Chen Shunyou
Published: June 2022

Purpose

Unstable femoral shaft fractures (UFSFs) in children aged 5–11 years remain challenging due to their intrinsic instability. The aim of this study was to evaluate the clinical and radiographic outcomes of UFSF in children aged 5 to 11 years managed by the combined use of ESIN and temporary EF.

Methods

Children with UFSF (long oblique and comminuted) treated by ESIN and temporary EF were retrospectively reviewed. Sex, age at injury, side involved, type of fracture, presence or absence of associated lesions or neurovascular complications, type of treatment, time from trauma to surgery, duration of surgery, radiation exposure and length of postoperative immobilization were collected from the medical charts. Radiological and functional outcomes were evaluated according to Beaty's and Flynn's criteria, respectively.

Results

A total of 28 consecutive patients with closed or open (Gustilo type I or II) UFSF were reviewed (18 boys and 10 girls). The mean age at injury was 8.7 ± 1.6 years (range, 5–11); the average weight was 38.1 ± 7.6 kg (range, 26–55). The mean hospital stay was 3.7 ± 1.4 days (range, 2–7), and the mean time to EF and ESIN removal was 6.5 ± 1.1 weeks (range, 4–8) and 9.4 ± 1.6 months (range, 6–12), respectively. Twenty-seven out of 28 patients had excellent radiographic outcomes according to Beaty's criteria, and 24/28 had excellent functional outcomes according to Flynn's criteria. Overall, 4 complications (14.3%) were recorded. No statistically significant correlation was found between complication rates and sex, age, weight or fracture characteristics (P < 0.05).

Conclusions

The combined use of ESIN and temporary EF provides good clinical and radiological outcomes in children with UFSF aged between 5 and 11 years, with a reduced complication rate.
Early-Life Exposure to Non-Absorbable Broad-Spectrum Antibiotics Affects the Dopamine Mesocorticolimbic Pathway of Adult Rats in a Sex-Dependent Manner
Authors: González-Arancibia Camila , Collio Victoria , Silva-Olivares Francisco , Montaña-Collao Paula , Martínez-Pinto Jonathan , Julio-Pieper Marcela , Sotomayor-Zárate Ramón , Bravo Javier A.
Published: June 2022

Gut microbiota with a stable, rich, and diverse composition is associated with adequate postnatal brain development. Colonization of the infant’s gut begins at birth when parturition exposes the newborn to a set of maternal bacteria, increasing richness and diversity until one to two first years of age when a microbiota composition is stable until old age. Conversely, alterations in gut microbiota by diet, stress, infection, and antibiotic exposure have been associated with several pathologies, including metabolic and neuropsychiatric diseases such as obesity, anxiety, depression, and drug addiction, among others. However, the consequences of early-life exposure to antibiotics (ELEA) on the dopamine (DA) mesocorticolimbic circuit are poorly studied. In this context, we administered oral non-absorbable broad-spectrum antibiotics to pregnant Sprague-Dawley dams during the perinatal period (from embryonic day 18 until postnatal day 7) and investigated their adult offspring (postnatal day 60) to assess methylphenidate-induced conditioned place preference (CPP) and locomotor activity, DA release, DA and 3,4-dihydroxyphenylacetic acid (DOPAC) content in ventral tegmental area (VTA), and expression of key proteins within the mesocorticolimbic system. Our results show that ELEA affect the rats conduct by increasing drug-seeking behavior and locomotor activity induced by methylphenidate of males and females, respectively, while reducing dopamine striatal release and VTA content of DOPAC in females. In addition, antibiotics increased protein levels of DA type 1 receptor in prefrontal cortex and VTA of female rats, and tyrosine hydroxylase in VTA of adult male and female rats. Altogether, these results suggest that ELEA alters the development of the microbiota-gut-brain axis affecting the reward system and the response to abuse drugs in adulthood.
Clinical Efficacy Protocol of Yinhuapinggan Granules: A Randomized, Double-Blind, Parallel, and Controlled Clinical Trial Program for the Intervention of Community-Acquired Drug-Resistant Bacterial Pneumonia as a Complementary Therapy
Authors: Wang Jiaoli , Hu Haoran , Du Haixia , Luo Man , Cao Yilan , Xu Jiaping , Chen Tianhang , Guo Yilei , Li Qixiang , Chen Wen , Zhang Yifei , Han Jin , Wan Haitong
Published: June 2022

