bluuebunny/crossref_metadata_2025 huggingface dataset:
PI3K/Akt/mTOR Pathway and Its Role in Cancer Therapeutics: Are We Making Headway?
Authors: Peng Yan , Wang Yuanyuan , Zhou Cheng , Mei Wuxuan , Zeng Changchun
Published: March 2022

Cancer is a severe public health issue that is a leading cause of mortality globally. It is also an impediment to improving life expectancy worldwide. Furthermore, the global burden of cancer incidence and death is continuously growing. Current therapeutic options are insufficient for patients, and tumor complexity and heterogeneity necessitate customized medicine or targeted therapy. It is critical to identify potential cancer therapeutic targets. Aberrant activation of the PI3K/AKT/mTOR pathway has a significant role in carcinogenesis. This review summarized oncogenic PI3K/Akt/mTOR pathway alterations in cancer and various cancer hallmarks associated with the PI3K/AKT/mTOR pathway, such as cell proliferation, autophagy, apoptosis, angiogenesis, epithelial-to-mesenchymal transition (EMT), and chemoresistance. Importantly, this review provided recent advances in PI3K/AKT/mTOR inhibitor research. Overall, an in-depth understanding of the association between the PI3K/AKT/mTOR pathway and tumorigenesis and the development of therapies targeting the PI3K/AKT/mTOR pathway will help make clinical decisions.
RelA Is an Essential Target for Enhancing Cellular Responses to the DNA Repair/Ref-1 Redox Signaling Protein and Restoring Perturbated Cellular Redox Homeostasis in Mouse PDAC Cells
Authors: Mijit Mahmut , Wireman Randall , Armstrong Lee , Gampala Silpa , Hassan Zonera , Schneeweis Christian , Schneider Guenter , Zhang Chi , Fishel Melissa L. , Kelley Mark R.
Published: March 2022

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers with a poor response to current treatment regimens. The multifunctional DNA repair-redox signaling protein Ref-1 has a redox signaling function that activates several transcriptional factors (TFs) including NF-κB (RelA), STAT3, AP-1. These have been implicated in signaling in PDAC and associated with cancer progression and therapy resistance. Numerous studies have shown a role for RelA in PDAC inflammatory responses and therapy resistance, little is known as to how these inflammatory responses are modulated through Ref-1 redox signaling pathways during pancreatic pathogenesis. RelA and STAT3 are two major targets of Ref-1 and are important in PDAC pathogenesis. To decipher the mechanistic role of RelA in response to Ref-1 inhibition, we used PDAC cells (KC3590) from a genetically engineered KrasG12D-driven mouse model that also is functionally deficient for RelA (Parent/Vector) or KC3590 cells with fully functional RelA added back (clone 13; C13). We demonstrated that RelA deficient cells are more resistant to Ref-1 redox inhibitors APX3330, APX2009, and APX2014, and their sensitivity is restored in the RelA proficient cells. Knockdown of STAT3 did not change cellular sensitivity to Ref-1 redox inhibitors in either cell type. Gene expression analysis demonstrated that Ref-1 inhibitors significantly decreased IL-8, FOSB, and c-Jun when functional RelA is present. We also demonstrated that PRDX1, a known Ref-1 redox modulator, contributes to Ref-1 inhibitor cellular response. Knockdown of PRDX1 when functional RelA is present resulted in dramatically increased PDAC killing in response to Ref-1 inhibitors. The enhanced cell killing was not due to increased intracellular ROS production. Although Ref-1 inhibition decreased the NADP/NADPH ratio in the cells, the addition of PRDX1 knockdown did not further this redox imbalance. This data suggests that the mechanism of cell killing following Ref-1 inhibition is at least partially mediated through RelA and not STAT3. Further imbalancing of the redox signaling through disruption of the PRDX1-Ref-1 interaction may have therapeutic implications. Our data further support a pivotal role of RelA in mediating Ref-1 redox signaling in PDAC cells with the KrasG12D genotype and provide novel therapeutic strategies to combat PDAC drug resistance.
Finite Element-Based Personalized Simulation of Duodenal Hydrogel Spacer: Spacer Location Dependent Duodenal Sparing and a Decision Support System for Spacer-Enabled Pancreatic Cancer Radiation Therapy
Authors: Hooshangnejad Hamed , Youssefian Sina , Narang Amol , Shin Eun Ji , Rao Avani Dholakia , Han-Oh Sarah , McNutt Todd , Lee Junghoon , Hu Chen , Wong John , Ding Kai
Published: March 2022

Purpose

Pancreatic cancer is the fourth leading cause of cancer-related death, with a very low 5-year overall survival rate (OS). Radiation therapy (RT) together with dose escalation significantly increases the OS at 2 and 3 years. However, dose escalation is very limited due to the proximity of the duodenum. Hydrogel spacers are an effective way to reduce duodenal toxicity, but the complexity of the anatomy and the procedure makes the success and effectiveness of the spacer procedure highly uncertain. To provide a preoperative simulation of hydrogel spacers, we presented a patient-specific spacer simulator algorithm and used it to create a decision support system (DSS) to provide a preoperative optimal spacer location to maximize the spacer benefits.

Materials and Methods

Our study was divided into three phases. In the validation phase, we evaluated the patient-specific spacer simulator algorithm (FEMOSSA) for the duodenal spacer using the dice similarity coefficient (DSC), overlap volume histogram (OVH), and radial nearest neighbor distance (RNND). For the simulation phase, we simulated four virtual spacer scenarios based on the location of the spacer in para-duodenal space. Next, stereotactic body radiation therapy (SBRT) plans were designed and dosimetrically analyzed. Finally, in the prediction phase, using the result of the simulation phase, we created a Bayesian DSS to predict the optimal spacer location and biological effective dose (BED).

