bluuebunny/crossref_metadata_2025 huggingface dataset:
Case Report: A Squamous Cell Lung Carcinoma Patient Who Responded to Neoadjuvant Immunochemotherapy but Died From Anastomosis Leakage or/and irAEs: Immune Microenvironment and Genomic Features Changes
Authors: Hao Liping , Hu Ying , Hu Jianjun , Liu Yang , Mao Beibei , Chen Huan , Gong Xiaoli , Wang Di , Wang Lin , Wang Dong
Published: July 2021

Clinical trials indicated that PD-1/PD-L1 inhibitors significantly improve the survival rate of patients with advanced non-small cell lung cancer (NSCLC) and induce immune-related adverse events (irAEs). Thus, the molecular and immune characteristics during PD-1/PD-L1 inhibitor therapy are worth investigating further. We report the case of a 62-year-old male patient diagnosed with stage IIIA squamous cell lung carcinoma (SQCC) who responded to neoadjuvant and adjuvant nivolumab combined chemotherapy but died from anastomosis leakage or/and irAEs. In the pretreatment tumor biopsy, PD-L1 expression was negative and a few T cells, NK cells, and macrophages had infiltrated the tumor. Wild-type EGFR/STK11, mutant TP53, microsatellite stability, and low tumor mutational burden were also found at baseline. After neoadjuvant immunochemotherapy, the tumor was significantly reduced, PD-L1 expression levels were increased by 50%, and more CD8+ and CD8+ PD-1+ T cells had infiltrated the resected tumor tissue. Immune-related lung injury occurred during adjuvant immunochemotherapy, and serum levels of C-reactive protein, IL-13, IL-4, eotaxin, VEGF-A, IL-8, and IFN-gamma were increased. This case demonstrates a squamous cell lung carcinoma patient who responded to neoadjuvant immunochemotherapy that reshaped the tumor immune environment from “cold” to “hot.” Unfortunately, the patient eventually died from anastomosis leakage or/and irAEs during adjuvant immunochemotherapy.
LncRNA HOTAIR: A Potential Prognostic Factor and Therapeutic Target in Human Cancers
Authors: Xin Xiaoru , Li Qianan , Fang Jinyong , Zhao Tiejun
Published: July 2021

Long non-coding RNAs (lncRNAs) are emerging as crucial regulators of gene expression and physiological processes. LncRNAs are a class of ncRNAs of 200 nucleotides in length. HOX transcript antisense RNA (HOTAIR), a trans-acting lncRNA with regulatory function on transcription, can repress gene expression by recruiting chromatin modifiers. HOTAIR is an oncogenic lncRNA, and numerous studies have determined that HOTAIR is highly upregulated in a wide variety of human cancers. In this review, we briefly summarize the impact of lncRNA HOTAIR expression and functions on different human solid tumors, and emphasize the potential of HOTAIR on tumor prognosis and therapy. Here, we review the recent studies that highlight the prognostic potential of HOTAIR in drug resistance and survival, and the progress of therapies developed to target HOTAIR to date. Furthermore, targeting HOTAIR results in the suppression of HOTAIR expression or function. Thus, HOTAIR knockdown exhibits great therapeutic potential in various cancers, indicating that targeting lncRNA HOTAIR may serve as a promising strategy for cancer therapy. We also propose that preclinical studies involving HOTAIR are required to provide a better understanding of the exact molecular mechanisms underlying the dysregulation of its expression and function in different human cancers and to explore effective methods of targeting HOTAIR and engineering efficient and targeted drug delivery methods in vivo.
A Recurrent Cryptic MED14-HOXA9 Rearrangement in an Adult Patient With Mixed-Phenotype Acute Leukemia, T/myeloid, NOS
Authors: Wang Qian , Zhang Ling , Zhu Ming-qing , Zeng Zhao , Fang Bao-zhi , Xie Jun-dan , Pan Jin-lan , Wu Chun-xiao , Wu Ni , Zhang Ri , Chen Su-ning , Dai Hai-ping
Published: July 2021

To define the fusion genes in T/myeloid mixed-phenotype acute leukemia (T/M MPAL), we performed transcriptome sequencing of diagnostic bone marrow samples from 20 adult patients. Our analysis identified a second instance of a recurrent MED14-HOXA9 chimeric gene resulting from the in-frame fusion of exon 23 of MED14 and exon 1 of HOXA9, the first in an adult patient. The MED14-HOXA9 fusion gene was detected in both the diagnostic and relapsed blasts with reverse transcription-polymerase chain reaction and Sanger sequencing. The patient received combined conventional chemotherapy but suffered relapse at 11 months and died of disease progression one year after the initial diagnosis. Our data suggest that MED14-HOXA9 is a cryptic recurrent aberration in T/M MPAL, which might indicate an aggressive clinical course and inferior outcome after conventional chemotherapy. Further studies will be carried out to reveal the effects of the MED14-HOXA9 fusion on the differentiation and proliferation of leukemia stem cells, as well as suitable treatment strategies for this emerging entity.
Geometric and Dosimetric Changes in Tumor and Lung Tissue During Radiotherapy for Lung Cancer With Atelectasis
Authors: Chen Hua , Shao Yan , Gu Xiaohua , Zheng Zhijie , Wang Hao , Gu Hengle , Duan Yanhua , Feng Aihui , Huang Ying , Gan Wutian , Chen Chongyang , Xu Zhiyong
Published: July 2021

Background and Purpose

This article retrospectively characterized the geometric and dosimetric changes in target and normal tissues during radiotherapy for lung cancer patients with atelectasis.

Materials and Methods

A total of 270 cone beam computed tomography (CBCT) scans of 18 lung patients with atelectasis were collected. The degree and time of resolution or expansion of the atelectasis were recorded. The geometric, dosimetric, and biological changes in the target and lung tissue were also quantified.