Background: Community-acquired bacterial pneumonia (CABP) is an important health care concern in the worldwide, and is associated with significant morbidity, mortality, and health care expenditure. Streptococcus pneumoniae is the most frequent causative pathogen of CABP. Common treatment for hospitalized patients with CABP is empiric antibiotic therapy using β-lactams in combination with macrolides, respiratory fluoroquinolones, or tetracyclines. However, overuse of antibiotics has led to an increased incidence of drug-resistant S. pneumoniae, exacerbating the development of community-acquired drug-resistant bacterial pneumonia (CDBP) and providing a challenge for physicians to choose empirical antimicrobial therapy.

Methods: Traditional Chinese medicine (TCM) is widely used as a complementary treatment for CDBP. Yinhuapinggan granules (YHPG) is widely used in the adjuvant treatment of CDBP. Experimental studies and small sample clinical trials have shown that YHPG can effectively reduce the symptoms of CDBP. However, there is a lack of high-quality clinical evidence for the role of YHPG as a complementary drug in the treatment of CDBP. Here, we designed a randomized, double-blind, placebo-controlled clinical trial to explore the efficacy and safety of YHPG. A total of 240 participants will be randomly assigned to the YHPG or placebo group in a 1:1 ratio. YHPG and placebo will be added to standard treatment for 10 days, followed by 56 days of follow-up. The primary outcome is the cure rate of pneumonia, and the secondary outcomes includes conversion rate of severe pneumonia, lower respiratory tract bacterial clearance, lactic acid (LC) clearance rate, temperature, C-reactive protein (CRP), criticality score (SMART-COP score), acute physiological and chronic health assessment system (APACHEII score) and clinical endpoint events. Adverse events will be monitored throughout the trial. Data will be analyzed according to a pre-defined statistical analysis plan. This research will disclose the efficacy of YHPG in acquired drug-resistant pneumonia.

Clinical Trial Registration: https://clinicaltrials.gov, identifier ChiCTR2100047501
Cost-Effectiveness of Apatinib and Cabozantinib for the Treatment of Radioiodine-Refractory Differentiated Thyroid Cancer
Authors: Shi Bo , Ma Wenbiao , Pan Hongshuai , Shi Yang , Zhang Huan , Xing Shenghai
Published: June 2022

Background: The effectiveness of apatinib and cabozantinib for the treatment of radioactive iodine–refractory differentiated thyroid cancer (RAIR-DTC) has been demonstrated recently. We aimed to evaluate the cost-effectiveness of these treatments from the Chinese healthcare system perspective.

Methods: Two partitioned survival models over a 10-year horizon were built to compare the cost and effectiveness of apatinib vs. placebo and cabozantinib vs. placebo based on the clinical data from the phase 3 randomized REALITY and COSMIC-311 trials. Costs and utility data were obtained from the literature and institutional database. The incremental cost-effectiveness ratio (ICER) was calculated. One-way and probabilistic sensitivity analysis was performed to test the robustness of the conclusion.

Results: Apatinib yielded an additional quality-adjusted life-year (QALY) of 0.74 at an additional cost of Chinese Renminbi ¥44,077. The ICER was ¥93,460 (US dollar $13545)/QALY and it was below the current willingness-to-pay (WTP) threshold of ¥217341/QALY. Cabozantinib was associated with an additional QALY of 0.79 at an extra cost of ¥3,55,614 when compared with placebo, and the ICER was ¥4,52,325 ($65,554)/QALY, which was above the WTP threshold. The conclusion were robust under one-way and probabilistic sensitivity analysis. The price of cabozantinib has to drop to ¥5.87/mg (39% of the current price) for it has a 50% likelihood of being cost-effective.