Results

A realistic simulation of the spacer was achieved, reflected in a statistically significant increase in average target and duodenal DSC for the simulated spacer. Moreover, the small difference in average mean and 5th-percentile RNNDs (0.5 and 2.1 mm) and OVH thresholds (average of less than 0.75 mm) showed that the simulation attained similar separation as the real spacer. We found a spacer-location-independent decrease in duodenal V20Gy, a highly spacer-location-dependent change in V33Gy, and a strong correlation between L1cc and V33Gy. Finally, the Bayesian DSS predicted the change in BED with a root mean squared error of 3.6 Gys.

Conclusions

A duodenal spacer simulator platform was developed and used to systematically study the dosimetric effect of spacer location. Further, L1cc is an informative anatomical feedback to guide the DSS to indicate the spacer efficacy, optimum location, and expected improvement.
Long-Term Real-World Outcomes of First-Line Pembrolizumab Monotherapy for Metastatic Non-Small Cell Lung Cancer With ≥50% Expression of Programmed Cell Death-Ligand 1
Authors: Velcheti Vamsidhar , Hu Xiaohan , Yang Lingfeng , Pietanza M. Catherine , Burke Thomas
Published: March 2022

Objectives

Immune checkpoint inhibitors (ICIs) of programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) have been rapidly adopted in US clinical practice for first-line therapy of metastatic non-small cell lung cancer (NSCLC) since regulatory approval in October 2016, and a better understanding is needed of long-term outcomes of ICI therapy administered in real-world settings outside of clinical trials. Our aim was to describe long-term outcomes of first-line pembrolizumab monotherapy at US oncology practices for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.

Methods

This retrospective two-cohort study used technology-enabled abstraction of deidentified electronic health records (EHR cohort) plus enhanced manual chart review (spotlight cohort) to study adult patients with stage IV NSCLC, PD-L1 expression ≥50%, no documented EGFR/ALK/ROS1 genomic aberration, and ECOG performance status 0–1 who initiated first-line pembrolizumab monotherapy from 1-November-2016 to 31-March-2020 (EHR cohort, with data cutoff 31-March-2021) or from 1-December-2016 to 30-November-2017 (spotlight cohort, with data cutoff 31-August-2020). Kaplan-Meier analysis was used to determine overall survival (OS; both cohorts) and, for the spotlight cohort, real-world progression-free survival (rwPFS) and real-world tumor response (rwTR).

Results

The EHR cohort included 566 patients (298 [53%] men); the spotlight cohort included 228 (105 [46%] men); median age in both cohorts was 71. Median follow-up from pembrolizumab initiation to data cutoff was 35.1 months (range, 12.0–52.7) and 38.4 months (range, 33.1–44.9) in EHR and spotlight cohorts, respectively. Median OS was 19.6 months (95% CI, 16.6–24.3) and 21.1 months (95% CI, 16.2–28.9), respectively; 3-year OS rates were 36.2% and 38.2% in EHR and spotlight cohorts, respectively. In the spotlight cohort, median rwPFS was 7.3 months (95% CI, 5.7–9.2); 88 patients (38.6%; 95% CI, 32.2–45.2) experienced rwTR of complete or partial response. For 151/228 patients (66%) who discontinued pembrolizumab, the most common reasons were disease progression (70 [46%]) and therapy-related adverse effects (35 [23%]).

Conclusions

Real-world outcomes remain consistent with outcomes observed in clinical trials, supporting long-term benefits of first-line pembrolizumab monotherapy for patients with metastatic NSCLC, PD-L1 expression ≥50%, and good performance status.
177Lu-PSMA-I&T Radioligand Therapy for Treating Metastatic Castration-Resistant Prostate Cancer: A Single-Centre Study in East Asians
Authors: Bu Ting , Zhang Lulu , Yu Fei , Yao Xiaochen , Wu Wenyu , Zhang Pengjun , Shi Liang , Zang Shiming , Meng Qingle , Ni Yudan , Shao Guoqiang , Qiu Xuefeng , Ai Shuyue , Jia Ruipeng , Guo Hongqian , Wang Feng
Published: March 2022

Purpose

There is increasing evidence for convincing efficacy and safety of 177Lu-labled prostate-specific membrane antigen (PSMA)-targeted radioligand therapy (PRLT) for metastatic castration-resistant prostate cancer (mCRPC). However, data are not available regarding the feasibility of 177Lu-labled PSMA-targeted RLT in East Asians. The present study summarized the first experience with 177Lu-PSMA-I&T therapy for mCRPC in China.

Methods

Forty consecutive patients with mCRPC were enrolled from December 2019 to September 2021. Eligible patients received 177Lu-PSMA-I&T RLT at intervals of 8-12 weeks. Toxicity was assessed based on standardized physicians’ reports and the Common Toxicity Criteria for Adverse Events criteria. Response to PRLT was evaluated according to the changes of prostate specific antigen (PSA) response and imaging response. Quality of life (QOL), Karnofsky performance status (KPS) and pain (visual analogue scale, VAS) were also evaluated. The impacts of baseline parameters on the therapeutic effects were explored by univariate and multivariate logistic regression analyses.

Results

All patients underwent a total of 86 cycles of 177Lu-PSMA-I&T (range: 1-5 cycles) with dosages of 3.70-14.43GBq per cycle, with a median of 8 months followed up. Six patients (15%) developed mild reversible xerostomia during follow-up, and 28 patients (70%) experienced grade 1-4 bone marrow dysfunction. Changes in PSA were assessed after therapy, accompanied by the partial response (PR) in 25 patients (62.5%), the stable disease (SD) in 5 patients (12.5%), and the progressive disease (PD) in 10 patients (25%), respectively. QOL, KPS (%) and VAS scores were improved significantly due to treatment (P<0.05). Overweight and elevated AST, ALP, and LDH were associated with poor outcomes.