Results

There were two patients with expansion, four patients with complete regression, six patients with partial regression, and six patients with no change. The time of resolution or expansion varied. The tumor volume increased by 3.8% in the first seven fractions, then decreased from the 9th fraction, and by 33.4% at the last CBCT. In the LR direction, the average center of mass (COM), boundaries of the tumors gradually shifted mediastinally. In the AP direction, the COM of the tumors was shifted slightly in the posterior direction and then gradually shifted to the anterior direction; the boundaries of the tumors all moved mediastinally. In the SI direction, the COM of the tumors on the right side of the body was substantially shifted toward the head direction. The boundaries of the tumors varied greatly. D2, D98, Dmean, V95, V107, and TCP of the PTV were reduced during radiotherapy and were reduced to their lowest values during the last two fractions. The volume of the ipsilateral lung tended to increase gradually. The V5, V10, V20, V30, V40, and NTCP of the total lung gradually increased with the fraction.

Conclusions

For most patients, regression of the atelectasis occurred, and the volume of the ipsilateral lung tended to increase while the tumor volume decreased, and the COM and boundary of the tumors shifted toward mediastinum, which caused an insufficient dose to the target and an overdose to the lungs. Regression or expansion may occur for any fraction, and it is therefore recommended that CBCT be performed at least every other day.
The Role of Non-Coding RNAs in the Sorafenib Resistance of Hepatocellular Carcinoma
Authors: Hu Xinyao , Zhu Hua , Shen Yang , Zhang Xiaoyu , He Xiaoqin , Xu Ximing
Published: July 2021

Hepatocellular carcinoma (HCC) is the second most common cause of cancer-related death. Sorafenib is approved by the U.S. Food and Drug Administration to be a first-line chemotherapy agent for patients with advanced HCC. A portion of advanced HCC patients can benefit from the treatment with sorafenib, but many patients ultimately develop sorafenib resistance, leading to a poor prognosis. The molecular mechanisms of sorafenib resistance are sophisticated and indefinite. Notably, non-coding RNAs (ncRNAs), which include long ncRNAs (lncRNAs), microRNAs (miRNAs) and circular RNAs (circRNAs), are critically participated in the occurrence and progression of tumors. Moreover, growing evidence has suggested that ncRNAs are crucial regulators in the development of resistance to sorafenib. Herein, we integrally and systematically summarized the molecular mechanisms and vital role of ncRNAs impact sorafenib resistance of HCC, and ultimately explored the potential clinical administrations of ncRNAs as new prognostic biomarkers and therapeutic targets for HCC.
Protein Tyrosine Kinase 7 Regulates EGFR/Akt Signaling Pathway and Correlates With Malignant Progression in Triple-Negative Breast Cancer
Authors: Cui Nai-Peng , Qiao Shu , Jiang Shan , Hu Jin-Lin , Wang Ting-Ting , Liu Wen-Wen , Qin Yan , Wang Ya-Nan , Zheng Li-Shuang , Zhang Jin-Chao , Ma Yong-Ping , Chen Bao-Ping , Shi Jian-Hong
Published: July 2021

Purpose

Triple-negative breast cancer (TNBC), the most aggressive subtype of breast cancer, is associated with high invasiveness, high metastatic occurrence and poor prognosis. Protein tyrosine kinase 7 (PTK7) plays an important role in multiple cancers. However, the role of PTK7 in TNBC has not been well addressed. This study was performed to evaluate the role of PTK7 in the progression of TNBC.

Methods

Correlation of PTK7 expression with clinicopathological parameters was assessed using tissue microarray immunohistochemistry (IHC) staining in 280 patients with breast cancer. PTK7 expression in TNBC (MDA-MB-468, MDA-MB-436 and MDA-MB-231) and non-TNBC (MCF7 and SK-BR-3) breast cancer cell lines were examined using immunoblotting assay. PTK7 correlated genes in invasive breast carcinoma were analyzed using cBioPortal breast cancer datasets including 1,904 patients. PTK7 overexpressed or knockdown TNBC cell lines (MDA-MB-468 and MDA-MB-436) were used to analyze the potential roles of PTK7 in TNBC metastasis and tumor progression. A TNBC tumor bearing mouse model was established to further analyze the role of PTK7 in TNBC tumorigenicity in vivo.

Results

PTK7 is highly expressed in breast cancer and correlates with worse prognosis and associates with tumor metastasis and progression in TNBC. Co-expression analysis and gain- or loss-of-function of PTK7 in TNBC cell lines revealed that PTK7 participates in EGFR/Akt signaling regulation and associated with extracellular matrix organization and migration genes in breast cancer, including COL1A1, FN1, WNT5B, MMP11, MMP14 and SDC1. Gain- or loss-of-function experiments of PTK7 suggested that PTK7 promotes proliferation and migration in TNBC cell lines. PTK7 knockdown MDA-MB-468 cell bearing mouse model further demonstrated that PTK7-deficiency inhibits TNBC tumor progression in vivo.

Conclusion

This study identified PTK7 as a potential marker of worse prognosis in TNBC and revealed PTK7 promotes TNBC metastasis and progression via EGFR/Akt signaling pathway.
Prediction of EGFR Mutation Status Based on 18F-FDG PET/CT Imaging Using Deep Learning-Based Model in Lung Adenocarcinoma
Authors: Yin Guotao , Wang Ziyang , Song Yingchao , Li Xiaofeng , Chen Yiwen , Zhu Lei , Su Qian , Dai Dong , Xu Wengui
Published: July 2021

Objective

The purpose of this study was to develop a deep learning-based system to automatically predict epidermal growth factor receptor (EGFR) mutant lung adenocarcinoma in 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT).

