bluuebunny/crossref_metadata_2025 huggingface dataset:
Deficiency of ROS‐Activated TRPM2 Channel Protects Neurons from Cerebral Ischemia‐Reperfusion Injury through Upregulating Autophagy
Authors: Hu Xupang , Wu Lijuan , Liu Xingyu , Zhang Yi , Xu Min , Fang Qiuyuan , Lu Lin , Niu Jianguo , Abd El-Aziz Tarek Mohamed , Jiang Lin-Hua , Li Fangfang , Yang Wei
Published: July 2021

Cerebral ischemia‐reperfusion (I‐R) transiently increased autophagy by producing excessively reactive oxygen species (ROS); on the other hand, activated autophagy would remove ROS‐damaged mitochondria and proteins, which led to cell survival. However, the regulation mechanism of autophagy activity during cerebral I‐R is still unclear. In this study, we found that deficiency of the TRPM2 channel which is a ROS sensor significantly decreased I‐R‐induced neuronal damage. I‐R transiently increased autophagy activity both in vitro and in vivo. More importantly, TRPM2 deficiency decreased I‐R‐induced neurological deficit score and infarct volume. Interestingly, our results indicated that TRPM2 deficiency could further activate AMPK rather than Beclin1 activity, suggesting that TRPM2 inhibits autophagy by regulating the AMPK/mTOR pathway in I‐R. In conclusion, our study reveals that ROS‐activated TRPM2 inhibits autophagy by downregulating the AMPK/mTOR pathway, which results in neuronal death induced by cerebral I‐R, further supporting that TRPM2 might be a potential drug target for cerebral ischemic injury therapy.
[Retracted] Evaluation of Microstructure, Hardness, and Tensile Properties: A Comparative Study of Stir Cast and Extruded Al7005/Glass‐/Fly‐Ash‐Reinforced Hybrid MMCs
Authors: Swamy Praveen Kumar , Mylaraiah Shantharaja , Basheer Dadapeer
Published: July 2021

The effect of extrusion ratio and addition of glass and fly ash on microstructural, mechanical properties, and fracture behavior of Al composites is examined. Both the composites and hybrid composites are prepared by the liquid metallurgical technique. Microstructure, extrusion effect on hardness, tensile properties, and fracture are studied using an optical micrograph, hardness tester, Universal Testing Machine, and scanning electron microscope, respectively. Experimental results show that increasing the extrusion ratio leads to a significant enhancement in mechanical properties such as tensile, compression, and yield strength and Young’s modulus, but results in a small reduction of ductility. It has been revealed that the presence of glass and fly ash improve the mechanical properties significantly with a slight reduction in ductility compared to the Al alloy. Fracture behaviour of the base alloy and composites show intergranular ductile and brittle cleavage mode failure as observed by SEM.
Atypical Kawasaki Disease in an Adolescent with Multivisceral Involvement
Authors: El Haddar Zohair , El Ouali Aziza , Ghanam Ayad , Rkain Maria , Benajiba Noufissa , Babakhouya Abdeladim
Published: July 2021

Kawasaki disease (KD) is a vasculitis mostly seen in children aged less than 5 years. It can involve different organs and tissues. Its diagnosis is based on the clinical criteria of the American Heart Association (AHA). We report a case of a Moroccan adolescent with an atypical presentation of KD initially treated as typhoid fever. Gastrointestinal, renal, and pulmonary signs were the main clinical findings that made the diagnosis of KD challenging and delayed. The consequence was a severe cardiac damage with myocarditis and coronary artery dilation. KD is uncommon in adolescents, and it is important to recognize the atypical forms and the different presentations of KD in order to prevent the delay of diagnosis and treatment, and hence the cardiac complications.
Si-Miao-Yong-An Decoction Maintains the Cardiac Function and Protects Cardiomyocytes from Myocardial Ischemia and Reperfusion Injury
Authors: Cui Wenwen , Xin Shen , Zhu Lingjuan , Wang Mingye , Hao Yuanyuan , Zhao Yuqian , Li Yang , Hou Yunlong
Published: July 2021