Conclusions

177Lu-PSMA-I&T achieves the favourable response and well tolerance in mCRPC, which associates with not only PSA decline but also with tumor remission including lymphadenopathy and bone metastasis. We also find that patients with overweight and high AST, ALP, and LDH should be cautious to undergo the PRLT. Large-cohort studies are warranted to confirm the initial findings and elucidate the survival benefit of the treatment.
Genetic Characteristics Associated With Drug Resistance in Lung Cancer and Colorectal Cancer Using Whole Exome Sequencing of Cell-Free DNA
Authors: Lee Jong Won , Park Young Soo , Choi Jung Yoon , Chang Won Jin , Lee Soohyeon , Sung Jae Sook , Kim Boyeon , Lee Saet Byeol , Lee Sung Yong , Choi Jungmin , Kim Yeul Hong
Published: March 2022

Circulating cell-free DNA (cfDNA) can be used to characterize tumor genomes through next-generation sequencing (NGS)-based approaches. We aim to identify novel genetic alterations associated with drug resistance in lung cancer and colorectal cancer patients who were treated with EGFR-targeted therapy and cytotoxic chemotherapy through whole exome sequencing (WES) of cfDNA. A cohort of 18 lung cancer patients was treated with EGFR TKI or cytotoxic chemotherapy, and a cohort of 37 colorectal cancer patients was treated with EGFR monoclonal antibody or cytotoxic chemotherapy alone. Serum samples were drawn before and after development of drug resistance, and the genetic mutational profile was analyzed with WES data. For 110 paired cfDNA and matched germline DNA WES samples, mean coverage of 138x (range, 52–208.4x) and 47x (range, 30.5–125.1x) was achieved, respectively. After excluding synonymous variants, mutants identified in more than two patients at the time of acquired resistance were selected. Seven genes in lung cancer and 16 genes in colorectal cancer were found, namely, APC, TP53, KRAS, SMAD4, and EGFR. In addition, the GPR155 I357S mutation in lung cancer and ADAMTS20 S1597P and TTN R7415H mutations in colorectal cancer were frequently detected at the time of acquired resistance, indicating that these mutations have an important function in acquired resistance to chemotherapy. Our data suggest that novel genetic variants associated with drug resistance can be identified using cfDNA WES. Further validation is necessary, but these candidate genes are promising therapeutic targets for overcoming drug resistance in lung cancer and colorectal cancer.
BUSnet: A Deep Learning Model of Breast Tumor Lesion Detection for Ultrasound Images
Authors: Li Yujie , Gu Hong , Wang Hongyu , Qin Pan , Wang Jia
Published: March 2022

Ultrasound (US) imaging is a main modality for breast disease screening. Automatically detecting the lesions in US images is essential for developing the artificial-intelligence-based diagnostic support technologies. However, the intrinsic characteristics of ultrasound imaging, like speckle noise and acoustic shadow, always degenerate the detection accuracy. In this study, we developed a deep learning model called BUSnet to detect the breast tumor lesions in US images with high accuracy. We first developed a two-stage method including the unsupervised region proposal and bounding-box regression algorithms. Then, we proposed a post-processing method to enhance the detecting accuracy further. The proposed method was used to a benchmark dataset, which includes 487 benign samples and 210 malignant samples. The results proved the effectiveness and accuracy of the proposed method.
Retinoic Acid Induces an IFN-Driven Inflammatory Tumour Microenvironment, Sensitizing to Immune Checkpoint Therapy
Authors: Tilsed Caitlin M. , Casey Thomas H. , de Jong Emma , Bosco Anthony , Zemek Rachael M. , Salmons Joanne , Wan Graeme , Millward Michael J. , Nowak Anna K. , Lake Richard A. , Lesterhuis Willem Joost
Published: March 2022

With immune checkpoint therapy (ICT) having reshaped the treatment of many cancers, the next frontier is to identify and develop novel combination therapies to improve efficacy. Previously, we and others identified beneficial immunological effects of the vitamin A derivative tretinoin on anti-tumour immunity. Although it is known that tretinoin preferentially depletes myeloid derived suppressor cells in blood, little is known about the effects of tretinoin on the tumour microenvironment, hampering the rational design of clinical trials using tretinoin in combination with ICT. Here, we aimed to identify how tretinoin changed the tumour microenvironment in mouse tumour models, using flow cytometry and RNAseq, and we sought to use that information to establish optimal dosing and scheduling of tretinoin in combination with several ICT antibodies in multiple cancer models. We found that tretinoin rapidly induced an interferon dominated inflammatory tumour microenvironment, characterised by increased CD8+ T cell infiltration. This phenotype completely overlapped with the phenotype that was induced by ICT itself, and we confirmed that the combination further amplified this inflammatory milieu. The addition of tretinoin significantly improved the efficacy of anti-CTLA4/anti-PD-L1 combination therapy, and staggered scheduling was more efficacious than concomitant scheduling, in a dose-dependent manner. The positive effects of tretinoin could be extended to ICT antibodies targeting OX40, GITR and CTLA4 monotherapy in multiple cancer models. These data show that tretinoin induces an interferon driven, CD8+ T cell tumour microenvironment that is responsive to ICT.
TRIM65 Promotes Cervical Cancer Through Selectively Degrading p53-Mediated Inhibition of Autophagy and Apoptosis
Authors: Wang Xiao-Yu , Mao Hai-Wei , Guan Xiao-Hui , Huang Qi-Ming , Yu Zhen-Ping , Wu Jie , Tan Hui-Lan , Zhang Feng , Huang Xuan , Deng Ke-Yu , Xin Hong-Bo
Published: March 2022