Methods

Three hundred and one lung adenocarcinoma patients with EGFR mutation status were enrolled in this study. Two deep learning models (SECT and SEPET) were developed with Squeeze-and-Excitation Residual Network (SE-ResNet) module for the prediction of EGFR mutation with CT and PET images, respectively. The deep learning models were trained with a training data set of 198 patients and tested with a testing data set of 103 patients. Stacked generalization was used to integrate the results of SECT and SEPET.

Results

The AUCs of the SECT and SEPET were 0.72 (95% CI, 0.62–0.80) and 0.74 (95% CI, 0.65–0.82) in the testing data set, respectively. After integrating SECT and SEPET with stacked generalization, the AUC was further improved to 0.84 (95% CI, 0.75–0.90), significantly higher than SECT (p<0.05).

Conclusion

The stacking model based on 18F-FDG PET/CT images is capable to predict EGFR mutation status of patients with lung adenocarcinoma automatically and non-invasively. The proposed model in this study showed the potential to help clinicians identify suitable advanced patients with lung adenocarcinoma for EGFR‐targeted therapy.
Case Report: Successful Chimeric Antigen Receptor T Cell Therapy in Haploidentical-Allogeneic Stem Cell Transplant Patients With Post-Transplant Lymphoproliferative Disorder
Authors: Yan Nan , Wang Na , Zhang Peiling , Wang Gaoxiang , Mao Xia , Peng Dan , Kuang Dong , Chen Liting , Zhu Li , Zhou Jianfeng , Zhang Yicheng , Cao Yang
Published: July 2021

Background

Epstein–Barr virus-associated post-transplant lymphoproliferative disorder (EBV-PTLD) is a potentially fatal complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Rituximab has been proven to dramatically improve the prognosis of patients with EBV reactivation and PTLD. However, reports on the curative management of refractory PTLD are scarce.

Case Presentation

In this report, we describe the successful management of two patients with EBV-PTLD with chimeric antigen receptor T-cell (CAR-T) therapy.

Conclusion

The present results demonstrated that patients with EBV-PTLD may benefit from CAR-T therapy and that the toxicity is manageable. Further studies are needed to verify these findings.
Comparison of Radiomic Features in a Diverse Cohort of Patients With Pancreatic Ductal Adenocarcinomas
Authors: Permuth Jennifer B. , Vyas Shraddha , Li Jiannong , Chen Dung-Tsa , Jeong Daniel , Choi Jung W.
Published: July 2021

Background

Significant racial disparities in pancreatic cancer incidence and mortality rates exist, with the highest rates in African Americans compared to Non-Hispanic Whites and Hispanic/Latinx populations. Computer-derived quantitative imaging or “radiomic” features may serve as non-invasive surrogates for underlying biological factors and heterogeneity that characterize pancreatic tumors from African Americans, yet studies are lacking in this area. The objective of this pilot study was to determine if the radiomic tumor profile extracted from pretreatment computed tomography (CT) images differs between African Americans, Non-Hispanic Whites, and Hispanic/Latinx with pancreatic cancer.

Methods

We evaluated a retrospective cohort of 71 pancreatic cancer cases (23 African American, 33 Non-Hispanic White, and 15 Hispanic/Latinx) who underwent pretreatment CT imaging at Moffitt Cancer Center and Research Institute. Whole lesion semi-automated segmentation was performed on each slice of the lesion on all pretreatment venous phase CT exams using Healthmyne Software (Healthmyne, Madison, WI, USA) to generate a volume of interest. To reduce feature dimensionality, 135 highly relevant non-texture and texture features were extracted from each segmented lesion and analyzed for each volume of interest.

Results

Thirty features were identified and significantly associated with race/ethnicity based on Kruskal-Wallis test. Ten of the radiomic features were highly associated with race/ethnicity independent of tumor grade, including sphericity, volumetric mean Hounsfield units (HU), minimum HU, coefficient of variation HU, four gray level texture features, and two wavelet texture features. A radiomic signature summarized by the first principal component partially differentiated African American from non-African American tumors (area underneath the curve = 0.80). Poorer survival among African Americans compared to Non-African Americans was observed for tumors with lower volumetric mean CT [HR: 3.90 (95% CI:1.19–12.78), p=0.024], lower GLCM Avg Column Mean [HR:4.75 (95% CI: 1.44,15.37), p=0.010], and higher GLCM Cluster Tendency [HR:3.36 (95% CI: 1.06–10.68), p=0.040], and associations persisted in volumetric mean CT and GLCM Avg Column after adjustment for key clinicopathologic factors.

Conclusions

This pilot study identified several textural radiomics features associated with poor overall survival among African Americans with PDAC, independent of other prognostic factors such as grade. Our findings suggest that CT radiomic features may serve as surrogates for underlying biological factors and add value in predicting clinical outcomes when integrated with other parameters in ongoing and future studies of cancer health disparities.
Clinical Outcomes of Salvage Endoscopic Nasopharyngectomy for Patients With Advanced Recurrent Nasopharyngeal Carcinoma
Authors: Li Wanpeng , Zhang Huankang , Lu Hanyu , Wang Huan , Gu Yurong , Li Houyong , Sun Xicai , Yu Hongmeng , Wang Dehui
Published: July 2021

Background

Salvage endoscopic nasopharyngectomy has better survival prognosis and fewer complications in the management of early stage rNPC, compared to re-irradiation. However, the treatment modality of advanced recurrent nasopharyngeal carcinoma (rNPC) remains controversial. Thus, the purpose of this study was to investigate the demographics, clinical outcomes, and prognostic factors associated with salvage endoscopic nasopharyngectomy in advanced rNPC.