Conclusion: Apatinib is cost-effective for RAIR-DTC when compared with placebo from the perspective of Chinese healthcare system. However, based on the current evidence, cabozantinib might not be cost-effective and a reduction of price is warranted.
Therapeutic Targeting of Innate Immune Receptors Against SARS-CoV-2 Infection
Authors: Farooq Mariya , Khan Abdul Waheed , Ahmad Bilal , Kim Moon Suk , Choi Sangdun
Published: June 2022

The innate immune system is the first line of host’s defense against invading pathogens. Multiple cellular sensors that detect viral components can induce innate antiviral immune responses. As a result, interferons and pro-inflammatory cytokines are produced which help in the elimination of invading viruses. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) belongs to Coronaviridae family, and has a single-stranded, positive-sense RNA genome. It can infect multiple hosts; in humans, it is responsible for the novel coronavirus disease 2019 (COVID-19). Successful, timely, and appropriate detection of SARS-CoV-2 can be very important for the early generation of the immune response. Several drugs that target the innate immune receptors as well as other signaling molecules generated during the innate immune response are currently being investigated in clinical trials. In this review, we summarized the current knowledge of the mechanisms underlying host sensing and innate immune responses against SARS-CoV-2 infection, as well as the role of innate immune receptors in terms of their therapeutic potential against SARS-CoV-2. Moreover, we discussed the drugs undergoing clinical trials and the FDA approved drugs against SARS-CoV-2. This review will help in understanding the interactions between SARS-CoV-2 and innate immune receptors and thus will point towards new dimensions for the development of new therapeutics, which can be beneficial in the current pandemic.
Characterization of ADME Gene Variation in Colombian Population by Exome Sequencing
Authors: Silgado-Guzmán Daniel Felipe , Angulo-Aguado Mariana , Morel Adrien , Niño-Orrego María José , Ruiz-Torres Daniel-Armando , Contreras Bravo Nora Constanza , Restrepo Carlos Martin , Ortega-Recalde Oscar , Fonseca-Mendoza Dora Janeth
Published: June 2022

In genes related to drug pharmacokinetics, molecular variations determine interindividual variability in the therapeutic efficacy and adverse drug reactions. The assessment of single-nucleotide variants (SNVs) is used with growing frequency in pharmacogenetic practice, and recently, high-throughput genomic analyses obtained through next-generation sequencing (NGS) have been recognized as powerful tools to identify common, rare and novel variants. These genetic profiles remain underexplored in Latin-American populations, including Colombia. In this study, we investigated the variability of 35 genes included in the ADME core panel (absorption, distribution, metabolism, and excretion) by whole-exome sequencing (WES) of 509 unrelated Colombian individuals with no previous reports of adverse drug reactions. Rare variants were filtered according to the minor allele frequencies (MAF) <1% and potential deleterious consequences. The functional impact of novel and rare missense variants was assessed using an optimized framework for pharmacogenetic variants. Bioinformatic analyses included the identification of clinically validated variants described in PharmGKB and ClinVar databases. Ancestry from WES data was inferred using the R package EthSEQ v2.1.4. Allelic frequencies were compared to other populations reported in the public gnomAD database. Our analysis revealed that rare missense pharmacogenetic variants were 2.1 times more frequent than common variants with 121 variants predicted as potentially deleterious. Rare loss of function (LoF) variants were identified in 65.7% of evaluated genes. Regarding variants with clinical pharmacogenetic effect, our study revealed 89 sequence variations in 28 genes represented by missense (62%), synonymous (22.5%), splice site (11.2%), and indels (3.4%). In this group, ABCB1, ABCC2, CY2B6, CYP2D6, DPYD, NAT2, SLC22A1, and UGTB2B7, are the most polymorphic genes. NAT2, CYP2B6 and DPYD metabolizer phenotypes demonstrated the highest variability. Ancestry analysis indicated admixture in 73% of the population. Allelic frequencies exhibit significant differences with other Latin-American populations, highlighting the importance of pharmacogenomic studies in populations of different ethnicities. Altogether, our data revealed that rare variants are an important source of variability in pharmacogenes involved in the pharmacokinetics of drugs and likely account for the unexplained interindividual variability in drug response. These findings provide evidence of the utility of WES for pharmacogenomic testing and into clinical practice.
Novel Global Asymptotic Stability and Dissipativity Criteria of BAM Neural Networks With Delays
Authors: Liu Mei , Jiang Haijun , Hu Cheng , Lu Binglong , Li Zhanfeng
Published: June 2022

