bluuebunny/crossref_metadata_2025 huggingface dataset:
Targeted Therapeutic Strategies for Triple-Negative Breast Cancer
Authors: Li Ying , Zhan Zhijun , Yin Xuemin , Fu Shujun , Deng Xiyun
Published: October 2021

Triple-negative breast cancer (TNBC) is the most aggressive subtype of breast cancer, which is characterized by the absence of estrogen receptor (ER) and progesterone receptor (PR) expression and the absence of human epidermal growth factor receptor 2 (HER2) expression/amplification. Conventional chemotherapy is the mainstay of systemic treatment for TNBC. However, lack of molecular targeted therapies and poor prognosis of TNBC patients have prompted a great effort to discover effective targets for improving the clinical outcomes. For now, poly (ADP-ribose) polymerase (PARP) inhibitors (PARPi’s) and immune checkpoint inhibitors have been approved for the treatment of TNBC. Moreover, agents that target signal transduction, angiogenesis, epigenetic modifications, and cell cycle are under active preclinical or clinical investigations. In this review, we highlight the current major developments in targeted therapies of TNBC, with some descriptions about their (dis)advantages and future perspectives.
Efficacy and Safety of PARP Inhibitors in Advanced or Metastatic Triple-Negative Breast Cancer: A Systematic Review and Meta-Analysis
Authors: Liu Xu , Wu Kan , Zheng Dan , Luo Chuanxu , Fan Yu , Zhong Xiaorong , Zheng Hong
Published: October 2021

Purpose

Poly (ADP-ribose) polymerase (PARP) inhibitors have shown promising results in metastatic triple-negative breast cancers (TNBCs). We therefore performed a systematic review and meta-analysis to evaluate the efficacy and safety of this drug in patients with advanced or metastatic TNBC.

Methods

A systematic literature search of PubMed, Embase, Scopus, Web of Science, and Cochrane Central Register of Controlled Trials for synonyms of “PARP inhibitors” and “breast cancer” was carried out. All published phase II/III clinical studies of PARP inhibitors in patients with advanced/metastatic TNBC were screened. Data were extracted independently by two authors and analyzed using Review Manager software version 5.3. End points include overall response rate (ORR), progression-free survival (PFS), and adverse events.

Results

Ten clinical trials were identified, with a total of 1,495 patients included. Pooled analyses showed that PARP inhibitors could provide a significant improvement of ORR [risk ratio (RR) = 2.00; 95% confidence interval (CI), 1.14–3.50; p = 0.02) and PFS [hazard ratio (HR) = 0.68; 95%Cl, 0.59–0.77; p < 0.0001) compared to chemotherapy in the whole population. In subgroup analysis, patients with BRCA mutation had a higher objective response to PARP inhibitor, with an RR of 2.85 (95%CI, 1.34–6.06; p = 0.007) compared to BRCA wild-type patients. However, no significant difference in ORR was observed between the homologous recombination deficiency (HRD) positive and non-HRD subgroups (RR = 1.82; 95%CI, 0.81–4.08; p = 0.14). Hematological toxicity is a common adverse event of PARP inhibitors.

Conclusions

PARP inhibitors are effective options for the treatment of patients with advanced or metastatic TNBC. Compared with patients without germline BRCA mutation, patients with germline BRCA mutation could benefit more from PARP inhibitors. In clinical setting, hematological toxicity associated with PARP inhibitors should be monitored regularly.
Glucose Metabolism Reprogramming of Primary Tumor and the Liver Is Associated With Disease-Free Survival in Patients With Early NSCLC
Authors: Tan Hongpei , Ma Mengtian , Huang Jing , Zhu Wenhao , Hu Shuo , Zheng Kai , Rong Pengfei
Published: October 2021

Purpose

Tumor promote disease progression by reprogramming their metabolism and that of distal organs, so it is of great clinical significance to study the changes in glucose metabolism at different tumor stages and their effect on glucose metabolism in other organs.

Methods

A retrospective single-centre study was conducted on 253 NSCLC (non-small cell lung cancer) patients with negative lymph nodes and no distant metastasis. According to the AJCC criteria, the patients were divided into different groups based on tumor size: stage IA, less than 3 cm (group 1, n = 121); stage IB, greater than 3-4 cm (group 2, n = 64); stage IIA, greater than 4-5 cm (group 3, n = 36); and stage IIB, greater than 5-7 cm (group 4, n = 32). All of the patients underwent baseline 18F-FDG PET/CT scans, and the primary lesion SUVmax (maximum standardized uptake value), liver SUVmean (mean standardized uptake value), spleen SUVmean, TLR (Tumor-to-liver SUV ratio) and TSR (Tumor-to-spleen SUV ratio) were included in the study, combined with clinical examination indicators to evaluate DFS (disease free survival).

Results

In NSCLC patients, with the increase in the maximum diameter of the tumor, the SUVmax of the primary lesion gradually increased, and the SUVmean of the liver gradually decreased. The primary lesion SUVmax, liver SUVmean, TLR and TSR were related to disease recurrence or death. The best predictive parameters were different when the tumor size differed. SUVmax had the highest efficiency when the tumor size was less than 4 cm (AUC:0.707 (95% CI, 0.430-0.984) tumor size < 3 cm), (AUC:0.726 (95% CI, 0.539-0.912) tumor size 3-4 cm), liver SUVmean had the highest efficiency when the tumor size was 4-5 cm (AUC:0.712 (95% CI, 0.535-0.889)), and TLR had the highest efficiency when the tumor size was 5-7 cm [AUC:0.925 (95%CI, 0.820-1.000)].