Methods

This study conducted a retrospective analysis of advanced rNPC patients who underwent salvage surgery betweenm January 2014 and December 2019. The overall survival (OS) and progression-free survival (PFS) were analyzed. Univariable and multivariable analyses of OS and PFS were performed using the Cox regression model. The predicted values of the parameters were determined by means of the receiver operating characteristic (ROC) curve analysis.

Results

Among the 120 patients included, there were 75 patients with rT3 stage and 45 patients with rT4 stage. With the median follow-up time of 18 months,the 3 -year OS and PFS were 55.2% and 29.4%, respectively. Multivariate analyses showed that the rNPC patients with older age, low BMI (Body Mass Index), rT4 stage, tumor necrosis, and tumor invasion into the ICA was predictive of worse OS, whereas low BMI and rT4 stage were associated with worse PFS. In addition, the rT stage was identified as a better predictor of OS (area under the ROC curve: 0.669; P=0.003) than the other clinical features.

Conclusions

Salvage treatment using endoscopic nasopharyngectomy appears to be an effective treatment in the management of patients with advanced rNPC. In addition, case matching studies and prospective studies with larger clinical samples are required to further evaluate the efficacy of endoscopic surgery compared with re-irradiation in advanced rNPC.
Impact of Dose, Sex, and Strain on Oxaliplatin-Induced Peripheral Neuropathy in Mice
Authors: Warncke Urszula O. , Toma Wisam , Meade Julie A. , Park Abigail J. , Thompson Danielle C. , Caillaud Martial , Bigbee John W. , Bryant Camron D. , Damaj M. Imad
Published: July 2021

Chemotherapy-induced peripheral neuropathy (CIPN) is a common, dose limiting, and long-lasting side effect of chemotherapy treatment. Unfortunately, no treatment has proven efficacious for this side effect. Rodent models play a crucial role in the discovery of new mechanisms underlying the initiation, progression, and recovery of CIPN and the potential discovery of new therapeutics. However, there is limited consistency in the dose, the sex, age, and genetic background of the animal used in these studies and the outcome measures used in evaluation of CIPN rely primarily on noxious and reflexive measures. The main objective of this study was to provide a comprehensive and systematic characterization of oxaliplatin-induced peripheral neuropathy in mice by using a battery of behavioral, sensory, electrophysiological, and morphometric measures in both sexes of the two widely used strains of mice, C57BL/6J and BALB/cJ. Mice received intraperitoneal injections of 3 or 30 mg/kg cumulative doses of oxaliplatin over the course of 2 weeks. Both doses induced long-term and time-dependent mechanical and cold hypersensitivity. Our results show that 30 mg/kg oxaliplatin reduced the locomotor activity in C57BL/6J mice, and C57BL/6J females showed anxiety-like behavior one-week post completion of treatment. In the same dose group, BALB/cJ males and females sustained a larger decrease in sucrose preference than either male or female C57BL/6J mice. Both strains failed to show significant changes in burrowing and nesting behaviors. Two clinically relevant assessments of changes to the peripheral nerve fibers, nerve conduction and intraepidermal nerve fiber density (IENFD) were evaluated. Only BALB/cJ females showed significant reduction in the nerve conduction amplitude 1 week after 30 mg/kg oxaliplatin regimen. Moreover, this dose of the chemo agent reduced the IENF density in both sexes and strains. Our findings suggest that mouse strain, sex, and assay type should be carefully considered when assessing the effects of oxaliplatin and potential therapeutic interventions.
Adverse Maternal and Neonatal Outcomes in Women With Elevated Intrapartum Temperature Complicated by Histological Chorioamnionitis at Term: A Propensity-Score Matched Study
Authors: Ge Yingzhou , Zhang Chen , Cai Yanqing , Huang Hefeng
Published: July 2021

Background: Elevated intrapartum temperature has been widely proven to be associated with adverse clinical outcomes in both mothers and neonates. Histological chorioamnionitis (HCA), the inflammation of chorion and amniotic membranes, is commonly observed in those with elevated intrapartum temperature. Thus, we aimed to explore whether the combination of HCA would further affect the pregnancy outcomes in those with intrapartum temperature ≥ 37.5°C.

Methods: This retrospective cohort study was conducted at the International Peace Maternity and Child Health Hospital (IPMCH), including all full-term women with intrapartum temperature ≥ 37.5°C from Jan 2017 to Jan 2019. Patients were divided in to HCA group or control group according to placental pathology results, and we used 1:1 propensity score matching (PSM) to reduce the effects of potential confounding factors between the two groups. Univariate and multivariable logistic regression were used to identify the association between HCA and different adverse maternal and neonatal outcomes.

Results: We formed a propensity-score matched cohort containing 464 women in each group. Higher positive rate of mycoplasma (14.01% vs. 7.33%, p = 0.001) was found in the vaginal secretion culture of women in the HCA group. After adjusting for various baseline clinical characteristics, women with HCA were more likely to end their delivery by cesarean section (AOR = 1.55, 95% CI: 1.05–2.28), and puerperal morbidity (AOR = 2.77, 95% CI: 1.44–5.33) as well as prolonged hospitalization (AOR = 1.56, 95% CI: 1.12–2.17) were more likely to be observed in the HCA group. The existence of HCA might also be associated with neonatal sepsis (AOR = 2.83, 95% CI: 1.14–7.04) and NICU admission (AOR = 1.40, 95% CI: 1.04–1.87) in newborns. In the study on the impact of different stages of HCA, we found that both maternal and neonatal outcomes would not be affected by mild HCA (stage I), while HCA of stage III was associated with increased need for neonatal respiratory support and elevated likelihood of prolonged hospitalization in neonates.

