bluuebunny/crossref_metadata_2025 huggingface dataset:
Differential Response of Acidobacteria to Water Content, Soil Type, and Land Use During an Extended Drought in African Savannah Soils
Authors: Huber Katharina J. , Vieira Selma , Sikorski Johannes , Wüst Pia K. , Fösel Bärbel U. , Gröngröft Alexander , Overmann Jörg
Published: February 2022

Although climate change is expected to increase the extent of drylands worldwide, the effect of drought on the soil microbiome is still insufficiently understood as for dominant but little characterized phyla like the Acidobacteria. In the present study the active acidobacterial communities of Namibian soils differing in type, physicochemical parameters, and land use were characterized by high-throughput sequencing. Water content, pH, major ions and nutrients were distinct for sandy soils, woodlands or dry agriculture on loamy sands. Soils were repeatedly sampled over a 2-year time period and covered consecutively a strong rainy, a dry, a normal rainy and a weak rainy season. The increasing drought had differential effects on different soils. Linear modeling of the soil water content across all sampling locations and sampling dates revealed that the accumulated precipitation of the preceding season had only a weak, but statistically significant effect, whereas woodland and irrigation exerted a strong positive effect on water content. The decrease in soil water content was accompanied by a pronounced decrease in the fraction of active Acidobacteria (7.9–0.7%) while overall bacterial community size/cell counts remained constant. Notably, the strongest decline in the relative fraction of Acidobacteria was observed after the first cycle of rainy and dry season, rather than after the weakest rainy season at the end of the observation period. Over the 2-year period, also the β-diversity of soil Acidobacteria changed. During the first year this change in composition was related to soil type (loamy sand) and land use (woodland) as explanatory variables. A total of 188 different acidobacterial sequence variants affiliated with the “Acidobacteriia,” Blastocatellia, and Vicinamibacteria changed significantly in abundance, suggesting either drought sensitivity or formation of dormant cell forms. Comparative physiological testing of 15 Namibian isolates revealed species-specific and differential responses in viability during long-term continuous desiccation or drying-rewetting cycles. These different responses were not determined by phylogenetic affiliation and provide a first explanation for the effect of drought on soil Acidobacteria. In conclusion, the response of acidobacterial communities to water availability is non-linear, most likely caused by the different physiological adaptations of the different taxa present.
Transcriptome Sequencing Reveals Key Genes in Three Early Phases of Osteogenic, Adipogenic, and Chondrogenic Differentiation of Bone Marrow Mesenchymal Stem Cells in Rats
Authors: Liu Fanxiao , Dong Jun , Zhang Peng , Zhou Dongsheng , Zhang Qingyu
Published: February 2022

Bone mesenchymal stem cells (BMSCs) of multi-directional differentiation and reproductive activity are attractive candidates for bone and cartilage repair. However, the molecular mechanisms underlying the early phase of osteogenesis, adipogenesis, and chondrogenesis of BMSCs are still far from understood. In the current study, BMSCs are isolated from rats, and the gene expressions during the initiation of differentiation (phase I), lineage acquisition (phase II), and early lineage progression (phase III) of three-directional differentiation of BMSCs were detected by using high-throughput sequencing. Then, 356, 540, and 299 differentially expressed genes (DEGs) were identified in phases I, II, and III of osteogenesis, respectively. The numbers are 507, 287, and 428 for adipogenesis, respectively, and 412, 336, and 513 for chondrogenesis, respectively. Time-dependent expression patterns of genes were also validated during three-directional differentiation in BMSCs. Hub genes including Ccna2, Cdc20, and Il6 may act as common participants in initiating osteogenesis, adipogenesis, and chondrogenesis. Mex3b, Sertad1, and Hopx showed an enhanced expression throughout three early phases during the osteogenic differentiation but no significant change in other two-directional differentiation. A similar pattern of Dtx4 and Ibsp expression occurred in adipogenesis and chondrogenesis, respectively. Our findings will help understand the underlying mechanism determining the differentiation fate of BMSCs and provide theoretical support for the clinical treatment of osteoporosis, osteoarthritis, and other age-related bone diseases.
Self-Stigma in Parkinson's Disease: A 3-Year Prospective Cohort Study
Authors: Lin Junyu , Ou Ruwei , Wei Qianqian , Cao Bei , Li Chunyu , Hou Yanbing , Zhang Lingyu , Liu Kuncheng , Shang Huifang
Published: February 2022

Purpose

Self-stigma is common in patients with Parkinson's disease (PD) and may lead to social isolation and delayed search for medical help. We conducted a 3-year prospective longitudinal study to investigate the development and evolution of self-stigma in patients with early stage PD and to explore the associated and predictive factors of self-stigma in PD.

Method

A total of 224 patients with early stage PD (disease duration <3 years) were enrolled at baseline and followed up annually for 3 consecutive years. Self-stigma was assessed by the stigma subscale of the Parkinson's Disease Questionnaire (items 23–26). The generalized estimating equation model was used to investigate the associated factors of self-stigma over 3 years, and the binary logistic model was used to explore the predictors of self-stigma in patients with PD without self-stigma at baseline.

Results

The prevalence of self-stigma decreased from 58.0% at baseline to 49.2% after 3 years. The Hamilton Depression Rating Scale (HDRS) score was the only associated factor [B: 0.160 (1.106–0.214), P < 0.001] of self-stigma over 3 years and the only predictor [OR: 1.252 (1.044–1.502), P = 0.015] of the onset of self-stigma.