Conclusions

In patients with early NSCLC, glucose metabolism reprogramming occurs in the primary lesion and liver. With the increase in tumor size, different metabolic parameters should be selected to evaluate the prognosis of patients.
Portal Venous Circulating Tumor Cells Undergoing Epithelial-Mesenchymal Transition Exhibit Distinct Clinical Significance in Pancreatic Ductal Adenocarcinoma
Authors: Pan Yujin , Li Deyu , Yang Jiuhui , Wang Ning , Xiao Erwei , Tao Lianyuan , Ding Xiangming , Sun Peichun , Li Dongxiao
Published: October 2021

Background

Much importance is attached to the clinical application value of circulating tumor cells (CTCs), meanwhile tumor-proximal CTCs detection has interested researchers for its unique advantage. This research mainly discusses the correlation of portal venous (PoV) CTCs counts in different epithelial-mesenchymal transition status with clinicopathologic parameters and postoperative prognosis in resectable pancreatic ductal adenocarcinoma patients (PDAC).

Methods

PDAC patients (n=60) who received radical resection were enrolled in this research. PoV samples from all patients and peripheral venous (PV) samples from 32 patients among them were collected to verify spatial heterogeneity of CTCs distribution, and explore their correlation with clinicopathologic parameters and clinical prognosis.

Results

CTCs detectable rate and each phenotype count of PoV were higher than those of PV. Patients with recurrence had higher PV and PoV epithelial CTCs (E-CTCs) counts than recurrence-free patients (P<0.05). Some unfavourable clinicopathologic parameters were closely related to higher PoV CTCs counts. Multivariate regression analysis demonstrated that PoV mesenchymal CTC (M-CTC)s≥1/5 ml was an independent risk factor for metastasis free survival (MFS) (P=0.003) and overall survival (OS) (P=0.043).

Conclusions

Our research demonstrated that portal venous was a preferable vessel for CTC test, and patients with PoV M-CTC≥1/5 ml had shorter MFS and OS time in resectable PDAC patients. PoV CTC phenotype detection has the potential to be a reliable and accurate tool to identify resectable PDAC patients with high tendency of postoperative metastasis for better stratified management.
Mechanisms of JARID1B Up-Regulation and Its Role in Helicobacter pylori-Induced Gastric Carcinogenesis
Authors: Zheng Lixin , Wu Yujiao , Shen Li , Liang Xiuming , Yang Zongcheng , Li Shuyan , Li Tongyu , Shang Wenjing , Shao Wei , Wang Yue , Liu Fen , Ma Lin , Jia Jihui
Published: October 2021

Gastric cancer (GC) is the third leading cause of cancer-related death worldwide. Helicobacter pylori infection can induce GC through a serial cascade of events, with emerging evidence suggesting the important role of epigenetic alterations in the development and progression of the disease. Here, we report on mechanisms responsible for Jumonji AT-rich interactive domain1B (JARID1B) upregulation in GC and its role in the malignant transformation induced by H. pylori infection. We found that upregulation of JARID1B was associated with poorer prognosis, greater tumor purity, and less immune cell infiltration into the tumor. Mechanistically, we showed that the upregulation of JARID1B in human GC was attributed to JARID1B amplification and its induction by H. pylori infection. Furthermore, we identified miR-29c as a negative regulator of JARID1B in GC. H. pylori caused downregulation of miR-29c in human GC and thereby contributed to JARID1B upregulation through relieving posttranscriptional regulation. Functionally, we showed that knockdown of JARID1B reduced GC cell proliferation induced by H. pylori infection. Subsequently, cyclinD1 (CCND1), a key molecule in GC, was shown to be a target gene of JARID1B. In conclusion, these results suggest that JARID1B may be an oncogene upregulated in human GC and could represent a novel therapeutic target to prevent malignant transformation induced by H. pylori infection.
Haploidentical Stem Cell Transplantation for Acute Myeloid Leukemia: Current Therapies, Challenges and Future Prospective
Authors: Chang Ying-Jun , Zhao Xiang-Yu , Huang Xiao-Jun
Published: October 2021

Haploidentical stem cell transplantation (haplo-SCT), an alternative donor source, offers a curative therapy for patients with acute myeloid leukemia (AML) who are transplant candidates. Advances in transplantation techniques, such as donor selection, conditioning regimen modification, and graft-versus-host disease prophylaxis, have successfully improved the outcomes of AML patients receiving haplo-SCT and extended the haploidentical transplant indictions for AML. Presently, treating de novo AML, secondary AML, therapy-related AML and refractory and relapsed AML with haplo-SCT can achieve comparable outcomes to those of human leukocyte antigen (HLA)-matched sibling donor transplantation (MSDT), unrelated donor transplantation or umbilical cord blood transplantation. For some subgroups of AML subjects, such as patients with positive pretransplantation minimal/measurable residual disease, recent studies suggest that haplo-SCT might be superior to MSDT in decreasing relapse and improving survival. Unfortunately, for patients with AML after haplo-SCT, relapse and infections remain the causes of death that restrict further improvement in clinical outcomes. In this review, we discuss the recent advances and challenges in haplo-SCT for AML treatment, mainly focusing on unmanipulated haplo-SCT protocols. We provide an outlook on future prospects and suggest that relapse prophylaxis, intervention, and treatment, as well as infection prevention and therapy, are areas of active research in AML patients who receive haploidentical allografts.
Dosimetric Comparison of Upfront Boosting With Stereotactic Radiosurgery Versus Intraoperative Radiotherapy for Glioblastoma
Authors: Sarria Gustavo R. , Smalec Zuzanna , Muedder Thomas , Holz Jasmin A. , Scafa Davide , Koch David , Garbe Stephan , Schneider Matthias , Hamed Motaz , Vatter Hartmut , Herrlinger Ulrich , Giordano Frank A. , Schmeel Leonard Christopher
Published: October 2021

Purpose

To simulate and analyze the dosimetric differences of intraoperative radiotherapy (IORT) or pre-operative single-fraction stereotactic radiosurgery (SRS) in addition to post-operative external beam radiotherapy (EBRT) in Glioblastoma (GB).