Conclusions: Elevated intrapartum temperature complicated by HCA might be related to the elevated occurrence of several adverse maternal and neonatal outcomes, except those with HCA of stage I. Advanced HCA stage correlated with a worse prognosis.
Effect of Osimertinib in Combination With Chemotherapy and Bevacizumab for Untreated Epidermal Growth Factor Receptor–Mutated Advanced Non-Small-Cell Lung Cancer: Case Report
Authors: Qin Haifeng , Wang Fang , Zeng Zhen , Jia Suting , Liu Yuan , Gao Hongjun
Published: July 2021

Introduction: Osimertinib is an oral, third-generation, irreversible epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) that selectively inhibits both EGFR-TKI–sensitizing and EGFR T790M resistance mutations. However, whether patients with EGFR mutations can be treated by osimertinib in combination with conventional therapies, remains unknown.

Case presentation: We treated a 67-year-old female diagnosed with non-small-cell lung cancer with an EGFR 21 exon L858R–positive mutation. The patient was treated with 80 mg orally administered osimertinib daily, 830 mg pemetrexed, 120 mg cisplatin, and 500 mg bevacizumab. After two cycles of therapy, the patient’s intrapulmonary lesions shrank from 18 × 24 mm to 16 × 4 mm. Moreover, two cycles of evaluation were PR, and four cycles of confirmation were PR. The patient continued to receive the treatments and tolerated them well.

Conclusions: The patient benefited from treatment with osimertinib in combination with chemotherapy and bevacizumab.
First-in-Human, Double-Blind, Randomized, Placebo-Controlled Trial of TQ-F3083, a New Dipeptidyl Peptidase-4 Inhibitor, in Healthy Chinese Adults
Authors: Liu Jingrui , Zhu Xiaoxue , Zhang Hong , Wei Haijing , Yang Deming , Xu Zhongnan , Huo Dandan , Li Xiaojiao , Ding Yanhua
Published: July 2021

Background: As a novel dipeptidyl peptidase-4 (DPP-4) inhibitor, TQ-F3083 represents a promising new drug for type 2 diabetes mellitus (T2DM). This phase I, first-in-human study evaluated the tolerability, pharmacokinetics, and pharmacodynamics of TQ-F3083 in healthy Chinese adults.

Methods: Sixty healthy participants total were enrolled in the single-ascending dose, multiple-dose, and food-effect studies. Safety endpoints included adverse events (AEs), vital signs, 12-lead electrocardiogram, abdominal ultrasound, chest X-ray, physical examination, and clinical laboratory tests. Blood, urine, and feces samples were collected for pharmacokinetic analyses. Pharmacodynamic parameters were evaluated based on DPP-4 activity and the active glucagon-like peptide-1 concentration.

Results: In total, 22 treatment-related AEs, mostly grade 1 or 2, were reported in 14 individuals. No deaths, serious AEs, or grade ≥4 AEs occurred, and no dose-dependent AEs were demonstrated. For pharmacokinetic characteristics, dose linearity was analyzed using power model. The slopes (90% CIs) were 1.08 (1.02–1.13) and 1.05 (0.99–1.11) for AUC0-t and AUC0-∞, suggesting liner pharmacokinetic characteristic after oral dose TQ-F3083 from 2 to 160 mg. The accumulation factor was 1.39 after multiple dose for 7 days. Decreased plasma exposure (84.87% decrease in Cmax, 49.23% in AUC0-t, and 47.77% in AUC0-∞) was observed with administration after a high-fat and high-calorie standardized breakfast. The 0–72 h TQ-F3083 excretion recovery percentages were 7.84% in urine and 5.76% in feces. Over 80% DPP-4 inhibition for 24 h was observed in the 20–160 mg cohorts, and the model-estimated 50% effective concentration was 1.10 ng/ml. The concentration of active glucagon-like peptide-1 increased after TQ-F3083 administration, but no obvious dose dependency was observed.

Conclusion: TQ-F3083 was well tolerated in healthy Chinese adults, and the pharmacokinetic and pharmacodynamic characteristics support further evaluation of TQ-F3083 in a trial in T2DM patients.
Recent Progresses in the Treatment of Osteoporosis
Authors: Li Shan-Shan , He Shi-Hao , Xie Peng-Yu , Li Wei , Zhang Xin-Xin , Li Tian-Fang , Li Dai-Feng
Published: July 2021

Osteoporosis (OP) is a chronic bone disease characterized by aberrant microstructure and macrostructure of bone, leading to reduced bone mass and increased risk of fragile fractures. Anti-resorptive drugs, especially, bisphosphonates, are currently the treatment of choice in most developing countries. However, they do have limitations and adverse effects, which, to some extent, helped the development of anabolic drugs such as teriparatide and romosozumab. In patients with high or very high risk for fracture, sequential or combined therapies may be considered with the initial drugs being anabolic agents. Great endeavors have been made to find next generation drugs with maximal efficacy and minimal toxicity, and improved understanding of the role of different signaling pathways and their crosstalk in the pathogenesis of OP may help achieve this goal. Our review focused on recent progress with regards to the drug development by modification of Wnt pathway, while other pathways/molecules were also discussed briefly. In addition, new observations made in recent years in bone biology were summarized and discussed for the treatment of OP.
A Novel Cell Vertex Model Formulation that Distinguishes the Strength of Contraction Forces and Adhesion at Cell Boundaries
Authors: Sato Katsuhiko , Umetsu Daiki
Published: July 2021