Objective. The aim of this study was to determine whether Si-Miao-Yong-An decoction (SMYAD) could protect cardiomyocytes from ischemia/reperfusion (I/R) injury and its underlying mechanisms. Methods. C57BL/6 mice were used to establish a model of myocardial infarction by I/R injury and treated by SMYAD for 4 weeks. Then, the cardiac functions of mice were evaluated by cardiac magnetic resonance (CMR). Histopathological analysis for the heart remodeling was detected by H&E and Masson staining. The protein expression of collagen I, MMP9, and TNFα was detected by western blot in the heart tissues. H9C2 cells were used to establish the hypoxia/reoxygenation (H/R) model and SMYAD intervention. MTT assays detected the cell viability of myocardial cells. The expression level of IL-1β was evaluated by ELISA. The expression levels of LC3B-II/LC3B-I, p-mTOR, mTOR, NLRP3, procaspase 1, and cleaved-caspase 1 in H9C2 cells were evaluated by Western blot. Results. SMYAD improved cardiac functions such as ventricular volume and ejection fraction of the rats with ischemia/reperfusion injury. Morphological assay indicated that SMYAD reduced the scar size and inhibited fibrosis formation. It was found that SMYAD could regulate collagen I, MMP9, and TNFα protein expression levels in the heart tissues. SMYAD improved the survival rate of H9C2 cardiomyocytes in the H/R injury model. SMYAD elevated the rate of LC3B-II/LC3B-I protein expression, decreased the rate of p-mTOR/mTOR protein expression, and reduced expressions of caspase 1, NLRP3, and IL-1β in H/R cardiomyocytes. Conclusion. SMYAD exerted protective effects on ischemia/reperfusion injury in myocardial cells by activating autophagy and inhibiting pyroptosis. This might be the reason why SMYAD protected myocardial tissue and improved cardiac function in mice with ischemia/reperfusion.
Determination of Alkaloids and Flavonoids in Sophora flavescens by UHPLC-Q-TOF/MS
Authors: Dong Yaqian , Jia Guoxiang , Hu Jingwen , Liu Hui , Wu Tingting , Yang Shenshen , Li Yubo , Cai Ting
Published: July 2021

This study is based on UHPLC-Q-TOF/MS and fragment ions to achieve classification and identification of alkaloids and flavonoids in Sophora flavescens. By reviewing the available and relevant literature, the mass fragmentation rules of alkaloids and flavonoids were summarized. 0.1% formic acid water (A) and acetonitrile (B) were used as mobile phases. 37 chemical constituents were identified, including 13 alkaloids and 24 flavonoids. This research method offers a complete strategy based on the fragmentation information of characteristic fragment ions and neutral loss obtained by MS/MS to characterize the chemical composition of Sophora flavescens.
Improved AND/OR Tree Search Algorithm in Analysis of Stochastic and Time-Dependent Shortest Path Problem
Authors: Xie Zhi-ying , He Yuan-Rong , Jiang Yuan-tong , Chen Chih-Cheng
Published: July 2021

Real-time vehicle guidance effectively reduces traffic jams and improves the operational efficiency of urban transportation. The trip time on a route is considered as a random process that changes with time, and the shortest path selection requires a random dynamic model and the solution of a decision-making problem. Thus, the shortest trip time is the criterion to determine the dynamic path selection by a random dynamic programming (DP) model which discretizes the trip times in the continuous segments on the route. In this study, a numerical model of random dynamic programming is established by using a probability tree model and an AND/OR (AO∗) algorithm to select the path of the shortest trip time. The results show that the branches of the probability tree are only accumulated on the “quantity” and do not cause a “qualitative” change. The inefficient accumulation of “quantity” affects the efficiency of the algorithm, so it is important to separate the accumulation of “quantity” from node expansion. The accumulation of “quantity” changes the trip time according to the entering time into a segment, which demands an improved AO∗ algorithm. The new AO∗ algorithm balances between efficiency and the trip time and provides the optimal real-time vehicle guidance on the road.
Roles of Nicotinamide N‐Methyltransferase in Obesity and Type 2 Diabetes
Authors: Liu Jie-Ru , Deng Zhao-Hui , Zhu Xiao-Juan , Zeng Yu-Rong , Guan Xiang-Xiang , Li Jiang-Hua
Published: July 2021