Methods

Imaging series of previously treated patients with adjuvant radiochemotherapy were analyzed. For SRS target definition, pre-operative MRIs were co-registered to planning CT scans and a pre-operative T1-weighted gross target volume (GTV) plus a 2-mm planning target volume (PTV) were created. For IORT, a modified (m)GTV was expanded from the pre-operative volume, in order to mimic a round cavity as during IORT. Dose prescription was 20 Gy, homogeneously planned for SRS and calculated at the surface for IORT, to cover 99% and 90% of the volumes, respectively. For tumors > 2cm in maximum diameter, a 15 Gy dose was prescribed. Plan assessment was performed after calculating the 2-Gy equivalent doses (EQD2) for both boost modalities and including them into the EBRT plan. Main points of interest encompass differences in target coverage, brain volume receiving 12 Gy or more (V12), and doses to various organs-at-risk (OARs).

Results

Seventeen pre-delivered treatment plans were included in the study. The mean GTV was 21.72 cm3 (SD ± 19.36) and mGTV 29.64 cm3 (SD ± 25.64). The mean EBRT and SRS PTV were 254.09 (SD ± 80.0) and 36.20 cm3 (SD ± 31.48), respectively. Eight SRS plans were calculated to 15 Gy according to larger tumor sizes, while all IORT plans to 20 Gy. The mean EBRT D95 was 97.13% (SD ± 3.48) the SRS D99 99.91% (SD ± 0.35) and IORT D90 83.59% (SD ± 3.55). Accounting for only-boost approaches, the brain V12 was 49.68 cm3 (SD ± 26.70) and 16.94 cm3 (SD ± 13.33) (p<0.001) for SRS and IORT, respectively. After adding EBRT results respectively to SRS and IORT doses, significant lower doses were found in the latter for mean Dmax of chiasma (p=0.01), left optic nerve (p=0.023), right (p=0.008) and left retina (p<0.001). No significant differences were obtained for brainstem and cochleae.

Conclusion

Dose escalation for Glioblastoma using IORT results in lower OAR exposure as conventional SRS.
Recent Advances in the Mechanism Research and Clinical Treatment of Anti-Angiogenesis in Biliary Tract Cancer
Authors: Wang Yue , Chen Tianli , Li Kangshuai , Mu Wentao , Liu Zengli , Shi Anda , Liu Jialiang , Zhao Wei , Lian Shuo , Huang Shaohui , Pan Chang , Zhang Zongli
Published: October 2021

Biliary tract cancers (BTCs), including cholangiocarcinoma (CCA) and gallbladder cancer (GC), are malignancies originating from the biliary tract with poor prognosis. In the early stage of BTCs, surgery is the only choice for cure. Unfortunately, most patients with BTC are diagnosed at an advanced stage and lose the opportunity for surgery. For many advanced solid tumors, antiangiogenic therapy has achieved encouraging results. While most clinical studies on antiangiogenic therapy in advanced BTCs have shown an excellent disease control rate (DCR), the improvement in overall survival (OS) is controversial. Understanding how the relevant signaling molecules influence the angiogenic response and the functional interaction is necessary for the formulation of new treatment regimens and the selection of enrolled patients. In this review, we aim to summarize and discuss the latest advances in antiangeogenesis for BTCs, mainly focusing on the molecular mechanism of angiogenesis in BTCs and the therapeutic effects from clinical trials. Furthermore, the horizon of antiangiogenesis for BTCs is highlighted.
Sevoflurane Increases Hippocampal Theta Oscillations and Impairs Memory Via TASK-3 Channels
Authors: Han Linlin , Zhao Shuai , Xu Feng , Wang Yafeng , Zhou Ruihui , Huang Shiqian , Ding Yuanyuan , Deng Daling , Mao Weike , Chen Xiangdong
Published: October 2021

Sevoflurane can induce memory impairment during clinical anesthesia; however, the underlying mechanisms are largely unknown. TASK-3 channels are one of the potential targets of sevoflurane. Accumulating evidence supports a negative role of intracranial theta rhythms (4–12 Hz) in memory formation. Here, we investigated whether TASK-3 channels contribute to sevoflurane-induced memory impairment by regulating hippocampal theta rhythms. In this study, the memory performance of mice was tested by contextual fear conditioning and inhibitory avoidance experiments. The hippocampal local field potentials (LFPs) were recorded from chronically implanted electrodes located in CA3 region. The results showed that sevoflurane concentration-dependently impaired the memory function of mice, as evidenced by the decreased time mice spent on freezing and reduced latencies for mice to enter the shock compartment. Our electrophysiological results revealed that sevoflurane also enhanced the spectral power of hippocampal LFPs (1–30 Hz), particularly in memory-related theta rhythms (4–12 Hz). These effects were mitigated by viral-mediated knockdown of TASK-3 channels in the hippocampal CA3 region. The knockdown of hippocampal TASK-3 channels significantly reduced the enhancing effect of sevoflurane on hippocampal theta rhythms and alleviated sevoflurane-induced memory impairment. Our data indicate that sevoflurane can increase hippocampal theta oscillations and impair memory function via TASK-3 channels.
Quercetin Attenuates Cardiac Hypertrophy by Inhibiting Mitochondrial Dysfunction Through SIRT3/PARP-1 Pathway
Authors: Chen Wen-Jing , Cheng Yan , Li Wen , Dong Xiao-Kang , Wei Jian-liang , Yang Chuan-Hua , Jiang Yue-Hua
Published: October 2021