The vertex model is a useful mathematical model to describe the dynamics of epithelial cell sheets. However, existing vertex models do not distinguish contraction forces on the cell boundary from adhesion between cells, employing a single parameter to express both. In this paper, we introduce the rest length of the cell boundary and its dynamics into the existing vertex model, giving a novel formulation of the model that treats separately the contraction force and the strength of adhesion between cells. We apply this vertex model to the phenomenon of compartment boundary in the fruit fly pupa, recapturing the observation that increasing the strength of adhesion between cells straightens the compartment boundary, even though contraction forces at cell boundaries remain unchanged. We also discuss possibilities of the novel vertex models by considering the stretching of a cell sheet by external forces.
Configuration of a Magnetic Cloud From Solar Orbiter and Wind Spacecraft In-situ Measurements
Authors: Hu Qiang , He Wen , Zhao Lingling , Lu Edward
Published: July 2021

Coronal mass ejections (CMEs) represent one type of the major eruption from the Sun. Their interplanetary counterparts, the interplanetary CMEs (ICMEs), are the direct manifestations of these structures when they propagate into the heliosphere and encounter one or more observing spacecraft. The ICMEs generally exhibit a set of distinctive signatures from thein-situspacecraft measurements. A particular subset of ICMEs, the so-called Magnetic Clouds (MCs), is more uniquely defined and has been studied for decades, based onin-situmagnetic field and plasma measurements. By utilizing the latest multiple spacecraft measurements and analysis tools, we report a detailed study of the internal magnetic field configuration of an MC event observed by both the Solar Orbiter (SO) and Wind spacecraft in the solar wind near the Sun-Earth line. Both two-dimensional (2D) and three-dimensional (3D) models are applied to reveal the flux rope configurations of the MC. Various geometrical as well as physical parameters are derived and found to be similar within error estimates for the two methods. These results quantitatively characterize the coherent MC flux rope structure crossed by the two spacecraft along different paths. The implication for the radial evolution of this MC event is also discussed.
Myogenic Tone in Peripheral Resistance Arteries and Arterioles: The Pressure Is On!
Authors: Jackson William F.
Published: July 2021

Resistance arteries and downstream arterioles in the peripheral microcirculation contribute substantially to peripheral vascular resistance, control of blood pressure, the distribution of blood flow to and within tissues, capillary pressure, and microvascular fluid exchange. A hall-mark feature of these vessels is myogenic tone. This pressure-induced, steady-state level of vascular smooth muscle activity maintains arteriolar and resistance artery internal diameter at 50–80% of their maximum passive diameter providing these vessels with the ability to dilate, reducing vascular resistance, and increasing blood flow, or constrict to produce the opposite effect. Despite the central importance of resistance artery and arteriolar myogenic tone in cardiovascular physiology and pathophysiology, our understanding of signaling pathways underlying this key microvascular property remains incomplete. This brief review will present our current understanding of the multiple mechanisms that appear to underlie myogenic tone, including the roles played by G-protein-coupled receptors, a variety of ion channels, and several kinases that have been linked to pressure-induced, steady-state activity of vascular smooth muscle cells (VSMCs) in the wall of resistance arteries and arterioles. Emphasis will be placed on the portions of the signaling pathways underlying myogenic tone for which there is lack of consensus in the literature and areas where our understanding is clearly incomplete.
Heart Rate and Muscle Oxygenation Kinetics During Dynamic Constant Load Intermittent Breath-Holds
Authors: Bouten Janne , De Bock Sander , Bourgois Gil , de Jager Sarah , Dumortier Jasmien , Boone Jan , Bourgois Jan G.
Published: July 2021

Introduction: Acute apnea evokes bradycardia and peripheral vasoconstriction in order to conserve oxygen, which is more pronounced with face immersion. This response is contrary to the tachycardia and increased blood flow to muscle tissue related to the higher oxygen consumption during exercise. The aim of this study was to investigate cardiovascular and metabolic responses of dynamic dry apnea (DRA) and face immersed apnea (FIA).

Methods: Ten female volunteers (17.1 ± 0.6 years old) naive to breath-hold-related sports, performed a series of seven dynamic 30 s breath-holds while cycling at 25% of their peak power output. This was performed in two separate conditions in a randomized order: FIA (15°C) and DRA. Heart rate and muscle tissue oxygenation through near-infrared spectroscopy were continuously measured to determine oxygenated (m[O2Hb]) and deoxygenated hemoglobin concentration (m[HHb]) and tissue oxygenation index (mTOI). Capillary blood lactate was measured 1 min after the first, third, fifth, and seventh breath-hold.

Results: Average duration of the seven breath-holds did not differ between conditions (25.3 s ± 1.4 s, p = 0.231). The apnea-induced bradycardia was stronger with FIA (from 134 ± 4 to 85 ± 3 bpm) than DRA (from 134 ± 4 to 100 ± 5 bpm, p < 0.001). mTOI decreased significantly from 69.9 ± 0.9% to 63.0 ± 1.3% (p < 0.001) which is reflected in a steady decrease in m[O2Hb] (p < 0.001) and concomitant increase in m[HHb] (p = 0.001). However, this was similar in both conditions (0.121 < p < 0.542). Lactate was lower after the first apnea with FIA compared to DRA (p = 0.038), while no differences were observed in the other breath-holds.