Type 2 diabetes (T2D) is thought to be a complication of metabolic syndrome caused by disorders of energy utilization and storage and characterized by insulin resistance or deficiency of insulin secretion. Though the mechanism linking obesity to the development of T2D is complex and unintelligible, it is known that abnormal lipid metabolism and adipose tissue accumulation possibly play important roles in this process. Recently, nicotinamide N‐methyltransferase (NNMT) has been emerging as a new mechanism‐of‐action target in treating obesity and associated T2D. Evidence has shown that NNMT is associated with obesity and T2D. NNMT inhibition or NNMT knockdown significantly increases energy expenditure, reduces body weight and white adipose mass, improves insulin sensitivity, and normalizes glucose tolerance and fasting blood glucose levels. Additionally, trials of oligonucleotide therapeutics and experiments with some small‐molecule NNMT inhibitors in vitro and in preclinical animal models have validated NNMT as a promising therapeutic target to prevent or treat obesity and associated T2D. However, the exact mechanisms underlying these phenomena are not yet fully understood and clinical trials targeting NNMT have not been reported until now. Therefore, more researches are necessary to reveal the acting mechanism of NNMT in obesity and T2D and to develop therapeutics targeting NNMT.
Network Pharmacological Study and Molecular Docking Analysis of Qiweitangping in Treating Diabetic Coronary Heart Disease
Authors: Liu Tianfu , Liu Jianbo , Hao Liang
Published: July 2021

Background. Coronary heart disease (CHD) is one of the most important complications of diabetes mellitus, having a high disability fatality rate. Qiweitangping is a Chinese medicine to control diabetes (type 1 and type 2 diabetes) and complications, having been used in clinic for more than 20 years, with the expected therapeutic effect. In a previous clinical study, the total effective rate of the drug for the treatment of type 2 diabetes reached 92.7%. However, the mechanism of the treatment process is unclear. Therefore, this research was conducted to explore the mechanism of treating diabetic coronary heart disease with the assistance of bioinformatics methods. Methods. The TCMSP database was used to collect the effective chemical constituents of Qiweitangping and the target genes of the chemical constituents, and the related genes of diabetic CHD were obtained from the GeneCard database. Furthermore, the intersection was found between the target gene of the drug and the related gene of the disease to obtain the candidate genes; the STRING database and DAVID database were used to perform protein interaction analysis and KEGG enrichment analysis on the candidate genes. Also, molecular docking was used for auxiliary verification. Finally, a “drug component-gene target-pathway” network was constructed by using Cytoscape software. Results. Sixty-two effective chemical components including naringin, diosgenin, formogenin, isorolin, and isocryptanshinone, fifty-nine candidate target genes (such as AKT1, CASP3, and VEGF-A), and thirty-nine related pathways in Qiweitangping were obtained. In addition, two pairs (CASP-naringenin and STAT3-cryptotanshinone) of molecular docking results showed good affinity (<−5.00 kcal/mol). Conclusion. The results of the study indicate that Qiweitangping treats diabetic CHD with multiple chemical components. Its mechanism of action may be related to the HIF-1 signaling pathway, PI3K-Akt signaling pathway, and ErbB signaling pathway. STAT3 and CASP genes have been verified by molecular docking to have a relatively good combination with Qiweitangping. This study is the theoretical basis for further experimental study on the treatment mechanism of diabetic CHD with Qiweitangping.
Electroacupuncture as an Adjuvant Approach to Rehabilitation during Postacute Phase after Total Knee Arthroplasty: A Systematic Review and Meta-Analysis of Randomized Controlled Trials
Authors: Chen Weijian , Chen Zehua , Li Jiao , Wang Yi , Chen Guoqian , Jiang Tao , Wu Zugui , Ye Zixuan , Zhang Jiayuan , Shan Jiaxin , Wu Huai , Shen Zhen , Liu Wengang , Xu Xuemeng
Published: July 2021