Conclusion

Self-stigma is very common in PD, but its prevalence tends to decrease as the disease progresses. Depression was the only associated and predictive factor of self-stigma in PD and could be an effective target of alleviating self-stigma.
A Framework for Composite Layup Skill Learning and Generalizing Through Teleoperation
Authors: Si Weiyong , Wang Ning , Li Qinchuan , Yang Chenguang
Published: February 2022

In this article, an impedance control-based framework for human-robot composite layup skill transfer was developed, and the human-in-the-loop mechanism was investigated to achieve human-robot skill transfer. Although there are some works on human-robot skill transfer, it is still difficult to transfer the manipulation skill to robots through teleoperation efficiently and intuitively. In this article, we developed an impedance-based control architecture of telemanipulation in task space for the human-robot skill transfer through teleoperation. This framework not only achieves human-robot skill transfer but also provides a solution to human-robot collaboration through teleoperation. The variable impedance control system enables the compliant interaction between the robot and the environment, smooth transition between different stages. Dynamic movement primitives based learning from demonstration (LfD) is employed to model the human manipulation skills, and the learned skill can be generalized to different tasks and environments, such as the different shapes of components and different orientations of components. The performance of the proposed approach is evaluated on a 7 DoF Franka Panda through the robot-assisted composite layup on different shapes and orientations of the components.
Transfer of Soleus Muscular Branch of Tibial Nerve to Deep Fibular Nerve to Repair Foot Drop After Common Peroneal Nerve Injury: A Retrospective Study
Authors: Bao Bingbo , Wei Haifeng , Zhu Hongyi , Zheng Xianyou
Published: February 2022

Objective

Common peroneal nerve (CPN) injury that leads to foot drop is difficult to manage and treat. We present a new strategy for management of foot drop after CPN injury. The soleus muscular branch of the tibial nerve is directly transferred to the deep fibular nerve, providing partial restoration of motor function.

Methods

We retrospectively reviewed eight patients treated for CPN injury between 2017 and 2019. The soleus muscular branch of the tibial nerve was transferred to the deep fibular nerve to repair foot drop. Electrophysiology was conducted, and motor function was assessed. Motor function was evaluated by measuring leg muscle strength during ankle dorsiflexion using the British Medical Research Council (BMRC) grading system and electromyography (EMG).

Results

In 10–15 months postoperatively, EMG revealed newly appearing electrical potentials in the tibialis anterior, extensor hallucis longus, and extensor toe longus muscle (N = 7). Two patients achieved BMRC grade of M4 for ankle dorsiflexion, 2 patients achieved M3, 1 patient achieved M2, and 2 patients achieved M1. Four patients showed good functional recovery after surgery and could walk and participate in activities without ankle-foot orthotics.

Conclusion

Surgical transfer of the soleus muscular branch of the tibial nerve to the deep fibular nerve after CPN injury provides variable improvements in ankle dorsiflexion strength. Despite variable strength gains, 50% of patients achieved BMRC M3 or greater motor recovery, which enabled them to walk without assistive devices.
Trends in the Utilization of Teleneurology and Other Healthcare Resources Prior to and During the COVID-19 Pandemic in an Urban, Tertiary Health System
Authors: Kummer Benjamin R. , Agarwal Parul , Sweetnam Chloe , Robinson-Papp Jessica , Blank Leah J. , Katz Sand Ilana , Naasan Georges , Palmese Christina A. , Jimenez-Shahed Joohi , Grant Jihan , Patterson Shanna , Navis Alison , Stein Laura K. , Jetté Nathalie
Published: February 2022

Background

Patient groups traditionally affected by health disparities were less likely to use video teleneurology (TN) care during the initial COVID-19 pandemic surge in the United States. Whether this asymmetry persisted later in the pandemic or was accompanied with a loss of access to care remains unknown.

Methods

We conducted a retrospective cohort study using patient data from a multicenter healthcare system in New York City. We identified all established pediatric or adult neurology patients with at least two prior outpatient visits between June 16th, 2019 and March 15th, 2020 using our electronic medical record. For this established pre-COVID cohort, we identified telephone, in-person, video TN or emergency department visits and hospital admissions for any cause between March 16th and December 15th, 2020 (“COVID period”). We determined clinical, sociodemographic, income, and visit characteristics. Our primary outcome was video TN utilization, and our main secondary outcome was loss to follow-up during the COVID period. We used multivariable logistic regression to model the relationship between patient-level characteristics and both outcomes.

Results

We identified 23,714 unique visits during the COVID period, which corresponded to 14,170 established patients from our institutional Neurology clinics during the pre-COVID period. In our cohort, 4,944 (34.9%) utilized TN and 4,997 (35.3%) were entirely lost to follow-up during the COVID period. In the adjusted regression analysis, Black or African-American race [adjusted odds ratio (aOR) 0.60, 97.5%CI 0.52–0.70], non-English preferred language (aOR 0.49, 97.5%CI 0.39–0.61), Medicaid insurance (aOR 0.50, 97.5%CI 0.44–0.57), and Medicare insurance (aOR 0.73, 97.5%CI 0.65–0.83) had decreased odds of TN utilization. Older age (aOR 0.98, 97.5%CI 0.98–0.99), female sex (aOR 0.90 97.5%CI 0.83–0.99), and Medicaid insurance (aOR 0.78, 0.68–0.90) were associated with decreased odds of loss to follow-up.