In this article, issues of both stability and dissipativity for a type of bidirectional associative memory (BAM) neural systems with time delays are investigated. By using generalized Halanay inequalities and constructing appropriate Lyapunov functionals, some novelty criteria are obtained for the asymptotic stability for BAM neural systems with time delays. Also, without assuming boundedness and differentiability for activation functions, some new sufficient conditions for proving the dissipativity are established by making use of matrix theory and inner product properties. The received conclusions extend and improve some previously known works on these problems for general BAM neural systems. In the end, numerical simulation examples are made to show the availability of the theoretical conclusions.
Historical Perspectives, State of art and Research Trends of Single Photon Avalanche Diodes and Their Applications (Part 1: Single Pixels)
Authors: Cusini Iris , Berretta Davide , Conca Enrico , Incoronato Alfonso , Madonini Francesca , Maurina Arianna Adelaide , Nonne Chiara , Riccardo Simone , Villa Federica
Published: June 2022

The ability to detect single photons is becoming an enabling key capability in an increasing number of fields. Indeed, its scope is not limited to applications that specifically rely on single photons, such as quantum imaging, but extends to applications where a low signal is overwhelmed by background light, such as laser ranging, or in which faint excitation light is required not to damage the sample or harm the patient. In the last decades, SPADs gained popularity with respect to other single-photon detectors thanks to their small size, possibility to be integrated in Complementary Metal-Oxide Semiconductor processes, room temperature operability, low power supply and, above all, the possibility to be fast gated (to time filter the incoming signal) and to precisely timestamp the detected photons. The development of large digital arrays that integrates the detectors and circuits has allowed the implementation of complex functionality on-chip, tailoring the detectors to suit the need of specific applications. This review proposes a complete overview of silicon SPADs characteristics and applications. In this Part I, starting with the working principle, simulation models and required frontend, the paper moves to the most common parameters adopted in literature for characterizing SPADs, and describes single pixels applications and their performance. In the next Part II, the focus is then posed on the development of SPAD arrays, presenting some of the most notable examples found in literature. The actual exploitation of these designs in real applications (e.g., automotive, bioimaging and radiation detectors) is then discussed.
Intraoperative Cell-Saver Caused More Autologous Salvage Hemolysis in a Hereditary Spherocytosis Patient Than in a Normal Erythrocyte Patient
Authors: Jin Di , Shen Le , Huang Yuguang
Published: June 2022

Hereditary spherocytosis is a common red blood cell disease caused by an inherited red blood cell membrane defect, leading to a spherical shape and propensity for hemolysis. There is a lack of reports on intraoperative autologous blood transfusion for hereditary spherocytosis patients. We hereby report our recent experience with using the Cell Saver®system for intraoperative red blood cell salvage on a hereditary spherocytosis patient. There was a drastic increase in salvaged blood free-hemoglobin compared with the preoperative sample (82.6 mg/dl vs. 6.2 mg/dl) which indicated severe hemolysis. Although our patient recovered smoothly with a normal liver and renal function test and reported no adverse reaction during follow-up, it is noteworthy that severe hemolysis could happen during the cell salvage process for patients with hemolytic anemia, as there are similar reports on sickle cell anemia, beta-thalassemia intermedia, and paroxysmal nocturnal hemoglobinuria. Therefore, more clinical attention and thorough research should be drawn into this perspective, namely, hemolysis during the red blood cell salvage process for patients with hemolytic anemia.
The Necrotroph Botrytis cinerea BcSpd1 Plays a Key Role in Modulating Both Fungal Pathogenic Factors and Plant Disease Development
Authors: Chen Huchen , He Shengnan , Zhang Shuhan , A Runa , Li Wenling , Liu Shouan
Published: June 2022