Cardiac hypertrophy is an important characteristic in the development of hypertensive heart disease. Mitochondrial dysfunction plays an important role in the pathology of cardiac hypertrophy. Recent studies have shown that sirtuin 3 (SIRT3)/poly (ADP-ribose) polymerase-1 (PARP-1) pathway modulation inhibits cardiac hypertrophy. Quercetin, a natural flavonol agent, has been reported to attenuate cardiac hypertrophy. However, the molecular mechanism is not completely elucidated. In this study, we aimed to explore the mechanism underlying the protective effect of quercetin on cardiac hypertrophy. Spontaneously hypertensive rats (SHRs) were treated with quercetin (20 mg/kg/d) for 8 weeks to evaluate the effects of quercetin on blood pressure and cardiac hypertrophy. Additionally, the mitochondrial protective effect of quercetin was assessed in H9c2 cells treated with Ang II. SHRs displayed aggravated cardiac hypertrophy and fibrosis, which were attenuated by quercetin treatment. Quercetin also improved cardiac function, reduced mitochondrial superoxide and protected mitochondrial structure in vivo. In vitro, Ang II increased the mRNA level of hypertrophic markers including atrial natriuretic factor (ANF) and β-myosin heavy chain (β-MHC), whereas quercetin ameliorated this hypertrophic response. Moreover, quercetin prevented mitochondrial function against Ang II induction. Importantly, mitochondrial protection and PARP-1 inhibition by quercetin were partly abolished after SIRT3 knockdown. Our results suggested that quercetin protected mitochondrial function by modulating SIRT3/PARP-1 pathway, contributing to the inhibition of cardiac hypertrophy.
Traditional Herbal Medicine for Insomnia in Patients With Cancer: A Systematic Review and Meta-Analysis
Authors: Yoon Jee-Hyun , Kim Eun Hye , Park Su Bin , Lee Jee Young , Yoon Seong Woo
Published: October 2021

Background: Insomnia is one of the most prevalent cancer-related symptoms and has a severe impact on the quality of life. This study aimed to evaluate the efficacy and safety of traditional herbal medicine (THM) for improving sleep quality in patients with cancer.

Methods: Randomized controlled trials (RCTs) evaluating orally administered THM in a cancer population with insomnia were searched using nine electronic databases up to November 30, 2020. The outcome measurements were sleep quality measured by validated questionnaire such as the Pittsburgh Sleep Quality Index (PSQI), total effective rate, and adverse effects. The included studies were appraised using the Cochrane risk of bias tool and meta-analyzed. The quality of evidence was assessed using the Grading of Recommendations Assessment, Development, and Evaluation (GRADE) method.

Results: Fourteen RCTs were included in the systematic review, and 10 RCTs were analyzed quantitatively. Compared to hypnotics, THM showed a significant improvement in sleep quality by reducing the PSQI score [mean difference (MD) -2.25, 95% confidence interval (CI) −3.46 to −1.05, I2 = 84%] and increasing the total effective rate [risk ratio (RR) 1.26, 95% CI 1.07 to 1.48, I2 = 70%] with low quality of evidence. Compared to placebo, THM also reduced the PSQI score significantly (MD −2.56, 95% CI −3.81 to −1.31, I2 = 91%) with moderate quality of evidence. The most frequently used herbs were Ziziphus jujuba Mill. No serious adverse events were observed.

Conclusion: This review suggests that THM may be an effective therapeutic option for insomnia in patients with cancer. However, considering the limited methodological qualities and inconsistent results of the included trials, further rigorous RCTs are required.

Systematic Review Registration: [https://www.crd.york.ac.uk/prospero], PROSPERO 2021 [CRD42021265070]
Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease
Authors: Kawanami Daiji , Takashi Yuichi , Muta Yoshimi , Oda Naoki , Nagata Dai , Takahashi Hiroyuki , Tanabe Makito
Published: October 2021

Diabetic kidney disease (DKD) is a major cause of end-stage kidney disease (ESKD) worldwide. Mineralocorticoid receptor (MR) plays an important role in the development of DKD. A series of preclinical studies revealed that MR is overactivated under diabetic conditions, resulting in promoting inflammatory and fibrotic process in the kidney. Clinical studies demonstrated the usefulness of MR antagonists (MRAs), such as spironolactone and eplerenone, on DKD. However, concerns regarding their selectivity for MR and hyperkalemia have remained for these steroidal MRAs. Recently, nonsteroidal MRAs, including finerenone, have been developed. These agents are highly selective and have potent anti-inflammatory and anti-fibrotic properties with a low risk of hyperkalemia. We herein review the current knowledge and future perspectives of MRAs in DKD treatment.
Targeting Aberrant Expression of STAT3 and AP-1 Oncogenic Transcription Factors and HPV Oncoproteins in Cervical Cancer by Berberis aquifolium
Authors: Singh Tejveer , Chhokar Arun , Thakur Kulbhushan , Aggarwal Nikita , Pragya Pragya , Yadav Joni , Tripathi Tanya , Jadli Mohit , Bhat Anjali , Gupta Pankaj , Khurana Anil , Chandra Bharti Alok
Published: October 2021

Background: Present study examines phytochemical preparation that uses berberine’s plant source B. aquifolium root for availability of similar anti-cervical cancer (CaCx) and anti-HPV activities to facilitate repurposing of the B. aquifolium based drug in the treatment of CaCx.