Tripartite motif containing 65 (TRIM65) is an E3 ubiquitin ligase that has been implicated in a variety of cellular processes as well as tumor progression, but its biological role and the underlying mechanism in cervical cancer is unclear. Here, we reported that TRIM65 expression in human cervical cancer tissues was significantly higher than that in the adjacent normal cervical tissues, and TRIM65 knockdown enhanced autophagic flux and cell apoptosis, but not cell cycle, to dramatically inhibit the proliferation and migration of cervical cancer cells. Furthermore, our experiments showed that TRIM65 exhibited oncogenic activities via directly targeting p53, a tumor suppressor and a common upsteam regulator between autophagy and apoptosis, promoting ubiquitination and proteasomal degradation of p53. Taken together, our studies demonstrated that TRIM65 knockdown promotes cervical cancer cell death through enhancing autophagy and apoptosis, suggesting that TRIM65 may be a potential therapeutic target for cervical cancer clinically.
A Novel Stool Methylation Test for the Non-Invasive Screening of Gastric and Colorectal Cancer
Authors: Ma Liang , Gong Jian , Zhao Meimei , Kong Xiaomu , Gao Peng , Jiang Yongwei , Liu Yi , Feng Xiaoyan , Si Shuang , Cao Yongtong
Published: March 2022

Background

Because of poor compliance or low sensitivity, existing diagnostic approaches are unable to provide an efficient diagnosis of patients with gastric and colorectal cancer. Here, we developed the ColoCaller test, which simultaneously detects the methylation status of the SDC2, TFPI2, WIF1, and NDRG4 genes in stool DNA, to optimize the screening of gastric and colorectal cancer in high-risk populations.

Methods

A total of 217 stool samples from patients with gastrointestinal cancer and from patients with negative endoscopy were prospectively collected, complete with preoperative and postoperative clinical data from patients. The methylation of these samples was detected using ColoCaller, which was designed by selecting CpGs with a two-step screening strategy, and was interpreted using a prediction model built using libSVM to evaluate its clinical value for gastric and colorectal cancer screening.

Results

Compared to pathological diagnosis, the sensitivity and specificity of the ColoCaller test in 217 stool DNA samples were 95.56% and 91.86%, respectively, for colorectal cancer, and 67.5% and 97.81%, respectively, for gastric cancer. The detection limit was as low as 1% in 8 ng of DNA.

Conclusion

In this study, we developed and established a new test, ColoCaller, which can be used as a screening tool or as an auxiliary diagnostic approach in high-risk populations with gastric and colorectal cancer to promote timely diagnosis and treatment.
Long Noncoding RNA: Shining Stars in the Immune Microenvironment of Gastric Cancer
Authors: Xiao Xian , Cheng Wen , Zhang Guixing , Wang Chaoran , Sun Binxu , Zha Chunyuan , Kong Fanming , Jia Yingjie
Published: March 2022

Gastric cancer (GC) is a kind of malignant tumor disease that poses a serious threat to human health. The GC immune microenvironment (TIME) is a very complex tumor microenvironment, mainly composed of infiltrating immune cells, extracellular matrix, tumor-associated fibroblasts, cytokines and chemokines, all of which play a key role in inhibiting or promoting tumor development and affecting tumor prognosis. Long non-coding RNA (lncRNA) is a non-coding RNA with a transcript length is more than 200 nucleotides. LncRNAs are expressed in various infiltrating immune cells in TIME and are involved in innate and adaptive immune regulation, which is closely related to immune escape, migration and invasion of tumor cells. LncRNA-targeted therapeutic effect prediction for GC immunotherapy provides a new approach for clinical research on the disease.
Bax/Bcl-2 Cascade Is Regulated by the EGFR Pathway: Therapeutic Targeting of Non-Small Cell Lung Cancer
Authors: Alam Manzar , Alam Shoaib , Shamsi Anas , Adnan Mohd , Elasbali Abdelbaset Mohamed , Al-Soud Waleed Abu , Alreshidi Mousa , Hawsawi Yousef MohammedRabaa , Tippana Anitha , Pasupuleti Visweswara Rao , Hassan Md. Imtaiyaz
Published: March 2022

Non-small cell lung carcinoma (NSCLC) comprises 80%–85% of lung cancer cases. EGFR is involved in several cancer developments, including NSCLC. The EGFR pathway regulates the Bax/Bcl-2 cascade in NSCLC. Increasing understanding of the molecular mechanisms of fundamental tumor progression has guided the development of numerous antitumor drugs. The development and improvement of rationally planned inhibitors and agents targeting particular cellular and biological pathways in cancer have been signified as a most important paradigm shift in the strategy to treat and manage lung cancer. Newer approaches and novel chemotherapeutic agents are required to accompany present cancer therapies for improving efficiency. Using natural products as a drug with an effective delivery system may benefit therapeutics. Naturally originated compounds such as phytochemicals provide crucial sources for novel agents/drugs and resources for tumor therapy. Applying the small-molecule inhibitors (SMIs)/phytochemicals has led to potent preclinical discoveries in various human tumor preclinical models, including lung cancer. In this review, we summarize recent information on the molecular mechanisms of the Bax/Bcl-2 cascade and EGFR pathway in NSCLC and target them for therapeutic implications. We further described the therapeutic potential of Bax/Bcl-2/EGFR SMIs, mainly those with more potent and selectivity, including gefitinib, EGCG, ABT-737, thymoquinone, quercetin, and venetoclax. In addition, we explained the targeting EGFR pathway and ongoingin vitroandin vivoand clinical investigations in NSCLC. Exploration of such inhibitors facilitates the future treatment and management of NSCLC.
HOTTIP Mediated Therapy Resistance in Glioma Cells Involves Regulation of EMT-Related miR-10b
Authors: Li Zhang , Li Ming , Xia Pengcheng , Lu Zhiming
Published: March 2022