Background. Increasing attention has been paid to electroacupuncture (EA) for promoting postoperative rehabilitation, but the effectiveness of EA for rehabilitation after total knee arthroplasty (TKA) remains obscure. Objective. To examine the effect of EA on rehabilitation after TKA. Methods. Database searches on PubMed, CINAHL, Embase, and China National Knowledge Infrastructure (CNKI) were carried out to obtain articles, from inception to 15 October 2020. All identified articles were screened, and data from each included study were extracted independently by two investigators. Meta-analysis was conducted to assess the effects of acupuncture on pain, range of knee motion, and postoperative vomiting after TKA. Results. In the current study, a total of ten randomized clinical trials were included according to the inclusion and exclusion criteria. Compared to basic treatment, EA combined with basic treatment showed a significantly greater pain reduction on 3, 7, and 14 days postoperatively after TKA. However, we found that EA had no significant improvement in enhancing the range of knee motion and decreasing the percentage of vomiting. Subgroup analysis suggested that a combination of EA and rehabilitation training was superior to rehabilitation training in pain relief, while EA combined with celecoxib capsules showed no significant difference in improving pain compared to celecoxib capsules alone. Conclusions. In the postacute phase after TKA, EA, as a supplementary treatment, could reduce postoperative pain, but no evidence supported the benefits of EA for improving ROM of knee and decreasing the ratio of vomiting. Additional high-quality and large-scale RCTs are warranted.
Picroside II Improves Severe Acute Pancreatitis‐Induced Hepatocellular Injury in Rats by Affecting JAK2/STAT3 Phosphorylation Signaling
Authors: Piao Xuehua , Sui Xiaodan , Liu Baohai , Cui Tingfang , Qi Zinan
Published: July 2021

Picroside II is an important ingredient agent in Traditional Chinese medicine and hoped to reduce hepatocellular injury caused by severe acute pancreatitis (SAP). An SAP‐induced hepatocellular injury model was established in rats by using pentobarbital sodium. 27 rats were divided into 3 groups: the sham group (SG), model group (MG), and Picroside groups (PG). SAP‐induced hepatocellular injury was assessed using hematoxylin and eosin staining. We measured hepatocellular enzymes (amylase (AMY), alanine aminotransferase (ALT), and aspartate aminotransferase (AST)), oxidative stress factors (superoxidase dismutase (SOD) and malondialdehyde (MDA)), and inflammatory factors (tumor necrosis factor α (TNF‐α), interleukin‐ (IL‐) 6, and IL‐10), apoptotic factors (BAX and cleaved caspase 3), and inflammatory signaling (Janus kinase 2 (JAK2)/signal transducer and activator of transcription 3 (STAT3), p‐JAK2, and p‐STAT3) in hepatocellular tissues. The SAP‐induced hepatocellular injury model was successfully established. Picroside II treatment repaired hepatocellular injury by reducing the activities of AMY, ALT, and AST; reducing the levels of MDA, TNF‐α, IL‐1, IL‐6, p‐JAK2, p‐STAT3, BAX, and cleaved caspase 3; and increasing the levels of SOD and IL‐10. Picroside II exerted protective function for the SAP‐induced hepatocellular injury model. Picroside II improved SAP‐induced hepatocellular injury and antioxidant and anti‐inflammatory properties by affecting JAK2/STAT3 phosphorylation signaling.
Gastrodia elata Blume Polysaccharides Attenuate Vincristine-Evoked Neuropathic Pain through the Inhibition of Neuroinflammation
Authors: Xie Hengtao , Chen Yingying , Wu Wei , Feng Xiaobo , Du Kairong
Published: July 2021