Conclusion

In the first 9 months of the COVID-19 pandemic, we found sociodemographic patterns in TN utilization that were similar to those found very early in the pandemic. However, these sociodemographic characteristics were not associated with loss to follow-up, suggesting that lack of TN utilization may not have coincided with loss of access to care.
Animal and Plant Protein Food Sources in Indonesia Differ Across Socio-Demographic Groups: Socio-Cultural Research in Protein Transition in Indonesia and Malaysia
Authors: Khusun Helda , Februhartanty Judhiastuty , Anggraini Roselynne , Mognard Elise , Alem Yasmine , Noor Mohd Ismail , Karim Norimah , Laporte Cyrille , Poulain Jean-Pierre , Monsivais Pablo , Drewnowski Adam
Published: February 2022

Background

Plant-based diets in lower-income countries are often associated with inadequate protein nutrition and adverse health outcomes.

Objective

To examine the diversity of protein food sources, in both animal and plant, across diverse socio-demographic groups in Indonesia as compared to Malaysia.

Design

The SCRiPT (Socio Cultural Research in Protein Transition) study was based on population-based samples recruited in Indonesia (N = 1665) and in Malaysia (N = 1604). Data from 24-h in-person dietary recalls in each country were used to construct the frequency counts of protein sources by food group. Protein sources were defined as fish, poultry, red meat (beef, pork, and mutton), eggs, dairy, and plants (cereals, pulses, and tubers). The percent reported frequencies for animal and plant proteins were compared across socio-demographic strata and by country. Analyses were based on one-way Anovas and general linear model regressions adjusting for covariates.

Results

Animal protein frequency counts were 34% of total in Indonesia, but 50% in Malaysia's. Higher reported consumption frequencies for poultry and red meat in both countries were associated with urban living, greater modernization, and higher socioeconomic status, with stronger social gradients observed in Indonesia. Reported fish consumption was higher in Indonesia than in Malaysia. Fish was more likely to be listed by rural island populations in Indonesia and was associated with lower education and incomes. Consumption frequencies for plant-based proteins were associated with lower socio-economic status in Indonesia and in Malaysia.

Conclusions

More affluent groups in both countries reported higher frequencies for meat, eggs, and dairy as opposed to fish. Greater economic development in Southeast (SE) Asia is associated with more animal protein, particularly from poultry, which may displace fish, the traditional source of high quality protein for the region.
Cumulative Betel Quid Chewing and the Risk of Significant Liver Fibrosis in Subjects With and Without Metabolic Syndrome
Authors: Chou Yu-Tsung , Sun Zih-Jie , Shen Wei-Chen , Yang Yi-Ching , Lu Feng-Hwa , Chang Chih-Jen , Li Chung-Yi , Wu Jin-Shang
Published: February 2022

Background

Betel quid chewing is associated with metabolic disorders, oral cancer, cardiovascular disease, and chronic liver diseases. Metabolic syndrome (MetS) is also a factor associated with liver fibrosis, cirrhosis, and hepatocellular carcinoma (HCC). However, studies on the relationship between betel quid and liver fibrosis while also considering MetS are lacking. The aim of this study was thus to investigate the association of betel quid chewing and liver fibrosis with MetS.

Methods

A total of 9,221 subjects were enrolled after excluding subjects <18 years of age, with past history of chronic liver diseases, cancer, significant alcohol consumption, and incomplete data. Betel nut chewing habit was classified into three groups: none, former-chewing, and current-chewing, and cumulative exposure was calculated by multiplying the duration with the quantity. Liver fibrosis was evaluated based on the NAFLD fibrosis score (NFS), which is a composite score of age, hyperglycemia, BMI, platelet count, albumin, and the AST/ALT ratio. Significant liver fibrosis was defined as NFS ≥-1.455.

Results

After adjusting for other variables, MetS was positively associated with significant liver fibrosis. Subjects with both MetS and betel quid chewing had a higher associated risk of significant liver fibrosis than those with neither MetS nor betel quid chewing (adjusted OR: 3.03, 95% CI: 2.04–4.50,p< 0.001). Betel quid chewing was associated with significant liver fibrosis (adjusted OR: 2.00, 95% CI: 1.14–3.49,p= 0.015) in subjects with MetS, but not in subjects without.

Conclusion

Metabolic syndrome increased the associated risk of significant liver fibrosis. Cumulative betel quid exposure increased the associated risk of significant liver fibrosis in subjects with MetS, but not in subjects without.
Immune Checkpoint and Telomerase Crosstalk Is Mediated by miRNA-138 in Bladder Cancer
Authors: El Ahanidi Hajar , El Azzouzi Meryem , Hafidi Alaoui Chaimae , Tetou Mohammed , Bensaid Mounia , Chaoui Imane , Benbacer Laila , Hassan Ilias , Oukabli Mohamed , Michaud Katarzyna , Ameur Ahmed , Al Bouzidi Abderrahmane , El Mzibri Mohammed , Jandus Camilla , Attaleb Mohammed
Published: February 2022

Background

Tumor recurrence and progression in non-muscle invasive bladder cancer (NMIBC), therapy failure, and severe side effects in muscle invasive bladder cancer (MIBC) are the major challenges in the clinical management of bladder cancer (BC). Here, we identify new molecular targetable signatures to improve BC patients’ stratification and the outcome of current immunotherapies.

Material and Methods

In a prospective cohort of 70 BC patients, we assessed the genetic and molecular regulation of TERT in maintaining telomere length in parallel to immune checkpoint and microRNA expression.

Results

TERT was undetectable in healthy bladder tissues but upregulated in invasive BC stages and high tumor grade. Its expression was linked with the combined effect of the C250T mutation and THOR hypermethylation, associated with progressing tumors and maintaining of telomere length. In the same cohort, PD-L1 scored highest in NMIBC, while PD-L2 was upregulated in MIBC. We also show that miR-100-5p and 138-5p were highly expressed in healthy bladder specimens and cell line, while expression decreased in the BC tissues and BC cell lines. In line with the binding prediction for these miRNAs on target genes, miRs 100-5p and 138-5p expression strongly inverse correlated with TERT, PD-L1, and PD-L2 expression, but not PD1.