The advanced grade glioblastomas are characterized by dismal five-year survival rates and are associated with worse outcomes. Additionally, resistance to therapies is an additional burden responsible for glioma associated mortality. We studied the resistance against temozolomide (TMZ) as a surrogate to understand the mechanism of therapy resistance in glioma cancer cells. Screening of three glioma cells lines, A172, LN229 and SF268 revealed that SF268 glioma cells were particularly resistant to TMZ with the IC-50 of this cell line for TMZ ten times higher than for the other two cell lines. A role of lncRNAs in glioma progression has been identified in recent years and, therefore, we focused on lncRNAs for their role in regulating TMZ resistance in glioma cancer cells. lncRNA HOTTIP was found to be particularly elevated in SF268 cells and over-expression of HOTTIP in both A172 and LN229 remarkably increased their TMZ IC-50s, along with increased cell proliferation, migration, clonogenicity and markers of angiogenesis and metastasis. As a mechanism we observed increased expression of miRNA-10b and mesenchymal markers Zeb1/Zeb2 and reduced expression of E-cadherin in SF268 cells indicating a role of EMT in TMZ resistance. A172 and LN229 cells with overexpressed HOTTIP also had similarly induced EMT and the elevated miR-10b levels. Further, silencing of miR-10b in HOTTIP overexpressing cells as well as the SF268 cells reversed EMT with associated sensitization of all the tested cells to TMZ. Our results thus present a case for HOTTIP in native as well as acquired resistance of glioma cells against chemotherapy, with a key mechanistic role of EMT and the miR-10b. Thus, HOTTIP as well as miR-10b are critical targets for glioma therapy, and need to be tested further.
Brainstem Diffusion Tensor Tractography and Clinical Applications in Pain
Authors: Zhang Yu , Furst Ansgar J.
Published: March 2022

The brainstem is one of the most vulnerable brain structures in many neurological conditions, such as pain, sleep problems, autonomic dysfunctions, and neurodegenerative disorders. Diffusion tensor imaging and tractography provide structural details and quantitative measures of brainstem fiber pathways. Until recently, diffusion tensor tractographic studies have mainly focused on whole-brain MRI acquisition. Due to the brainstem's spatial localization, size, and tissue characteristics, and limits of imaging techniques, brainstem diffusion MRI poses particular challenges in tractography. We provide a brief overview on recent advances in diffusion tensor tractography in revealing human pathways connecting the brainstem to the subcortical regions (e.g., basal ganglia, mesolimbic, basal forebrain), and cortical regions. Each of these pathways contains different distributions of fiber tracts from known neurotransmitter-specific nuclei in the brainstem. We compare the brainstem tractographic approaches in literature and our in-lab developed automated brainstem tractography in terms of atlas building, technical advantages, and neuroanatomical implications on neurotransmitter systems. Lastly, we summarize recent investigations of using brainstem tractography as a promising tool in association with pain.
Additional Adverse Perinatal Outcomes With No Effect on Neonatal Mortality and Birth Defects in Pregnancies Conceived by Assisted Reproductive Technology
Authors: Xiong Yingying , Zang Xiaodong , Xie Tingting , Yang Chaolei , Jiang Xiaohua , Chen Mingwu
Published: March 2022

Background

Pregnancy outcomes and perinatal diseases of children conceived by assisted reproductive technology (ART) and spontaneous conception (SC) are still unclear. We sought to compare the effects of ART and SC on adverse neonatal outcomes.

Methods

We included 5,913 neonates admitted to the neonatal intensive care unit (NICU) of the First Affiliated Hospital of the University of Science and Technology of China between January 2017 and December 2020. There were 1,112 (18.8%) ART pregnancies and 4,801 (81.2%) SC pregnancies. Data on maternal characteristics, comorbidities during pregnancy, and neonatal outcomes were collected and analyzed. Logistic regression models estimated the odds ratios (ORs) and 99% CIs of neonatal outcomes according to ART pregnancy. Neonatal outcomes primarily included neonatal respiratory distress syndrome (NRDS), bronchopulmonary dysplasia (BPD), retinopathy of prematurity (ROP), neonatal anemia, birth defects, and mortality.

Results

Among 5,913 neonates, 485 (8.2%) had NRDS, 165 (2.8%) had BPD, 113 (1.9%) had ROP, 602 (10.2%) had neonatal anemia, and 1,112 (18.8%) were ART infants. The incidence of pregnancy-related complications, such as gestational diabetes mellitus (GDM), gestational hypothyroidism, and rheumatic immune diseases, in mothers receiving ART, was higher than that in the SC group. On multivariate analysis, ART was independently associated with NRDS (OR = 1.46; 95% CI, 1.11–1.93; p = 0.008) and ROP (OR = 1.79; 95% CI, 1.06–3.05; p = 0.031). Moreover, the association persisted after adjustment for maternal age, history of cesarean section, preconception factors, and pregnancy complications. For BPD (OR = 1.44; 95% CI, 0.91–2.27; p = 0.117) and neonatal anemia (OR = 1.12; 95% CI, 0.87–1.45; p = 0.373), the associations were attenuated substantially when adjusting for pregnancy complications. ART was associated with neither birth defects (OR = 0.98; 95% CI, 0.77–1.25; p = 0.889) nor mortality (OR = 0.98; 95% CI, 0.51–1.91; p = 0.961).