Botrytis cinerea is a necrotrophic microbe that causes gray mold disease in a broad range of hosts. In the present study, we conducted molecular microbiology and transcriptomic analyses of the host–B. cinerea interaction to investigate the plant defense response and fungal pathogenicity. Upon B. cinerea infection, plant defense responses changed from activation to repression; thus, the expression of many defense genes decreased in Arabidopsis thaliana. B. cinerea Zn(II)2Cys6 transcription factor BcSpd1 was involved in the suppression of plant defense as ΔBcSpd1 altered wild-type B05.10 virulence by recovering part of the defense responses at the early infection stage. BcSpd1 affected genes involved in the fungal sclerotium development, infection cushion formation, biosynthesis of melanin, and change in environmental pH values, which were reported to influence fungal virulence. Specifically, BcSpd1 bound to the promoter of the gene encoding quercetin dioxygenase (BcQdo) and positively affected the gene expression, which was involved in catalyzing antifungal flavonoid degradation. This study indicates BcSpd1 plays a key role in the necrotrophic microbe B. cinerea virulence toward plants by regulating pathogenicity-related compounds and thereby suppressing early plant defense.
Metabolomic and Transcriptomic Analysis of Flavonoid Biosynthesis in Two Main Cultivars of Actinidia arguta Sieb.Zucc. Grown in Northern China
Authors: Wang Yubo , Wang Yong , Sun Jun , Dai Yue , Yang Fengyan , Jiang Hui , Irfan Muhammad , Chen Lijing
Published: June 2022

Actinidia arguta Sieb.Zucc. is a fruit that is rich in flavonoids. Nevertheless, details of flavonoid formation and the potential mechanism behind flavonoid biosynthesis have not previously been reported. In order to explore the biosynthetic regulation mechanism of flavonoids in A. arguta Sieb.Zucc., we conducted a combination of extensive targeted metabolite analysis and analyzed transcriptomes to determine the flavonoids present and the genes bound up with flavonoid biosynthesis in the two main cultivated varieties of A. arguta Sieb.Zucc. in Northern China. The maturity period is from August to September. A total of 118 flavonoids were found in fruits. Among them, 39 flavonoids were accumulated at significant levels after fruit ripening. Transcriptome analysis indicated that most flavonoid biosynthesis structural genes and certain regulatory genes exhibited differential expression between the two varieties. Correlation analysis of transcriptome and metabolite profiles showed that the ways of expression of 21 differentially expressed genes related to structure and regulation between the 2 varieties were more highly correlated with 7 flavonoids after fruit ripening. These results contribute to the development of A. arguta Sieb.Zucc. as a food and drug homologous functional food.
Phylogeography and Population Genetics Analyses Reveal Evolutionary History of the Desert Resource Plant Lycium ruthenicum (Solanaceae)
Authors: Yisilam Gulbar , Wang Chen-Xi , Xia Mao-Qin , Comes Hans Peter , Li Pan , Li Jin , Tian Xin-Min
Published: June 2022

Climactic oscillations during the Quaternary played a significant role in the formation of genetic diversity and historical demography of numerous plant species in northwestern China. In this study, we used 11 simple sequence repeats derived from expressed sequence tag (EST-SSR), two chloroplast DNA (cpDNA) fragments, and ecological niche modeling (ENM) to investigate the population structure and the phylogeographic history of Lycium ruthenicum, a plant species adapted to the climate in northwestern China. We identified 20 chloroplast haplotypes of which two were dominant and widely distributed in almost all populations. The species has high haplotype diversity and low nucleotide diversity based on the cpDNA data. The EST-SSR results showed a high percentage of total genetic variation within populations. Both the cpDNA and EST-SSR results indicated no significant differentiation among populations. By combining the evidence from ENM and demographic analysis, we confirmed that both the last interglacial (LIG) and late-glacial maximum (LGM) climatic fluctuations, aridification might have substantially narrowed the distribution range of this desert species, the southern parts of the Junggar Basin, the Tarim Basin, and the eastern Pamir Plateau were the potential glacial refugia for L. ruthenicum during the late middle Pleistocene to late Pleistocene Period. During the early Holocene, the warm, and humid climate promoted its demographic expansion in northwestern China. This work may provide new insights into the mechanism of formation of plant diversity in this arid region.
Regulation of the Zinc Deficiency Response in the Legume Model Medicago truncatula
Authors: Liao Feixue , Lilay Grmay Hailu , Castro Pedro Humberto , Azevedo Herlander , Assunção Ana G. L.
Published: June 2022