Vincristine (Vin) is a well-known antitumor agent that frequently evokes neuropathic pain and decreases the quality of life of patients. Polysaccharides (GBP) extracted from Gastrodia elata Blume have been demonstrated to possess anti-inflammatory and neuroprotective effects in vivo; however, the effects of GBP on Vin-induced neuropathic pain remain unknown. The present study is aimed at exploring the alleviative potential of GBP against chemotherapy-evoked peripheral neuropathy to better understand and extend its pharmacological application. Vin was administered intraperitoneally to evoke neuropathic pain. GBP was orally administered for 21 days. The mechanical allodynia and thermal hyperalgesia were assessed using the Von Frey test and hot-plate test. Histopathological changes were assessed by hematoxylin and eosin staining. ELISA kits were used to measure the levels of inflammatory cytokines in the sciatic nerve, spinal cord, and dorsal root ganglion (DRG). qRT-PCR was employed to examine the expression of inflammatory cytokines and Sirtuin1 (SIRT1) in the sciatic nerve, spinal cord, and DRG. Our findings revealed that GBP treatment enhanced the paw withdrawal latency and paw withdrawal threshold and restored Vin-induced sciatic nerve damage in rats. GBP also attenuated the Vin-induced increase of proinflammatory cytokine levels, including IL-6, IL-8, TNF-α, IL-1β, and NF-κB. On the molecular level, treatment with GBP downregulated the mRNA levels of IL-6, IL-8, TNF-α, and IL-1β in the sciatic nerve, spinal cord, and DRG. Meanwhile, GBP increased SIRT1 activity and mRNA expression levels. Our data indicated that GBP exerted a potential protective effect against chemotherapy-induced neuropathic pain which might be mediated via the inhibition of neuroinflammation.
Retrospective Analysis of Treatment Patterns in Pseudophakic Diabetic Macular Oedema Eyes Treated with Anti-VEGF
Authors: Zou Di , Jawaid Imran , Amoaku Winfried M.
Published: July 2021

Background/Objectives. Currently, in England, antivascular endothelial growth factor (anti-VEGF) is the first-line treatment for diabetic macular oedema (DMO) where central macular thickness (CMT) is ≥400 microns. In pseudophakic eyes with suboptimal response to first-line therapy, intravitreal corticosteroids may also be used. In practice, despite rigorous anti-VEGF therapy, suboptimal response occurs in nearly half of all eyes with DMO. The objective of this study was to investigate structural and functional outcomes and examine anti-VEGF treatment delivery in pseudophakic eyes receiving anti-VEGF injections for DMO. Methods. We performed a retrospective review of outcomes in 81 pseudophakic eyes with DMO that received at least 6 anti-VEGF injections. We reviewed baseline and posttreatment optical coherence tomography images, visual acuity, prescribing patterns, time taken to deliver anti-VEGF injections, and structural and functional outcomes. Results. It took an average of 913 ± 454.1 days to deliver a mean of 11.1 ± 4.7 anti-VEGF injections. Time from baseline to receiving the first 6 anti-VEGF injections was longer than 9 months in 74.7% (n = 59/79) of eyes. There was a mean gain of 1.6 letters (−0.03 logMAR) from baseline to the end point. After 5 anti-VEGF intravitreal injections, the mean CMT was 391.9 μm from 474.4 μm at baseline (

p
<
0.0001

). In 52 of 79 eyes (65.8%), more than one type of anti-VEGF agent was used. Conclusions. The anti-VEGF treatment used to treat these eyes with DMO was suboptimal, a finding consistent with recently published “real-world” data. There was a strong tendency for patients to be switched within the class to a second anti-VEGF agent.
Long Noncoding RNA NIHCOLE Promotes Ligation Efficiency of DNA Double-Strand Breaks in Hepatocellular Carcinoma
Authors: Unfried Juan P. , Marín-Baquero Mikel , Rivera-Calzada Ángel , Razquin Nerea , Martín-Cuevas Eva M. , de Bragança Sara , Aicart-Ramos Clara , McCoy Christopher , Prats-Mari Laura , Arribas-Bosacoma Raquel , Lee Linda , Caruso Stefano , Zucman-Rossi Jessica , Sangro Bruno , Williams Gareth , Moreno-Herrero Fernando , Llorca Oscar , Lees-Miller Susan P. , Fortes Puri
Published: July 2021

Long noncoding RNAs (lncRNA) are emerging as key players in cancer as parts of poorly understood molecular mechanisms. Here, we investigated lncRNAs that play a role in hepatocellular carcinoma (HCC) and identified NIHCOLE, a novel lncRNA induced in HCC with oncogenic potential and a role in the ligation efficiency of DNA double-stranded breaks (DSB). NIHCOLE expression was associated with poor prognosis and survival of HCC patients. Depletion of NIHCOLE from HCC cells led to impaired proliferation and increased apoptosis. NIHCOLE deficiency led to accumulation of DNA damage due to a specific decrease in the activity of the nonhomologous end-joining (NHEJ) pathway of DSB repair. DNA damage induction in NIHCOLE-depleted cells further decreased HCC cell growth. NIHCOLE was associated with DSB markers and recruited several molecules of the Ku70/Ku80 heterodimer. Further, NIHCOLE putative structural domains supported stable multimeric complexes formed by several NHEJ factors including Ku70/80, APLF, XRCC4, and DNA ligase IV. NHEJ reconstitution assays showed that NIHCOLE promoted the ligation efficiency of blunt-ended DSBs. Collectively, these data show that NIHCOLE serves as a scaffold and facilitator of NHEJ machinery and confers an advantage to HCC cells, which could be exploited as a targetable vulnerability.