Conclusion

ART was independently associated with adverse neonatal outcomes, including NRDS and ROP. Therefore, women who conceive by ART must improve their perinatal health and management of pregnancy-related comorbidities to enhance the quality of life of their offspring.
Neonatologist Performed Echocardiography for Evaluating the Newborn Infant
Authors: Nestaas Eirik
Published: March 2022

The interest in the use of cardiac ultrasound for hemodynamic evaluation in neonates has increased in the last decades. Several overlapping terms exists, and a non-comprehensive list includes point-of-care ultrasound, clinician-performed ultrasound, focused cardiac ultrasound, targeted neonatal echocardiography, and neonatologist performed echocardiography. This review will use the term neonatologist performed echocardiography. Neonatologist performed echocardiography is primarily echocardiography to obtain snapshots of hemodynamics and heart function, usually as repeated exams during intensive care. It provides the neonatologist with in-depth information on the hemodynamics not available by blood pressure, pulse oximetry, capillary refill time, and various blood tests. The review provides a brief overview of some relevant methods for assessment of hemodynamics and heart function. It does not discuss training, implementation, accreditation, and certification nor in-depth technical aspects and detailed use of neonatologist performed echocardiography. If the information obtainable by neonatologist performed echocardiography had been accessible easily (e.g., via a sensor put on the neonate similarly to a pulse oximeter), neonatologist performed echocardiography would have been more widely used. Acquiring skills for neonatologist performed echocardiography take time and resources. Future developments probably include a stronger focus on education, training, and certification. It is likely that echocardiographic methods will evolve further, probably involving establishing new indexes and methods and implementing artificial intelligence in the analyses procedure to improve accuracy and workflow. It is important to acknowledge that neonatologist performed echocardiography is not a therapeutic intervention; it is a diagnostic tool providing additional information.
Patient-Patient Similarity-Based Screening of a Clinical Data Warehouse to Support Ciliopathy Diagnosis
Authors: Chen Xiaoyi , Faviez Carole , Vincent Marc , Briseño-Roa Luis , Faour Hassan , Annereau Jean-Philippe , Lyonnet Stanislas , Zaidan Mohamad , Saunier Sophie , Garcelon Nicolas , Burgun Anita
Published: March 2022

A timely diagnosis is a key challenge for many rare diseases. As an expanding group of rare and severe monogenic disorders with a broad spectrum of clinical manifestations, ciliopathies, notably renal ciliopathies, suffer from important underdiagnosis issues. Our objective is to develop an approach for screening large-scale clinical data warehouses and detecting patients with similar clinical manifestations to those from diagnosed ciliopathy patients. We expect that the top-ranked similar patients will benefit from genetic testing for an early diagnosis. The dependence and relatedness between phenotypes were taken into account in our similarity model through medical concept embedding. The relevance of each phenotype to each patient was also considered by adjusted aggregation of phenotype similarity into patient similarity. A ranking model based on the best-subtype-average similarity was proposed to address the phenotypic overlapping and heterogeneity of ciliopathies. Our results showed that using less than one-tenth of learning sources, our language and center specific embedding provided comparable or better performances than other existing medical concept embeddings. Combined with the best-subtype-average ranking model, our patient-patient similarity-based screening approach was demonstrated effective in two large scale unbalanced datasets containing approximately 10,000 and 60,000 controls with kidney manifestations in the clinical data warehouse (about 2 and 0.4% of prevalence, respectively). Our approach will offer the opportunity to identify candidate patients who could go through genetic testing for ciliopathy. Earlier diagnosis, before irreversible end-stage kidney disease, will enable these patients to benefit from appropriate follow-up and novel treatments that could alleviate kidney dysfunction.
Efficacy and Safety of Xingnaojing Injection for Emergency Treatment of Acute Ischemic Stroke: A Systematic Review and Meta-Analysis
Authors: Wang Liuding , Fan Xueming , Chen Yifan , Liang Xiao , Shen Wei , Zhang Yunling
Published: March 2022

Background: Xingnaojing injection (XNJ) is derived from a traditional Chinese prescription named Angong Niuhuang pill. As an adjuvant treatment widely used in acute ischemic stroke (AIS), XNJ has proven to be effective with certain clinical evidence. The aim of this study is to collect the latest evidence and evaluate efficacy and safety of XNJ for emergency treatment of AIS.

Methods: We searched seven literature databases and two clinical trial registries from their inception to November 14, 2021 for randomized controlled trials (RCTs) examining the efficacy of XNJ for AIS. Two reviewers independently selected relevant trials, extracted data, and assessed the risk of bias. We pooled data into a meta-analysis using RevMan 5.4 software.

Results: Thirty-eight RCTs were included in this review, with a total of 3,677 participants. XNJ plus conventional treatments (CTs) showed a significant advantage, compared with CTs alone, in improving functional independence at 14 days (RR = 1.70, 95% CI = 1.03 to 2.81, p = 0.04), neurological function (MDNIHSS < 6h = −3.81, 95% CI = −5.25 to −2.38, p < 0.00001; MDNIHSS < 24h = −3.75, 95% CI = −4.92 to −2.59, p < 0.00001; MDNIHSS < 72h = −3.74, 95% CI = −5.48 to −2.00, p < 0.0001; MDNIHSS < 14d = −1.97, 95% CI = −3.25 to −0.69, p = 0.003), and activities of daily living on the Barthel index (MDBI-14day = 9.97, 95% CI = 9.29 to 10.65, p < 0.00001; MDBI-30day = 10.04, 95% CI = 5.82, to 14.26, p < 0.00001). In addition, the results showed that XNJ plus CTs was superior to CTs alone in reducing IL-6, TNF-α, hs-CRP, and MMP-9. Regarding safety of XNJ, the incidence of adverse reactions in the XNJ group was lower than that in the control group (RR = 0.57, 95% CI = 0.38 to 0.87, p = 0.009). The certainty of evidence was evaluated as low or very low for all.