Conclusion

We identify a loop involving TERT, PD1-ligands, and miR-138-5p in BC, that might represent not only a useful biomarker for improved diagnosis and patients’ stratification but also as a promising axis that might be therapeutically targeted in situ.
Associations of DDX60L With the Clinical Features and Prognosis of Hepatocellular Carcinoma
Authors: Ye Ziqi , Zhang Xin , Zhang Yanfang , Liu Linqing , Xuan Zixue , Huang Ping
Published: February 2022

Objective

Although the pathogenesis of hepatocellular carcinoma (HCC) is still unclear, hepatitis C virus (HCV) infection is considered a common cause of HCC. It has been reported that DDX60L can inhibit HCV replication, but its role in HCC is still poorly understood.

Methods

The expression levels of DDX60L in HCC tissues and in tissues adjacent to the tumor and their correlation with the clinicopathological features of patients were analyzed. We also used Kaplan–Meier curves of overall survival (OS) with Cox regression analysis and log-rank test to investigate the prognostic value of DDX60L in HCC. We further performed cell proliferation, Transwell, and wound healing assays to elucidate the role of DDX60L in HCC using the siRNA-DDX60L Hep3B or HCCLM3 cell line.

Results

Univariate analysis showed that sex, Edmondson grade, microvascular invasion, tumor stage (III–IV/I–II), AFP, and DDX60L expression were strongly associated with the prognosis of HCC patients. The results of multivariate analysis further suggested that DDX60L might be an independent prognostic factor for OS in patients with HCC (Pmoderate/low = 0.015, Phigh/low = 0.011). The low DDX60L expression in HCC patients with no-metastasis, age ≥55 years, tumor size <5 cm, Edmondson grade = I–II, microvascular invasion, no cirrhosis, HBV positivity, tumor stage = III–IV, AFP >20 μg/L, and multiple tumor was associated with poorer prognosis (P <0.05). Moreover, the expression of DDX60L was significantly lower in HCC samples (N = 285) than in the normal tissues adjacent to the tumor (N = 167, P <0.001). There were no HCV-related HCC patients in this study. Additionally, we found that DDX60L knockdown can promote the proliferation of Hep3B cells, migration and invasion ability of Hep3B and HCCLM3 cells.

Conclusion

We found that the downregulation of DDX60L expression correlated with poor prognosis in patients with HCC, which may be independent of the HCV-related pathway. Furthermore, DDX60L significantly inhibited the proliferation of Hep3B cells, migration and invasion of Hep3B and HCCLM3 cells. Therefore, DDX60L can serve as a prognostic biomarker and therapeutic target for HCC.
Chimeric Peptides/Proteins Encoded by circRNA: An Update on Mechanisms and Functions in Human Cancers
Authors: Khan Faiz Ali , Nsengimana Bernard , Khan Nazeer Hussain , Song Zhenhua , Ngowi Ebenezeri Erasto , Wang Yunyun , Zhang Weijuan , Ji Shaoping
Published: February 2022

The discovery of circular RNAs and exploration of their biological functions are increasingly attracting attention in cell bio-sciences. Owing to their unique characteristics of being highly conserved, having a relatively longer half-life, and involvement in RNA maturation, transportation, epigenetic regulation, and transcription of genes, it has been accepted that circRNAs play critical roles in the variety of cellular processes. One of the critical importance of these circRNAs is the presence of small open reading frames that enable them to encode peptides/proteins. In particular, these encoded peptides/proteins mediate essential cellular activities such as proliferation, invasion, epithelial–mesenchymal transition, and apoptosis and develop an association with the development and progression of cancers by modulating diverse signaling pathways. In addition, these peptides have potential roles as biomarkers for the prognosis of cancer and are being used as drug targets against tumorigenesis. In the present review, we thoroughly discussed the biogenesis of circRNAs and their functional mechanisms along with a special emphasis on the reported chimeric peptides/proteins encoded by circRNAs. Additionally, this review provides a perspective regarding the opportunities and challenges to the potential use of circRNAs in cancer diagnosis and therapeutic targets in clinics.
Advances in Cellular Therapy for T-Cell Prolymphocytic Leukemia
Authors: Varadarajan Indumathy , Ballen Karen
Published: February 2022

T-cell prolymphocytic leukemia (T-PLL) is a rare, aggressive hematologic malignancy with a poor prognosis. Alemtuzumab (Campath) remains the cornerstone for treatment, with an 80% complete response (CR). Hematopoietic stem cell transplant (HSCT) is considered the standard of care as consolidative therapy in eligible patients. However, allogeneic stem cell transplant is also complicated by increased rates of infections from chemotherapy, acute graft-versus-host disease (GVHD), and chronic GVHD. This review aims to report the available literature on the efficacy and complications of consolidative HSCT. It also discusses the importance of patient selection and pre- and post-transplant complications including atypical infections and GVHD.
SPINKs in Tumors: Potential Therapeutic Targets
Authors: Liao Chengcheng , Wang Qian , An Jiaxing , Zhang Minglin , Chen Jie , Li Xiaolan , Xiao Linlin , Wang Jiajia , Long Qian , Liu Jianguo , Guan Xiaoyan
Published: February 2022