Purpose: To evaluate therapeutic potential of different concentrations of ethanolic extract of B. aquifolium root mother tincture (BAMT) against HPV-positive (HPV16: SiHa, HPV18: HeLa) and HPV-negative (C33a) CaCx cell lines at molecular oncogenic level.

Materials and Methods: BAMT was screened for anti-proliferative activity by MTT assay. Cell cycle progression was analyzed by flowcytometry. Then, the expression level of STAT3, AP-1, HPV E6 and E7 was detected by immunoblotting, whereas nuclear localization was observed by fluorescence microscopy. Phytochemicals reportedly available in BAMT were examined for their inhibitory action on HPV16 E6 by in silico molecular docking.

Results: BAMT induced a dose-dependent decline in CaCx cell viability in all cell types tested. Flowcytometric evaluation of BAMT-treated cells showed a small but specific cell growth arrest in G1-phase. BAMT-treatment resulted in reduced protein expression of key transcription factors, STAT3 with a decline of its active form pSTAT3 (Y705); and components of AP-1 complex, JunB and c-Jun. Immunocytochemistry revealed that BAMT did not prevent the entry of remnant active transcription factor to the nucleus, but loss of overall transcription factor activity resulted in reduced availability of transcription factors in the cancer cells. These changes were accompanied by gradual loss of HPV E6 and E7 protein in BAMT-treated HPV-positive cells. Molecular docking of reported active phytochemicals in B. aquifolium root was performed, which indicated a potential interference of HPV16 E6’s interaction with pivotal cellular targets p53, E6AP or both by constituent phytochemicals. Among these, berberine, palmatine and magnoflorine showed highest E6 inhibitory potential.

Conclusion: Overall, BAMT showed multi-pronged therapeutic potential against HPV infection and cervical cancer and the study described the underlying molecular mechanism of its action.
Safety Profile of Ibrutinib: An Analysis of the WHO Pharmacovigilance Database
Authors: Allouchery Marion , Tomowiak Cécile , Lombard Thomas , Pérault-Pochat Marie-Christine , Salvo Francesco
Published: October 2021

As ibrutinib has become a standard of care in B-cell malignancies in monotherapy or in combination with other agents, definition of its safety profile appears essential. The aim of this study was to further characterize the safety profile of ibrutinib through the identification of potential safety signals in a large-scale pharmacovigilance database. All serious individual case safety reports (ICSRs) in patients aged ≥18 years involving ibrutinib suspected in the occurrence of serious adverse drug reactions or drug interacting from November 13th, 2013 to December 31st, 2020 were extracted from VigiBase, the World Health Organization global safety database. Disproportionality reporting was assessed using the information component (IC) and the proportional reporting ratio (PRR), with all other anticancer drugs used as the reference group. To mitigate the confounding of age, two subgroups were considered: patients aged<75 years and ≥75 years. A signal of disproportionate reporting (SDR) was defined if both IC and PRR were significant. A total of 16,196 ICSRs were included. The median age of patients was 72.9 years, 42.6% of ICSRs concerned patients aged ≥75 years, and 64.2% male patients. More than half (56.2%) of ICSRs resulted in hospitalization or prolonged hospitalization. Among 713 SDRs, 36 potential safety signals emerged in ibrutinib-treated patients, mainly ischemic heart diseases, pericarditis, uveitis, retinal disorders and fractures. All potential safety signals having arisen in this analysis may support patient care and monitoring of ongoing clinical trials. However, owing to the mandatory limitations of this study, our results need further confirmation using population-based studies.
RETRACTED: Novel Insights Into the Role of Mitochondria-Derived Peptides in Myocardial Infarction
Authors: Wu Dan , Kampmann Enny , Qian Geng
Published: October 2021

Mitochondria-derived peptides (MDPs) are a new class of bioactive peptides encoded by small open reading frames (sORFs) within known mitochondrial DNA (mtDNA) genes. MDPs may affect the expression of nuclear genes and play cytoprotective roles against chronic and age-related diseases by maintaining mitochondrial function and cell viability in the face of metabolic stress and cytotoxic insults. In this review, we summarize clinical and experimental findings indicating that MDPs act as local and systemic regulators of glucose homeostasis, immune and inflammatory responses, mitochondrial function, and adaptive stress responses, and focus on evidence supporting the protective effects of MDPs against myocardial infarction. These insights into MDPs actions suggest their potential in the treatment of cardiovascular diseases and should encourage further research in this field.
Microtubules as Major Regulators of Endothelial Function: Implication for Lung Injury
Authors: Karki Pratap , Birukova Anna A.
Published: October 2021