Conclusion: XNJ appears to be effective and safe for emergency treatment of AIS. The first 72 h after the onset of stroke, in particular the first 6 hours, may be the optimum initiation time. However, further high-quality RCTs are warranted to determine an appropriate initiation time.

Systematic Review Registration: [https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=233211], identifier [CRD42021233211].
Three-Day Continuous Oxytocin Infusion Attenuates Thermal and Mechanical Nociception by Rescuing Neuronal Chloride Homeostasis via Upregulation KCC2 Expression and Function
Authors: Ba Xiyuan , Ran Chenqiu , Guo Wenjun , Guo Jing , Zeng Qian , Liu Tao , Sun Wuping , Xiao Lizu , Xiong Donglin , Huang Yelan , Jiang Changyu , Hao Yue
Published: March 2022

Oxytocin (OT) and its receptor are promising targets for the treatment and prevention of the neuropathic pain. In the present study, we compared the effects of a single and continuous intrathecal infusion of OT on nerve injury-induced neuropathic pain behaviours in mice and further explore the mechanisms underlying their analgesic properties. We found that three days of continuous intrathecal OT infusion alleviated subsequent pain behaviours for 14 days, whereas a single OT injection induced a transient analgesia for 30 min, suggesting that only continuous intrathecal OT attenuated the establishment and development of neuropathic pain behaviours. Supporting this behavioural finding, continuous intrathecal infusion, but not short-term incubation of OT, reversed the nerve injury-induced depolarizing shift in Cl− reversal potential via restoring the function and expression of spinal K+-Cl- cotransporter 2 (KCC2), which may be caused by OT-induced enhancement of GABA inhibitory transmission. This result suggests that only continuous use of OT may reverse the pathological changes caused by nerve injury, thereby mechanistically blocking the establishment and development of pain. These findings provide novel evidence relevant for advancing understanding of the effects of continuous OT administration on the pathophysiology of pain.
Neuroinflammation Upregulated Neuronal Toll-Like Receptors 2 and 4 to Drive Synucleinopathy in Neurodegeneration
Authors: Chung Lucia Yi-Ru , Lin Yi-Ting , Liu Chi , Tai Yi-Cheng , Lin Han-Yi , Lin Chin-Hsien , Chen Ching-Chow
Published: March 2022

Background: Parkinson’s disease (PD) is characterized by intraneuronal α-synuclein aggregation called Lewy bodies and progressive dopaminergic neurodegeneration. Toll-like receptor (TLR) signaling is a major pathway mediating inflammation. The molecular link on how neuroinflammation upregulates neuronal TLRs and induces accumulation of α-synuclein aggregates to drive synucleinopathy remains to be determined.

Objective: Despite conditioned medium from microglia and TLR agonists were utilized to study their effects on neuronal cells, a Transwell coculture system, comprising lipopolysaccharide-activated microglia on top and retinoic acid-differentiated SH-SY5Y cells at the bottom more mimicking in vivo neuroinflammation, was employed to elucidate the mechanism of activated microglia on neuronal cells.

Methods: Genetic variants of TLRs in PD patients were genotyped and the multiplex cytokines, sRAGE, and HMGB1were assessed. A coculture system was employed to measure α-synuclein aggregates and neurite shortening by confocal microscope. The expression of TLR2/4 and autophagy flux was detected by western blot and immunofluorescence.

Results: PD patients showed higher plasma levels of proinflammatory cytokines and genetic TLR4 variant, c.896 A > G (p. D299G). Elevated proinflammatory cytokines in coculture medium was also seen. Phosphorylation and aggregation of α-synuclein, shortening of neurite, upregulation of TLR2/4 expression, activation of downstream p38 and JNK, and dampening of autophagic flux were seen in SH-SY5Y cells cocultured with activated microglia. Those were prevented by inhibiting TLR2/4 and p38/JNK signaling.

Conclusion: Activated microglia-derived neuroinflammation induced neuronal TLR2/4-p38/JNK activation to perturb autophagy, causing accumulation of α-synuclein aggregates and neurite shortening. Targeting neuronal TLR2/4 pathway might be a mechanistic-based therapy for neurodegenerative disease, such as PD.
Pharmacological Validation of ASIC1a as a Druggable Target for Neuroprotection in Cerebral Ischemia Using an Intravenously Available Small Molecule Inhibitor
Authors: Qi Xin , Lu Jian-Fei , Huang Zi-Yue , Liu Yi-Jun , Cai Lu-Bing , Wen Xin-Lan , Song Xing-Lei , Xiong Jian , Sun Pei-Yi , Zhang Hao , Zhang Ting-Ting , Zhao Xuan , Jiang Qin , Li Ying , Krishtal Oleg , Hou Leng-Chen , Zhu Michael X. , Xu Tian-Le
Published: March 2022

Acidosis is a hallmark of ischemic stroke and a promising neuroprotective target for preventing neuronal injury. Previously, genetic manipulations showed that blockade of acid-sensing ion channel 1a (ASIC1a)-mediated acidotoxicity could dramatically alleviate the volume of brain infarct and restore neurological function after cerebral ischemia. However, few pharmacological candidates have been identified to exhibit efficacy on ischemic stroke through inhibition of ASIC1a. In this work, we examined the ability of a toxin-inspired compound 5b (C5b), previously found to effectively inhibit ASIC1a in vitro, to exert protective effects in animal models of ischemic stroke in vivo. We found that C5b exerts significant neuroprotective effects not only in acid-induced neuronal death in vitro but also ischemic brain injury in vivo, suggesting that ASIC1a is a druggable target for therapeutic development. More importantly, C5b is able to cross the blood brain barrier and significantly reduce brain infarct volume when administered intravenously in the ischemic animal model, highlighting its systemic availability for therapies against neurodegeneration due to acidotoxicity. Together, our data demonstrate that C5b is a promising lead compound for neuroprotection through inhibiting ASIC1a, which warrants further translational studies.
Biomimetic ZIF8 Nanosystem With Tumor Hypoxia Relief Ability to Enhance Chemo-Photothermal Synergistic Therapy
Authors: Zhao Ziming , Liu Zhaorong , Hua Yabing , Pan Yuanjie , Yi Ge , Wu Shengyue , He Cong , Zhang Yanzhuo , Yang Yihua
Published: March 2022