The serine protease inhibitor Kazal type (SPINK) family includes SPINK1-14 and is the largest branch in the serine protease inhibitor family. SPINKs play an important role in pancreatic physiology and disease, sperm maturation and capacitation, Nager syndrome, inflammation and the skin barrier. Evidence shows that the unregulated expression of SPINK1, 2, 4, 5, 6, 7, and 13 is closely related to human tumors. Different SPINKs exhibit various regulatory modes in different tumors and can be used as tumor prognostic markers. This article reviews the role of SPINK1, 2, 4, 5, 6, 7, and 13 in different human cancer processes and helps to identify new cancer treatment targets.
Development and Validation of a Novel Model to Predict Regional Lymph Node Metastasis in Patients With Hepatocellular Carcinoma
Authors: Chen Xiaoyuan , Lu Yiwei , Shi Xiaoli , Han Guoyong , Zhao Jie , Gao Yun , Wang Xuehao
Published: February 2022

Background

The evaluation of the nodal status of hepatocellular carcinoma (HCC) is a classic but controversial topic. This study aimed to investigate the incidence of lymph node metastasis (LNM), explore the role of lymph node dissection (LND), and develop and validate a novel model to predict LNM in patients with HCC, not other specified (NOS).

Methods

The study cohort was taken from the Surveillance, Epidemiology, and End Results database. The annual percent change (APC) was calculated using the Joinpoint regression. Survival analyses adopted the competing risk model. The nomogram was constructed based on the least absolute shrinkage and selection operator (LASSO) logistic regression algorithm and validated by calibration curves. The area under the receiver operating characteristic curve (AUROC) was obtained to compare prognostic performance. Decision curve and clinical impact curve analyses were introduced to examine the clinical value of the models.

Results

A total of 8,829 patients were finally enrolled in this study, and 1,346 (15.2%) patients received LND. The LND rate showed no noticeable fluctuation in the last decade, with an APC of 0.5% (P=0.593). LNM was identified in 56 (4.2%) patients and confirmed an independent prognostic factor of HCC patients (P=0.005). There were 2,497 lymph nodes retrieved, and 93 (3.7%) of them were positive. After propensity score matching, LND indicated no direct oncologic benefit and did not worsen competing risks. Moreover, an increased number of lymph nodes retrieved could not improve prognoses. 1,346 patients with LND were further randomly divided into the training and validation sets with the ratio of 1:1. Race, tumor size, clinical T stage, extrahepatic bile duct invasion, and tumor grade were independent risk factors for LNM. The constructed model was well calibrated and showed good discrimination power and net benefits in clinical practice.

Conclusion

LNM is an independent prognostic factor in HCC, but routine LND seems to be unnecessary in HCC patients. The constructed model could predict the presence of LNM in HCC patients with good performance, which is meaningful to patient stratification and individual treatment strategies optimization.
The Lifted Veil of Uncommon EGFR Mutation p.L747P in Non-Small Cell Lung Cancer: Molecular Feature and Targeting Sensitivity to Tyrosine Kinase Inhibitors
Authors: Yang Guangjian , Liu Chengming , Hu Jiaqi , Sun Yang , Hu Peizeng , Liu Liu , Xu Haiyan , Li Dazhou , Li Weihua , Yang Yaning , Sun Nan , He Jie , Wang Yan
Published: February 2022

Objectives

The uncommon p.L747P mutation in epidermal growth factor receptor (EGFR) exon 19 reveals to alter the response to tyrosine kinase inhibitors (TKIs) in patients diagnosed with advanced non-small cell lung cancer (NSCLC). However, the underlying mechanism is still not clear. This study aimed to investigate the clinical outcomes, binding affinities, and modes of action of currently available EGFR TKIs towards p.L747P mutation.

Materials and Methods

Clinical data of NSCLC patients harboring p.L747P mutation who had received different generations of EGFR TKIs were collected from medical records. Computational structure of p.L747P was constructed and in vitro cellular kinase inhibition assay and mice xenograft experiment were performed to predict and confirm the binding affinities and antitumor activities of diverse EGFR TKIs.

Results

A total of five metastatic NSCLC patients with p.L747P mutation were included in the final analysis. Patients treated with second-generation (2G) TKI afatinib achieved numerically longer progression-free survival (range 2.4-8.5 months) than that with first-generation (1G, range 1.4-5.5 months) or third-generation (3G, range 1.6-7.5 months) TKIs. None of the patients administered 1G or 3G TKIs achieved tumor response, but two-thirds of them treated with afatinib achieved partial response. Dynamics simulation predicted that 2G TKIs presented the best binding affinity to p.L747P mutation. The cellular kinase inhibition assay and mice xenograft experiment confirmed that afatinib could potently inhibit p.L747P-mutant cells and significantly reduce p.L747P-mutant tumor growth (P< 0.001), together with reduced phosphorylation of EGFR and its downstream signalings.

Conclusions

The uncommon p.L747P mutation in EGFR exon 19 resulted in a poor response to first-generation EGFR TKIs. Afatinib revealed a better clinical response and binding affinity compared with osimertinib for this specific alteration.
Prevalence of Visual Impairment Among Students Before and During the COVID-19 Pandemic, Findings From 1,057,061 Individuals in Guangzhou, Southern China
Authors: Liang Jing-hong , Chen Yi-can , Zhao Yu , Kakaer Aerziguli , Jiang Nan , Huang Shan , Zhang Shu-xin , Chen Ya-jun
Published: February 2022

Background

Visual impairment (VI) is a growing public health concern among students as a result of the COVID-19 pandemic.

Objective

This study investigated the change in VI before and during the pandemic among students.