Endothelial dysfunction has been attributed as one of the major complications in COVID-19 patients, a global pandemic that has already caused over 4 million deaths worldwide. The dysfunction of endothelial barrier is characterized by an increase in endothelial permeability and inflammatory responses, and has even broader implications in the pathogenesis of acute respiratory syndromes such as ARDS, sepsis and chronic illnesses represented by pulmonary arterial hypertension and interstitial lung disease. The structural integrity of endothelial barrier is maintained by cytoskeleton elements, cell-substrate focal adhesion and adhesive cell junctions. Agonist-mediated changes in endothelial permeability are directly associated with reorganization of actomyosin cytoskeleton leading to cell contraction and opening of intercellular gaps or enhancement of cortical actin cytoskeleton associated with strengthening of endothelial barrier. The role of actin cytoskeleton remodeling in endothelial barrier regulation has taken the central stage, but the impact of microtubules in this process remains less explored and under-appreciated. This review will summarize the current knowledge on the crosstalk between microtubules dynamics and actin cytoskeleton remodeling, describe the signaling mechanisms mediating this crosstalk, discuss epigenetic regulation of microtubules stability and its nexus with endothelial barrier maintenance, and overview a role of microtubules in targeted delivery of signaling molecules regulating endothelial permeability and inflammation.
Studying Lipid-Related Pathophysiology Using the Yeast Model
Authors: Ralph-Epps Tyler , Onu Chisom J. , Vo Linh , Schmidtke Michael W. , Le Anh , Greenberg Miriam L.
Published: October 2021

Saccharomyces cerevisiae, commonly known as baker’s yeast, is one of the most comprehensively studied model organisms in science. Yeast has been used to study a wide variety of human diseases, and the yeast model system has proved to be an especially amenable tool for the study of lipids and lipid-related pathophysiologies, a topic that has gained considerable attention in recent years. This review focuses on how yeast has contributed to our understanding of the mitochondrial phospholipid cardiolipin (CL) and its role in Barth syndrome (BTHS), a genetic disorder characterized by partial or complete loss of function of the CL remodeling enzyme tafazzin. Defective tafazzin causes perturbation of CL metabolism, resulting in many downstream cellular consequences and clinical pathologies that are discussed herein. The influence of yeast research in the lipid-related pathophysiologies of Alzheimer’s and Parkinson’s diseases is also summarized.
The Programming of Antioxidant Capacity, Immunity, and Lipid Metabolism in Dojo Loach (Misgurnus anguillicaudatus) Larvae Linked to Sodium Chloride and Hydrogen Peroxide Pre-treatment During Egg Hatching
Authors: Wang Mengya , Xu Wenyu , Zou Jiahong , Li Shuaitong , Song Zixi , Zheng Feifei , Ji Wei , Xu Zhen , Wang Qingchao
Published: October 2021

Non-nutritional stress during early life period has been reported to promote the metabolic programming in fish induced by nutritional stimulus. Sodium chloride (NaCl) and hydrogen peroxide (H2O2) have been widely applied during fish egg hatching, but the influences on health and metabolism of fish in their later life remain unknown. In the present study, H2O2 treatment at 400mg/L but not 200mg/L significantly increased the loach hatchability and decreased the egg mortality, while NaCl treatment at 1,000 and 3,000mg/L showed no significant influences on the loach hatchability nor egg mortality. Further studies indicated that 400mg/L H2O2 pre-treatment significantly enhanced the antioxidant capacity and the mRNA expression of genes involved in immune response of loach larvae, accompanied by the increased expression of genes involved in fish early development. However, the expression of most genes involved in lipid metabolism, including catabolism and anabolism of loach larvae, was significantly upregulated after 200mg/L H2O2 pre-treatment. NaCl pre-treatment also increased the expression of antioxidant enzymes; however, only the expression of C1q within the detected immune-related genes was upregulated in loach larvae. One thousand milligram per liter NaCl pre-treatment significantly increased the expression of LPL and genes involved in fish early development. Thus, our results suggested the programming roles of 400mg/L H2O2 pre-treatment during egg hatching in enhancing antioxidant capacity and immune response of fish larvae via promoting fish early development.
Identification of Micro Ribonucleic Acids and Their Targets in Response to Plasmodiophora brassicae Infection in Brassica napus
Authors: Li Qian , Shah Nadil , Zhou Xueqing , Wang Huiying , Yu Wenlin , Luo Jiajie , Liu Yajun , Li Genze , Liu Chao , Zhang Chunyu , Chen Peng
Published: October 2021

Clubroot disease, which is caused by the soil-borne pathogen Plasmodiophora brassicae War (P. brassicae), is one of the oldest and most destructive diseases of Brassica and cruciferous crops in the world. Plant microRNAs [micro ribonucleic acids (miRNAs)] play important regulatory roles in several developmental processes. Although the role of plant miRNAs in plant-microbe interaction has been extensively studied, there are only few reports on the specific functions of miRNAs in response to P. brassicae. This study investigated the roles of miRNAs and their targets during P. brassicae infection in a pair of Brassica napus near-isogenic lines (NILs), namely clubroot-resistant line 409R and clubroot-susceptible line 409S. Small RNA sequencing (sRNA-seq) and degradome-seq were performed on root samples of 409R and 409S with or without P. brassicae inoculation. sRNA-seq identified a total of 48 conserved and 72 novel miRNAs, among which 18 had a significant differential expression in the root of 409R, while only one miRNA was differentially expressed in the root of 409S after P. brassicae inoculation. The degradome-seq analysis identified 938 miRNA target transcripts, which are transcription factors, enzymes, and proteins involved in multiple biological processes and most significantly enriched in the plant hormone signal transduction pathway. Between 409R and 409S, we found eight different degradation pathways in response to P. brassicae infection, such as those related to fatty acids. By combining published transcriptome data, we identified a total of six antagonistic miRNA-target pairs in 409R that are responsive to P. brassicae infection and involved in pathways associated with root development, hypersensitive cell death, and chloroplast metabolic synthesis. Our results reveal that P. brassicae infection leads to great changes in miRNA pool and target transcripts. More interestingly, these changes are different between 409R and 409S. Clarification of the crosstalk between miRNAs and their targets may shed new light on the possible mechanisms underlying the pathogen resistance against P. brassicae.
The Influence of Gratitude on the Meaning of Life: The Mediating Effect of Family Function and Peer Relationship
Authors: Zhang Ping , Ye Lin , Fu Fang , Zhang Lan Ge
Published: October 2021

Objective: This study aimed to explore the influence of gratitude on the meaning of life of college students and the mediating effect of family function and peer relationships.