Conclusion: Our data show strong decreases in heart rate and muscle tissue oxygenation during dynamic apneas. A stronger bradycardia was observed in FIA, while muscle oxygenation was not different, suggesting that FIA did not influence muscle oxygenation. An order of mechanisms was observed in which, after an initial tachycardia, heart rate starts to decrease after muscle tissue deoxygenation occurs, suggesting a role of peripheral vasoconstriction in the apnea-induced bradycardia. The apnea-induced increase in lactate was lower in FIA during the first apnea, probably caused by the stronger bradycardia.
Blood Plasma Biomarkers for Woody Breast Disease in Commercial Broilers
Authors: Kong Byungwhi , Khatri Bhuwan , Kang Seong , Shouse Stephanie , Kadhim Hakeem , Kidd Michael , Lassiter Kentu , Hiltz Joseph , Mallmann Barbara , Orlowski Sara , Anthony Nicholas , Bottje Walter , Kuenzel Wayne , Owens Casey
Published: July 2021

Woody breast (WB) myopathy results in poor muscle quality. The increasing incidence of WB over the last several years indicates a need for improved prediction or early diagnosis. We hypothesized that the use of body fluids, including blood, may be more suitable than breast muscle tissue in developing a minimally invasive diagnostic tool for WB detection. To identify potential early-age-biomarkers that may represent the potential onset of WB, blood samples were collected from 100, 4 wks old commercial male broilers. At 8 wks of age, WB conditions were scored by manual palpation. A total of 32 blood plasma samples (eight for each group of WB and non-WB control birds at two time points, 4 wks and 8 wks) were subjected to shotgun proteomics and untargeted metabolomics to identify differentially abundant plasma proteins and metabolites in WB broilers compared to non-WB control (Con) broilers. From the proteomics assay, 25 and 16 plasma proteins were differentially abundant (p < 0.05) in the 4 and 8 wks old samples, respectively, in WB compared with Con broilers. Of those, FRA10A associated CGG repeat 1 (FRAG10AC1) showed >2-fold higher abundance in WB compared with controls. In the 8 wks old broilers, 4 and 12 plasma proteins displayed higher and lower abundances, respectively, in WB compared with controls. Myosin heavy chain 9 (MYH9) and lipopolysaccharide binding protein (LBP) showed more than 2-fold higher abundances in WB compared with controls, while transferrin (TF) and complement C1s (C1S) showed more than 2-fold lower abundances compared with controls. From the untargeted metabolomics assay, 33 and 19 plasma metabolites were differentially abundant in birds at 4 and 8 wks of age, respectively, in WB compared with controls. In 4 wks old broilers, plasma 3-hydroxybutyric acid (3-HB) and raffinose concentrations showed the highest and lowest fold changes, respectively, in WB compared with controls. The blood plasma 3-HB and raffinose concentrations were confirmed with targeted biochemical assays. Blood biomarkers, such as 3-HB and raffinose, may be suitable candidate targets in the prediction of WB onset at early ages.
Role of Jasmonates, Calcium, and Glutathione in Plants to Combat Abiotic Stresses Through Precise Signaling Cascade
Authors: Aslam Saima , Gul Nadia , Mir Mudasir A. , Asgher Mohd. , Al-Sulami Nadiah , Abulfaraj Aala A. , Qari Sameer
Published: July 2021

Plant growth regulators have an important role in various developmental processes during the life cycle of plants. They are involved in abiotic stress responses and tolerance. They have very well-developed capabilities to sense the changes in their external milieu and initiate an appropriate signaling cascade that leads to the activation of plant defense mechanisms. The plant defense system activation causes build-up of plant defense hormones like jasmonic acid (JA) and antioxidant systems like glutathione (GSH). Moreover, calcium (Ca2+) transients are also seen during abiotic stress conditions depicting the role of Ca2+in alleviating abiotic stress as well. Therefore, these growth regulators tend to control plant growth under varying abiotic stresses by regulating its oxidative defense and detoxification system. This review highlights the role of Jasmonates, Calcium, and glutathione in abiotic stress tolerance and activation of possible novel interlinked signaling cascade between them. Further, phyto-hormone crosstalk with jasmonates, calcium and glutathione under abiotic stress conditions followed by brief insights on omics approaches is also elucidated.
Characterization of Arsenic-Resistant Endophytic Bacteria From Alfalfa and Chickpea Plants
Authors: Tashan Hazhir , Harighi Behrouz , Rostamzadeh Jalal , Azizi Abdolbaset
Published: July 2021

The present investigation was carried out to isolate arsenic (As)-resistant endophytic bacteria from the roots of alfalfa and chickpea plants grown in arsenic-contamination soil, characterize their As tolerance ability, plant growth-promoting characteristics, and their role to induce As resistance by the plant. A total of four root endophytic bacteria were isolated from plants grown in As-contaminated soil (160–260-mg As kg−1 of soil). These isolates were studied for plant growth-promoting (PGP) characteristics through siderophore, phosphate solubilization, nitrogen fixation, protease, and lipase production, and the presence of the arsenate reductase (arsC) gene. Based on 16S rDNA sequence analysis, these isolates belong to the genera Acinetobacter, Pseudomonas, and Rahnella. All isolates were found As tolerant, of which one isolate, Pseudomonas sp. QNC1, showed the highest tolerance up to 350-mM concentration in the LB medium. All isolates exhibited phosphate solubilization activity. Siderophore production activity was shown by only Pseudomonas sp. QNC1, while nitrogen fixation activity was shown by only Rahnella sp. QNC2 isolate. Acinetobacter sp. QNA1, QNA2, and Rahnella sp. QNC2 exhibited lipase production, while only Pseudomonas sp. QNC1 was able to produce protease. The presence of the arsC gene was detected in all isolates. The effect of endophytic bacteria on biomass production of alfalfa and chickpea in five levels of arsenic concentrations (0-, 10-, 50-, 75-, and 100-mg kg−1 soil) was evaluated. The fresh and dry weights of roots of alfalfa and chickpea plants were decreased as the arsenic concentration of the soil was increased. Results indicate that the fresh and dry root weights of alfalfa and chickpea plants were significantly higher in endophytic bacteria-treated plants compared with non-treated plants. Inoculation of chickpea plants with Pseudomonas sp. QNC1 and Rahnella sp. QNC2 induced lower NPR3 gene expression in chickpea roots grown in soil with the final concentration of 100-mg kg−1 sodium arsenate compared with the non-endophyte-treated control. The same results were obtained in Acinetobacter sp. QNA2-treated alfalfa plants grown in the soil plus 50-mg kg−1 sodium arsenate. These results demonstrated that arsenic-resistant endophytic bacteria are potential candidates to enhance plant-growth promotion in As contamination soils. Characterization of bacterial endophytes with plant growth potential can help us apply them to improve plant yield under stress conditions.
Practicing Ballot Secrecy: Postal Voting and the Witness Requirement at the 2019 Finnish Elections
Authors: Weide Marjukka
Published: July 2021