Methods

Data on 547,864 and 497,371 students were obtained from the Guangzhou Survey on Students' Constitution and Health (GSSCH) collected in October 2019 and October 2020, respectively. VI was defined as the unaided distance visual acuity lower than 20/25 Snellen equivalent (LogMAR 0.10) in the worse eye. Change in VI based on age and sociodemographic variables were evaluated by chi-square test for trend as appropriate. Comparisons of different categorical variables were tested by contingency tables-based chi-square test. We have further analysis of the students who went through both of the 2019 and 2020 examinations for evaluating the VI incidence during the COVID-19 pandemic.

Results

More than 1,045,235 students were involved in our study, among whom 271,790 (54.65%) out of 497,371 students in Guangzhou suffered from VI during the COVID-19 compared with 293,001(53.48%) visually impaired students (total tested participants = 547,864) before the COVID-19 pandemic. During the pandemic, the overall prevalence of VI actually showed an increased age tendency and reached the highest level in the 17 [80.04%, 95%Confidence interval (CI):79.53 to 80.54%] and the 18 (79.64, 95%CI: 79.06 to 80.23%) age groups. Rapid growth was detected among students aged between 9 and 16 years old (raised by 46.21) while older students were more likely to get moderate and severe VI than younger ones. Students involved in more screen-based activities [(64.83%, 2019); (66.59%, 2020)] appeared to have a higher prevalence of VI than those involved in less [(49.17%, 2019); (49.26%, 2020)].

Conclusion

A rising trend of VI among students was detected before and during the COVID-19 pandemic. Moreover, the pandemic appeared to be associated with a rapid VI shift in younger and boy populations. Potential danger may arise when public health emergencies occur in the school, and more effort should be made to improve students' vision.
Effects of Arterial Carbon Dioxide Tension on Cerebral and Somatic Regional Tissue Oxygenation and Blood Flow in Neonates After the Norwood Procedure With Deep Hypothermic Cardiopulmonary Bypass
Authors: Hoffman George M. , Scott John P. , Stuth Eckehard A.
Published: February 2022

Neonates undergoing the Norwood procedure for hypoplastic left heart syndrome are at higher risk of impaired systemic oxygen delivery with resultant brain, kidney, and intestinal ischemic injury, shock, and death. Complex developmental, anatomic, and treatment-related influences on cerebral and renal-somatic circulations make individualized treatment strategies physiologically attractive. Monitoring cerebral and renal circulations with near infrared spectroscopy can help drive rational therapeutic interventions. The primary aim of this study was to describe the differential effects of carbon dioxide tension on cerebral and renal circulations in neonates after the Norwood procedure. Using a prospectively-maintained database of postoperative physiologic and hemodynamic parameters, we analyzed the relationship between postoperative arterial carbon dioxide tension and tissue oxygen saturation and arteriovenous saturation difference in cerebral and renal regions, applying univariate and multivariate multilevel mixed regression techniques. Results were available from 7,644 h of data in 178 patients. Increases in arterial carbon dioxide tension were associated with increased cerebral and decreased renal oxygen saturation. Differential changes in arteriovenous saturation difference explained these effects. The cerebral circulation showed more carbon dioxide sensitivity in the early postoperative period, while sensitivity in the renal circulation increased over time. Multivariate models supported the univariate findings and defined complex time-dependent interactions presented graphically. The cerebral and renal circulations may compete for blood flow with critical limitations of cardiac output. The cerebral and renal-somatic beds have different circulatory control mechanisms that can be manipulated to change the distribution of cardiac output by altering the arterial carbon dioxide tension. Monitoring cerebral and renal circulations with near infrared spectroscopy can provide rational physiologic targets for individualized treatment.
Correlation Between Matrix Metalloproteinases With Coronary Artery Lesion Caused by Kawasaki Disease
Authors: Tian Fang , Ma Linxi , Zhao Renbing , Ji Lijuan , Wang Xiufen , Sun Wenli , Jiang Yu
Published: February 2022

This study was designed to clarify the role of matrix metalloproteinases (MMPs) in coronary artery lesions (CAL). Serum samples were acquired from healthy, febrile, and Kawasaki disease (KD) children with or without CAL. Standard blood parameters were examined and enzyme-linked immunosorbent assay (ELISA) was used to assess the levels of MMP-2 and MMP-9. Intravenous immunoglobulin (IVIG) therapy was conducted on the KD patients and the changes of MMPs before and after treatment were compared. The correlations between MMP levels and clinical parameters were also evaluated. Compared to febrile and healthy controls, KD patients demonstrated clinical signs characteristic of abnormal immunoregulation. However, the clinical parameters of KD patients with or without CAL were not significantly different. MMP-2 and MMP-9 levels, however, were significantly higher in KD patients with CAL than those without CAL. IVIG treatment effectively downregulated the levels of MMPs in KD patients, which was more prominent in those with CAL. Significant correlations were found between MMP levels and some clinical parameters of KD, such as fever time, white blood cell count, etc. The upregulation of MMPs significantly correlates with coronary artery aneurysms (CAAs) in KD patients, making it important biomarkers of CAL in KD patients.
Inflammatory Related Reactions in Humans and in Canine Breast Cancers, A Spontaneous Animal Model of Disease
Authors: Tricarico Domenico , Convertino Anna Sara , Mehmeti Irsida , Ranieri Girolamo , Leonetti Francesco , Laface Carmelo , Zizzo Nicola
Published: February 2022