The zinc deficiency response in Arabidopsis thaliana is regulated by F-group basic region leucine-zipper (F-bZIP) transcription factors, and there is evidence of evolutionary conservation of this regulatory network in land plants. Fundamental knowledge on the zinc homeostasis regulation in crop species will contribute to improving their zinc nutritional value. Legumes are protein-rich crops, used worldwide as part of traditional diets and as animal forage, being therefore a good target for micronutrient biofortification. Here, we identified F-bZIP transcription factors in representative legume species and functionally characterized the two F-bZIPs from Medicago truncatula. Results indicate that MtFbZIP1 is the functional homolog of A. thaliana bZIP19 and bZIP23, while MtFbZIP2 does not play a role in the zinc deficiency response. Additionally, analysis of M. truncatula genes from the Zrt/Irt-like protein (ZIP) family of zinc transporters or encoding nicotianamine synthase enzymes that produce the zinc ligand nicotianamine, support the conservation of the F-bZIP-regulated zinc deficiency response in M. truncatula. Phylogenetic analysis of F-bZIP homologs enriched in legume species reinforces the branching into two groups, with MtFbZIP1 and MtFbZIP2 mapping in Groups 1 and 2, respectively. This phylogeny combined with the functional characterization of MtFbZIPs supports the suggested conservation of the zinc deficiency response associated with Group 1 F-bZIPs, and the more variable evolutionary paths associated with Group 2. Overall, we provide novel insight on the mechanisms of response to zinc deficiency in M. truncatula, which contributes to developing strategies for improving zinc content in legume crops.
Taxonomically Restricted Genes Are Associated With Responses to Biotic and Abiotic Stresses in Sugarcane (Saccharum spp.)
Authors: Cardoso-Silva Cláudio Benício , Aono Alexandre Hild , Mancini Melina Cristina , Sforça Danilo Augusto , da Silva Carla Cristina , Pinto Luciana Rossini , Adams Keith L. , de Souza Anete Pereira
Published: June 2022

Orphan genes (OGs) are protein-coding genes that are restricted to particular clades or species and lack homology with genes from other organisms, making their biological functions difficult to predict. OGs can rapidly originate and become functional; consequently, they may support rapid adaptation to environmental changes. Extensive spread of mobile elements and whole-genome duplication occurred in the Saccharum group, which may have contributed to the origin and diversification of OGs in the sugarcane genome. Here, we identified and characterized OGs in sugarcane, examined their expression profiles across tissues and genotypes, and investigated their regulation under varying conditions. We identified 319 OGs in the Saccharum spontaneum genome without detected homology to protein-coding genes in green plants, except those belonging to Saccharinae. Transcriptomic analysis revealed 288 sugarcane OGs with detectable expression levels in at least one tissue or genotype. We observed similar expression patterns of OGs in sugarcane genotypes originating from the closest geographical locations. We also observed tissue-specific expression of some OGs, possibly indicating a complex regulatory process for maintaining diverse functional activity of these genes across sugarcane tissues and genotypes. Sixty-six OGs were differentially expressed under stress conditions, especially cold and osmotic stresses. Gene co-expression network and functional enrichment analyses suggested that sugarcane OGs are involved in several biological mechanisms, including stimulus response and defence mechanisms. These findings provide a valuable genomic resource for sugarcane researchers, especially those interested in selecting stress-responsive genes.