Methods: A total of 1,049 college students (mean age: 18.59 ± 0.96 years) were investigated by gratitude scale, family function scale, peer relationship questionnaire, and meaning of life scale.

Results: (1) Gratitude was positively correlated with meaning existence (r = 0.39, P < 0.05), meaning seeking (r = 0.23, P < 0.05), and peer relationship (r = 0.32, P < 0.05); meanwhile, it is also positively correlated with family function (r = 0.34, P < 0.05); (2) family function partially mediates the relationship between gratitude and meaning of life. Similarly, peer relationship partially mediates the relationship between gratitude and meaning of life.

Conclusion: The mediating model showed that grateful individuals can better sense the meaning of life by perceiving good family function and good peer relationships.
A Counseling Application as an Alternative Tool in Increasing Coping Self-Efficacy Among University Students With Academic Distress During Coronavirus Disease 2019 Pandemic in Indonesia: A Study Protocol for a Randomized Controlled Non-Inferiority Trial
Authors: Hinduan Zahrotur Rusyda , Wedyaswari Miryam , Reswara Ilham Phalosa , Setyowibowo Hari
Published: October 2021

The coronavirus disease 2019 (COVID-19) pandemic increased education-related distress among University students globally, including in Indonesia. Psychological factors, such as academic demands, limited opportunity to meet their peers, problematic use of technology, and domestic problems, influenced the well-being of the students, leading to poor academic performance. A mobile-based counseling application was developed to address the distress among University students. The application was meant to reach students living remotely to enable them to access psychological assistance. Therefore, the purpose of this study was to describe a protocol aimed to evaluate the equivalence of the application when compared to the Treatment-As-Usual (TAU) in increasing the coping self-efficacy (CSE) and resilience of students as well as in decreasing their level of depression. A two-armed parallel randomized control non-inferiority trial will be conducted among approximately 430 students with selected academic problems. The participants will be randomly allocated into the TAU and the intervention groups. The primary and secondary outcomes will be measured by the Indonesian versions of the Coping Self-Efficacy (CSE) Scale, the Resilience Scale (RS-14), and the Patient Health Questionnaire (PHQ-9). The data will be collected at baseline, at the end of each session, and after 3 months. The outcomes will be analyzed using repeated-measures ANOVAs, intention-to-treat, and per-protocol analysis. If proven, the application will be used as an alternative media in helping the students.

Clinical Trial Registration: Thailand Clinical Trials Registry (TCTR20200530001); Date of registration: May 28, 2020.
Student Perceptions of Academic Engagement and Student-Teacher Relationships in Problem-Based Learning
Authors: Amerstorfer Carmen M. , Freiin von Münster-Kistner Clara
Published: October 2021

Students’ academic engagement depends on a variety of factors that are related to personal learner characteristics, the teacher, the teaching methodology, peers, and other features in the learning environment. Components that influence academic engagement can be cognitive, metacognitive, affective, social, task-related, communicative, and foreign language-related. Rather than existing in isolated spheres, the factors contributing to an individual’s academic engagement intertwine and overlap. The relationships students cultivate with others are prominent in several of these areas. Positive interpersonal relationships enhance individuals’ enthusiasm for learning (Mercer and Dörnyei, 2020), which benefits sustainable learning success and self-confidence. The relationships between students and teachers and the perceptions students have of their teachers seem to be particularly influential on students’ engagement in academic undertakings. Problem-based learning (PBL), a teaching approach particularly suitable for tertiary education, involves students in authentic problem-solving processes and fosters students’ self-regulation and teamwork. Intensive relationship-building is one of the key characteristics of this student-centered approach (Amerstorfer, 2020). The study reported in this article explores the connection between the academic engagement of 34 students and their perceptions of three instructors in a teacher education program for pre-service English teachers in Austria. An online questionnaire was used to investigate the participants’ perceived academic engagement (effort, dedication, learning success) in a university course that implements PBL as its underlying teaching methodology in comparison to conventional teaching approaches. The study further examines how the students perceived the course instructors’ caring, credibility, communication style, and feedback, which leads to new information about how PBL shapes student-teacher relationships. Due to Covid-19, the otherwise face-to-face course was taught online.
Translation and Validation of a State-Measure of Body Image Satisfaction: The Body Image State Scale
Authors: Bardi Luc , Arnaud Claire , Bagès Céline , Langlois Frédéric , Rousseau Amelie
Published: October 2021