Inflammatory cells are emerging markers in various cancers in human trials. The relationship between the inflammatory cells response, cancer grade, and progression has been investigated experimentally in a spontaneous canine model of breast cancer and in the unselected population (18–64 years.o.) under anti-HER2 treatments that represent the most prevalent population in this cancer type. The canine data (N samples = 101) were collected retrospectively for diagnosis in our regional area and evaluated by immunohistochemistry and haemato-chemistry. The inflammatory and immune-related adverse reactions (ADR) in humans were evaluated using EudraVigilance. The “Proportional Reporting Ratio” (PRR) of the mabs was calculated for each ADR with values >2 indicative of high risk. In dogs, we found elevated immunostaining of CD68-macrophages in the lymph node of the aggressive cancer G3 and infiltrating CD20+-lymphocyte. A high density of CD20 + lymphocytes was observed in G1 and a decrease in the density was observed with the histological degree of the tumors. The animals with the sample in G1 showed reduced serum platelet and neutrophil count and elevated lymphocytes and the opposite in severely affected animals. Inflammatory reactions with edema, skin reactions, extravasation, loss of effectiveness, and platelet count decrease (PRR > 13) were found with trastuzumab emtansine in humans, in the absence of immune system reactions. Trastuzumab i.v.-s.c. showed immune system reactions, loss of effectiveness, intolerances with drug withdrawal, technological issues (PRR > 7), and neutrophil count decrease reports. These reactions were less frequently reported for pertuzumab i.v. Case reports of platelet and neutrophil count decrease were not associated with disease progression with a better outcome in humans as in canine breast cancer. Therefore, infiltrating CD68-macrophages are associated with G3, while infiltrating CD20+ and elevated serum lymphocytes in parallel with reduced platelet and neutrophil count play a favorable role in human and canine breast cancer.
Molecular Mechanisms and Potential New Therapeutic Drugs for Liver Fibrosis
Authors: Wang Fa-Da , Zhou Jing , Chen En-Qiang
Published: February 2022

Liver fibrosis is the pathological process of excessive extracellular matrix deposition after liver injury and is a precursor to cirrhosis, hepatocellular carcinoma (HCC). It is essentially a wound healing response to liver tissue damage. Numerous studies have shown that hepatic stellate cells play a critical role in this process, with various cells, cytokines, and signaling pathways engaged. Currently, the treatment targeting etiology is considered the most effective measure to prevent and treat liver fibrosis, but reversal fibrosis by elimination of the causative agent often occurs too slowly or too rarely to avoid life-threatening complications, especially in advanced fibrosis. Liver transplantation is the only treatment option in the end-stage, leaving us with an urgent need for new therapies. An in-depth understanding of the mechanisms of liver fibrosis could identify new targets for the treatment. Most of the drugs targeting critical cells and cytokines in the pathogenesis of liver fibrosis are still in pre-clinical trials and there are hardly any definitive anti-fibrotic chemical or biological drugs available for clinical use. In this review, we will summarize the pathogenesis of liver fibrosis, focusing on the role of key cells, associated mechanisms, and signaling pathways, and summarize various therapeutic measures or drugs that have been trialed in clinical practice or are in the research stage.
Quantification of Tissue Microstructure Using Tensor-Valued Diffusion Encoding: Brain and Body
Authors: Afzali Maryam , Mueller Lars , Szczepankiewicz Filip , Jones Derek K. , Schneider Jürgen E.
Published: February 2022

Diffusion-weighted magnetic resonance imaging (DW-MRI) is a non-invasive technique to probe tissue microstructure. Conventional Stejskal–Tanner diffusion encoding (i.e., encoding along a single axis), is unable to disentangle different microstructural features within a voxel; If a voxel contains microcompartments that vary in more than one attribute (e.g., size, shape, orientation), it can be difficult to quantify one of those attributes in isolation using Stejskal–Tanner diffusion encoding. Multidimensional diffusion encoding, in which the water diffusion is encoded along multiple directions in q-space (characterized by the so-called “b-tensor”) has been proposed previously to solve this problem. The shape of the b-tensor can be used as an additional encoding dimension and provides sensitivity to microscopic anisotropy. This has been applied in multiple organs, including brain, heart, breast, kidney and prostate. In this work, we discuss the advantages of using b-tensor encoding in different organs.
Relationship Between Inflow Impairment and Skin Oxygen Availability to the Upper Limb During Standardized Arm Abduction in Patients With Suspected Thoracic Outlet Syndrome
Authors: Hersant Jeanne , Lecoq Simon , Ramondou Pierre , Papon Xavier , Feuilloy Mathieu , Abraham Pierre , Henni Samir
Published: February 2022

Objective

Thoracic outlet syndrome (TOS) should be considered of arterial origin only if patients have clinical symptoms that are the result of documented symptomatic ischemia. Simultaneous recording of inflow impairment and forearm ischemia in patients with suspected TOS has never been reported to date. We hypothesized that ischemia would occur in cases of severely impaired inflow, resulting in a non-linear relationship between changes in pulse amplitude (PA) and the estimation of ischemia during provocative attitudinal upper limb positioning.

Design

Prospective single center interventional study.

Material

Fifty-five patients with suspected thoracic outlet syndrome.

Methods

We measured the minimal decrease from rest of transcutaneous oximetry pressure (DROPm) as an estimation of oxygen deficit and arterial pulse photo-plethysmography to measure pulse amplitude changes from rest (PA-change) on both arms during the candlestick phase of a “Ca + Pra” maneuver. “Ca + Pra” is a modified Roos test allowing the estimation of maximal PA-change during the “Pra” phase. We compared the DROPm values between deciles of PA-changes with ANOVA. We then analyzed the relationship between mean PA-change and mean DROPm of each decile with linear and second-degree polynomial (non-linear) models. Results are reported as median [25/75 centiles]. Statistical significance was p < 0.05.