Electoral rights belong to the core of citizenship in democratic nation-states. Voting, then, represents an actualization of the relationship between the citizen and the political community. For citizens living outside the country in which they are eligible to vote, voting signifies a rare institutional connection to the country of origin. The aim of this article is to explore the introduction of the postal vote, a new form of voting for external voters at Finnish elections, from the grassroots perspective. The study focuses on how a central policy concern, safeguarding ballot secrecy, was resolved in the policy implementation by the witness requirement, and how the individual voters subsequently applied it. According to the voters’ accounts of the act of voting, the adopted method for underlining the importance of ballot secrecy in the Finnish overseas postal voting system, for many voters, makes little sense. While they effectively practice ballot secrecy, many fail to demonstrate this to the witnesses they were supposed to convince. Conversely, for these voters, the witness requirement merely works to break the secondary secrecy of elections, namely the secrecy of their participation itself. The empirical material for the article comprises policy documents and thematic text material (interviews, written responses) from 31 Finnish citizens living outside Finland. The article contributes to the scholarly debates on voting as a social, institutional and material practice. It further provides policy-relevant knowledge about grassroots implementation to various electoral administrations many of which, at the time of writing, face pressure to reform their repertoire of voting methods to function better in exceptional circumstances, such as a pandemic.
Having the Cake and Eating It Too: First-Order, Second-Order and Bifactor Representations of Work Engagement
Authors: Salamon Janos , Tóth-Király István , Bõthe Beáta , Nagy Tamás , Orosz Gábor
Published: July 2021

Even though work engagement is a popular construct in organizational psychology, the question remains whether it is experienced as a global construct, or as its three components (vigor, dedication, absorption). The present study thus contributes to the ongoing scientific debate about the dimensionality of work engagement systematically compared one-factor, first-order, higher-order, and bifactor confirmatory factor analytic (CFA) representations of work engagement measured by the short version of Utrecht Work Engagement Scale (UWES-9). We also documented the validity evidence of the most optimal representation based on its test-criterion relationship with basic psychological need fulfillment at work, turnover intentions, work addiction, and work satisfaction. Based on responses provided by two distinct samples of employees (N1= 242,N2= 505), our results supported the superiority of the bifactor-CFA representation including a global factor of work engagement and three co-existing specific factors of vigor, dedication, and absorption. This representation replicated well across the two samples through tests of measurement invariance. Finally, while global work engagement was substantially related to all correlates, the specific factors also demonstrated meaningful associations over and above the global levels of work engagement.
Depression as a Failed Anxiety: The Continuum of Precision-Weighting Dysregulation in Affective Disorders
Authors: Krupnik Valery
Published: July 2021

Depressive, anxiety, and trauma-related disorders have many symptoms in common such as unstable mood, high anxiety, sleep disturbance, impaired concentration among others. This degeneracy creates ambiguity in classifying psychiatric disorders and raises the question of their categorical vs. dimensional nature. Consequently, such ambiguity presents a dilemma for choosing diagnosis-specific vs. trans-diagnostic therapies. In this paper, I build on a theory that considers affective disorders on the continuum of stress response from normative to traumatic. Using an integrative evolutionary-stress response-predictive processing (iESP) model, I arrange affective disorders on a continuum of precision-weighting dysregulation, where depressive, anxiety and trauma-induced disorders have a characteristic pattern of precision-weighting dysregulation. I specifically address the relationship between anxiety and depressive stress responses, exploring the role of anxiety in the dynamics of depressive stress response and the resulting high co-occurrence of anxiety and depression symptoms. Finally, I discuss the model's relevance for therapy of depression.
Predictable Words Are More Likely to Be Omitted in Fragments–Evidence From Production Data
Authors: Lemke Robin , Reich Ingo , Schäfer Lisa , Drenhaus Heiner
Published: July 2021

Instead of a full sentence likeBring me to the university(uttered by the passenger to a taxi driver) speakers often use fragments likeTo the universityto get their message across. So far there is no comprehensive and empirically supported account of why and under which circumstances speakers sometimes prefer a fragment over the corresponding full sentence. We propose an information-theoretic account to model this choice: A speaker chooses the encoding that distributes information most uniformly across the utterance in order to make the most efficient use of the hearer's processing resources (Uniform Information Density, Levy and Jaeger,2007). Since processing effort is related to the predictability of words (Hale,2001) our account predicts two effects of word probability on omissions: First, omitting predictable words (which are more easily processed), avoids underutilizing processing resources. Second, inserting words before very unpredictable words distributes otherwise excessively high processing effort more uniformly. We test these predictions with a production study that supports both of these predictions. Our study makes two main contributions: First we develop an empirically motivated and supported account of fragment usage. Second, we extend previous evidence for information-theoretic processing constraints on language in two ways: We find predictability effects on omissions driven by extralinguistic context, whereas previous research mostly focused on effects of local linguistic context. Furthermore, we show that omissions of content words are also subject to information-theoretic well-formedness considerations. Previously, this has been shown mostly for the omission of function words.