The aim of the present study is to test the validity and reliability of the French Body Image State Scale (F-BISS). The scale was translated using a back-translation technique, with discrepancies being settled through consensus. Three hundred and twelve female participants were recruited. Convergent validity was assessed using eating disorder evaluation and social comparison. Exploratory and confirmatory factor analyses were also conducted. The translated Body Image State Scale (BISS) demonstrated good psychometric properties, with good internal consistency (α = 0.83), and adequate goodness-of-fit. The translated BISS presented a unifactorial structure, with one factor explaining 56% of the variance. The exploratory factor analysis led to the removal of a single item due to insufficient factor loading (<0.45). Its convergent validity seems consistent with previous literature. Discriminant analyses showed a significant difference in F-BISS score between participants relative to eating disorder symptomatology (t= 11.65;p< 0.001). This translation could prove useful in both research and clinical settings to assess state body satisfaction in French populations.
Meaning Reflectivity in Later Life: The Relationship Between Reflecting on Meaning in Life, Presence and Search for Meaning, and Depressive Symptoms in Older Adults Over the Age of 75
Authors: Dewitte Laura , Dezutter Jessie
Published: October 2021

Background: Over the last decades, there is growing attention for the importance of meaning in life for older adults. However, there is virtually no insight into the mental processes that contribute to this experience. Some scholars recently called for an investigation of meaning reflectivity, or the process of reflecting on issues specifically related to meaning in life. In this study, we explored to what extent older adults talk and think about issues of meaning in life, and how this meaning reflectivity is related to the search for and presence of meaning in life, and to depressive symptoms.

Method: In this cross-sectional observational study, 282 community-residing older adults (75 or older) in Belgium filled in paper questionnaires on meaning in life (presence and search), depressive symptoms, and meaning reflectivity (categorical item). ANOVA analyses were used to explore differences in meaning in life and depressive symptoms across the meaning reflectivity categories. Regression and negative binomial models investigated the association between meaning reflectivity and presence, search and depressive symptoms. Finally, an exploratory structural equation model examined whether presence of meaning statistically mediated the relationship between meaning reflectivity and depressive symptoms.

Results: The majority of participants (42.4%) indicated that they had thought about meaning in life before, 23.2% indicated that they had talked about it before, 18% indicated that they hadn’t thought about it before but found it interesting, and 16.4% indicated that they were indifferent/unconcerned about meaning in life. The latter group reported lower levels of presence of meaning and search for meaning and higher levels of depressive symptoms. Belonging to this category was also associated with lower presence and search in regression analyses, but not with depressive symptoms above the effect of presence of meaning. Exploratory mediation analyses suggested that presence of meaning may be a mediator between meaning reflectivity and depressive symptoms.

Conclusion: Meaning reflectivity is an important process to consider in the context of the experience of meaning in life for older adults. Those older adults who are indifferent about issues of meaning in life might be more vulnerable to experience a lack of meaning and depressive symptoms.
How Does House Demolition Affect Family Conspicuous Consumption?
Authors: Yuan Wei , Gong Shuying , Gao Jun
Published: October 2021

Family conspicuous consumption behavior is affected by many factors. Existing pieces of literature seldom focus on the impact of house demolition on family conspicuous consumption and its underlying mechanism. Based on the mental accounting theory and conservation of resources theory, this study uses the micro-data of the 2011 China Household Finance Survey to empirically examine the relationship between house demolition and family conspicuous consumption. Robustness results suggest that house demolition positively affects household conspicuous consumption, which is not only reflected in the overall consumption level but also in the level of average consumption. Further analysis finds that household wealth and materialism value have a significant positive moderating effect on the relationship of the main effect. In addition, in order to clarify the relationship between conspicuous consumption and luxury consumption, this study finds that conspicuous consumption and luxury consumption are not completely equivalent through in-depth theoretical analysis and exploratory investigation. There are similarities in both consumption motivation and pattern, but with differences on consumer subject and object. The contribution of this research is to enrich the theory of decision-making in consumer behavior, which also has certain significance in deepening the understanding of the relationship between conspicuous consumption and luxury consumption.
Limited Scope for Group Coordination in Stylistic Variations of Kolam Art
Authors: Tran N.-Han , Kucharský Šimon , Waring Timothy M. , Atmaca Silke , Beheim Bret A.
Published: October 2021

In large, complex societies, assorting with others with similar social norms or behaviors can facilitate successful coordination and cooperation. The ability to recognize others with shared norms or behaviors is thus assumed to be under selection. As a medium of communication, human art might reflect fitness-relevant information on shared norms and behaviors of other individuals thus facilitating successful coordination and cooperation. Distinctive styles or patterns of artistic design could signify migration history, different groups with a shared interaction history due to spatial proximity, as well as individual-level expertise and preferences. In addition, cultural boundaries may be even more pronounced in a highly diverse and socially stratified society. In the current study, we focus on a large corpus of an artistic tradition calledkolamthat is produced by women from Tamil Nadu in South India (N= 3, 139kolamdrawings from 192 women) to test whether stylistic variations in art can be mapped onto caste boundaries, migration and neighborhoods. Since thekolamart system with its sequential drawing decisions can be described by a Markov process, we characterize variation in styles of art due to different facets of an artist's identity and the group affiliations, via hierarchical Bayesian statistical models. Our results reveal that stylistic variations inkolamart only weakly map onto caste boundaries, neighborhoods, and regional origin. In fact, stylistic variations or patterns in art are dominated by artist-level variation and artist expertise. Our results illustrate that although art can be a medium of communication, it is not necessarily marked by group affiliation. Rather, artistic behavior in this context seems to be primarily a behavioral domain within which individuals carve out a unique niche for themselves to differentiate themselves from others. Our findings inform discussions on the evolutionary role of art for group coordination by encouraging researchers to use systematic methods to measure the mapping between specific objects or styles onto groups.