Results

DROPm values ranged −11.5 [−22.9/−7.2] and − 12.3 [−23.3/−7.4] mmHg and PA-change ranged 36.4 [4.6/63.8]% and 38.4 [−2.0/62.1]% in the right and left forearms, respectively. The coefficient of determination between median DROPm and median PA-change was r2 = 0.922 with a second-degree polynomial fitting, but only r2 = 0.847 with a linear approach.

Conclusion

Oxygen availability was decreased in cases of severe but not moderate attitudinal inflow impairments. Undertaking simultaneous A-PPG and forearm oximetry during the “Ca + Pra” maneuver is an interesting approach for providing objective proof of ischemia in patients with symptoms of TOS suspected of arterial origin.
Tibial Bone Geometry Is Associated With Bone Stress Injury During Military Training in Men and Women
Authors: Koltun Kristen J. , Sekel Nicole M. , Bird Matthew B. , Lovalekar Mita , Mi Qi , Martin Brian J. , Nindl Bradley C.
Published: February 2022

Bone stress injuries (BSI) are a common musculoskeletal condition among exercising and military populations and present a major burden to military readiness. The purpose of this investigation was to determine whether baseline measures of bone density, geometry, and strength, as assessed via peripheral quantitative computed tomography (pQCT), are predictive of tibial BSI during Marine Officer Candidates School training. Tibial pQCT scans were conducted prior to the start of physical training (n = 504; Male n = 382; Female n = 122) to measure volumetric bone mineral density (vBMD), geometry, robustness, and estimates of bone strength. Bone parameters were assessed at three tibial sites including the distal metaphysis (4% of tibial length measured from the distal endplate), mid-diaphysis (38% of tibial length measured from the distal endplate), and proximal diaphysis (66% of tibial length measured from the distal endplate). Injury surveillance data was collected throughout training. Four percent (n = 21) of the sample were diagnosed with a BSI at any anatomical site during training, 10 injuries were of the tibia. Baseline bone parameters were then tested for associations with the development of a tibial BSI during training and it was determined that cortical bone measures at diaphyseal (38 and 66%) sites were significant predictors of a prospective tibial BSI. At the mid-diaphysis (38% site), in a simple model and after adjusting for sex, age, and body size, total area [Odds Ratio (OR): 0.987, 0.983], endosteal circumference (OR: 0.853, 0.857), periosteal circumference (OR: 0.863, 0.824), and estimated bending strength (SSI; OR: 0.998, 0.997) were significant predictors of a BSI during training, respectively, such that lower values were associated with an increased likelihood of injury. Similarly, at the proximal diaphysis (66% site), total area (OR: 0.989, 0.985), endosteal circumference (OR: 0.855, 0.854), periosteal circumference (OR: 0.867, 0.823), robustness (OR: 0.007, 0.003), and SSI (OR: 0.998, 0.998) were also significant predictors of BSI in the simple and adjusted models, respectively, such that lower values were associated with an increased likelihood of injury. Results from this investigation support that narrower bones, with reduced circumference, lower total area, and lower estimated strength are associated with increased risk for tibial BSI during military training.
MicroRNA-122-5p Inhibition Improves Inflammation and Oxidative Stress Damage in Dietary-Induced Non-alcoholic Fatty Liver Disease Through Targeting FOXO3
Authors: Hu Yiyi , Peng Xuetao , Du Guoping , Zhang Zhiqiao , Zhai Yingji , Xiong Xingbo , Luo Xiaoliang
Published: February 2022

Misregulated microRNA network has been emerging as the main regulator in non-alcoholic fatty liver disease (NAFLD). The deregulation of miR-122-5p is associated with the liver disease. However, the specific role and molecular mechanism of miR-122-5p in NAFLD remain unclear. In this study, we have reported that the high-fat diet (HFD) or palmitic acid (PA) significantly upregulated the hepatic miR-122-5p expression in vivo and in vitro. Inhibition of miR-122-5p suppressed accumulation-induced inflammation of lipids and oxidative stress damage in PA-treated L02 cells and HFD-induced fatty liver. The effect of the miR-122-5p inhibitor on NAFLD did not depend on insulin resistance-mediated PI3K/AKT/mammalian target of rapamycin (mTOR) signaling pathway but rather on the upregulation of its downstream FOXO3. Subsequently, we validated that miR-122-5p directly binds to the predicted 3′-UTR of FOXO3 to inhibit its gene expression. Conversely, silencing FOXO3 abolished the hepatic benefits of miR-122-5p inhibition to obese mice by decreasing the activity of antioxidant enzymes of superoxide dismutase (SOD). This study provides a novel finding that FOXO3 was the target gene of miR-122-5p to attenuate inflammatory response and oxidative stress damage in dietary-induced NAFLD. Our study provided evidence to reveal the physiological role of miR-122-5p in dietary-induced NAFLD.
Cortical–Hypothalamic Integration of Autonomic and Endocrine Stress Responses
Authors: Schaeuble Derek , Myers Brent
Published: February 2022

The prevalence and severity of cardiovascular disease (CVD) are exacerbated by chronic stress exposure. While stress-induced sympathetic activity and elevated glucocorticoid secretion impair cardiovascular health, the mechanisms by which stress-responsive brain regions integrate autonomic and endocrine stress responses remain unclear. This review covers emerging literature on how specific cortical and hypothalamic nuclei regulate cardiovascular and neuroendocrine stress responses. We will also discuss the current understanding of the cellular and circuit mechanisms mediating physiological stress responses. Altogether, the reviewed literature highlights the current state of stress integration research, as well unanswered questions about the brain basis of CVD risk.