Tumor hypoxic microenvironment can reduce the therapeutic effects of chemotherapy, radiotherapy, photodynamic therapy, immunotherapy, etc. It is also a potential source of tumor recurrence and metastasis. A biomimetic nanosystem based on zeolitic imidazolate framework 8 (ZIF8), which had multifunctions of hypoxia relief, chemotherapy, and photothermal therapy, was established to improve tumor hypoxic microenvironment and overcome the corresponding therapeutic resistance. ZIF8 enveloped with DOX and CuS nanoparticles (DC@ZIF8) was synthesized by a sedimentation method. Red blood cell membrane and catalase (CAT) were coated onto DC@ZIF8 and biomimetic nanosystem (DC@ZIF8-MEMC) was formed. The designed DC@ZIF8-MEMC had a shape of polyhedron with an average particle size around 254 nm. The loading content of DOX, CAT, and CuS was 4.9%, 6.2%, and 2.5%, separately. The release of DOX from DC@ZIF8-MEMC was pH dependent and significantly faster at pH 5 due to the degradation of ZIF8. DC@ZIF8-MEMC exhibited outstanding photothermal conversion properties and excellent antitumor effect in vitro and in vivo. Moreover, the hypoxia relief by CAT was proved to have good sensitization effect on chemo-photothermal combined therapy. DC@ZIF8-MEMC is a prospective nanosystem, which can realize great chemo-photothermal synergistic antitumor effect under the sensitization of CAT. The biomimetic multifunctional nanoplatform provides a potential strategy of chemo-photothermal synergistic antitumor effect under the sensitization of CAT.
Identification of Polysaccharides From Dipsacus asperoides and Their Effects on Osteoblast Proliferation and Differentiation in a High-Glucose Environment
Authors: Xu Duoduo , Liu Jia , Zheng Wei , Gao Qipin , Gao Yang , Leng Xiangyang
Published: March 2022

Polysaccharides (DAI-1 and DAI-2) from Dipsacus asperoides (D. asperoides) were obtained using mixed-bed ion exchange resin and Sephadex G-50 column chromatography following which their properties, structures, and activities were investigated. The results showed that DAI-1 and DAI-2 were homogeneous in nature, with glucose the only constituent, and had molecular masses of 17 and 4 kDa, respectively. Methylation analysis indicated that the backbones of DAI-1 and DAI-2 were mainly composed of (1→6)-linked glucose residues. DAI-1 possessed a small number of side chains and a branch point of (1→3, 6)-glucose, while DAI-2 lacked branching. Activity assays demonstrated that exposing osteoblasts to different DAI-1 concentrations (25, 50, or 100 μg/mL) in a high-glucose environment induced cell proliferation and led to a significant increase in bone morphogenetic protein 2 (BMP-2) and runt-related transcription factor 2 (Runx2) expressions at both the mRNA and protein levels. Moreover, DAI-1 treatment significantly increased alkaline phosphatase (ALP) and osteocalcin (OCN) activities in osteoblasts. Combined, our results suggested that DAI-1 may promote osteoblast proliferation and differentiation in a high-glucose environment.
Fraxin Promotes the Activation of Nrf2/ARE Pathway via Increasing the Expression of Connexin43 to Ameliorate Diabetic Renal Fibrosis
Authors: Chen Rui , Zeng Jingran , Li Chuting , Xiao Haiming , Li Shanshan , Lin Zeyuan , Huang Kaipeng , Shen Juan , Huang Heqing
Published: March 2022

Diabetic nephropathy (DN) is quickly becoming the largest cause of end-stage renal disease (ESRD) in diabetic patients, as well as a major source of morbidity and mortality. Our previous studies indicated that the activation of Nrf2/ARE pathway via Connexin43 (Cx43) considerably contribute to the prevention of oxidative stress in the procession of DN. Fraxin (Fr), the main active glycoside of Fraxinus rhynchophylla Hance, has been demonstrated to possess many potential pharmacological activities. Whereas, whether Fr could alleviate renal fibrosis through regulating Cx43 and consequently facilitating the activation of Nrf2/ARE pathway needs further investigation. The in vitro results showed that: 1) Fr increased the expression of antioxidant enzymes including SOD1 and HO-1 to inhibit high glucose (HG)-induced fibronectin (FN) and inflammatory cell adhesion molecule (ICAM-1) overexpression; 2) Fr exerted antioxidant effect through activating the Nrf2/ARE pathway; 3) Fr significantly up-regulated the expression of Cx43 in HG-induced glomerular mesangial cells (GMCs), while the knock down of Cx43 largely impaired the activation of Nrf2/ARE pathway induced by Fr; 4) Fr promoted the activation of Nrf2/ARE pathway via regulating the interaction between Cx43 and AKT. Moreover, in accordance with the results in vitro, elevated levels of Cx43, phosphorylated-AKT, Nrf2 and downstream antioxidant enzymes related to Nrf2 were observed in the kidneys of Fr-treated group compared with model group. Importantly, Fr significantly improved renal dysfunction pathological changes of renal fibrosis in diabetic db/db mice. Collectively, Fr could increase the Cx43-AKT-Nrf2/ARE pathway activation to postpone the diabetic renal fibrosis and the up-regulation of Cx43 is probably a novel mechanism in this process.