Significance:

This study characterizes the role of lncRNA NIHCOLE in DNA repair and cellular fitness in HCC, thus implicating it as a therapeutic target.

See related commentary by Barcena-Varela and Lujambio, p. 4899
Acquired RAD51C Promoter Methylation Loss Causes PARP Inhibitor Resistance in High-Grade Serous Ovarian Carcinoma
Authors: Nesic Ksenija , Kondrashova Olga , Hurley Rachel M. , McGehee Cordelia D. , Vandenberg Cassandra J. , Ho Gwo-Yaw , Lieschke Elizabeth , Dall Genevieve , Bound Nirashaa , Shield-Artin Kristy , Radke Marc , Musafer Ashan , Chai Zi Qing , Ghamsari Mohammad Reza Eftekhariyan , Harrell Maria I. , Kee Damien , Olesen Inger , McNally Orla , Traficante Nadia , Study Australian Ovarian Cancer , DeFazio Anna , Bowtell David D.L. , Swisher Elizabeth M. , Weroha S. John , Nones Katia , Waddell Nicola , Kaufmann Scott H. , Dobrovic Alexander , Wakefield Matthew J. , Scott Clare L.
Published: July 2021

In high-grade serous ovarian carcinoma (HGSC), deleterious mutations in DNA repair gene RAD51C are established drivers of defective homologous recombination and are emerging biomarkers of PARP inhibitor (PARPi) sensitivity. RAD51C promoter methylation (meRAD51C) is detected at similar frequencies to mutations, yet its effects on PARPi responses remain unresolved.

In this study, three HGSC patient-derived xenograft (PDX) models with methylation at most or all examined CpG sites in the RAD51C promoter show responses to PARPi. Both complete and heterogeneous methylation patterns were associated with RAD51C gene silencing and homologous recombination deficiency (HRD). PDX models lost meRAD51C following treatment with PARPi rucaparib or niraparib, where a single unmethylated copy of RAD51C was sufficient to drive PARPi resistance. Genomic copy number profiling of one of the PDX models using SNP arrays revealed that this resistance was acquired independently in two genetically distinct lineages.

In a cohort of 12 patients with RAD51C-methylated HGSC, various patterns of meRAD51C were associated with genomic “scarring,” indicative of HRD history, but exhibited no clear correlations with clinical outcome. Differences in methylation stability under treatment pressure were also observed between patients, where one HGSC was found to maintain meRAD51C after six lines of therapy (four platinum-based), whereas another HGSC sample was found to have heterozygous meRAD51C and elevated RAD51C gene expression (relative to homozygous meRAD51C controls) after only neoadjuvant chemotherapy.

As meRAD51C loss in a single gene copy was sufficient to cause PARPi resistance in PDX, methylation zygosity should be carefully assessed in previously treated patients when considering PARPi therapy.

Significance:

Homozygous RAD51C methylation is a positive predictive biomarker for sensitivity to PARP inhibitors, whereas a single unmethylated gene copy is sufficient to confer resistance.
Psychologic Stress Drives Progression of Malignant Tumors via DRD2/HIF1α Signaling
Authors: Liu Huijuan , Yang Jiahuan , Zhang Yang , Han Jingxia , Yang Yuyan , Zhao Zihan , Dai Xintong , Wang Hongqi , Ding Xiujuan , Liu Yanrong , Zhong Weilong , Gao Wenqing , Sun Tao
Published: July 2021

Although it is established that the sustained psychologic stress conditions under which patients with tumors often reside accelerates malignant progression of tumors, the molecular mechanism behind this association is unclear. In this work, the effect of psychologic stress on tumor progression was verified using a stress-stimulated tumor-bearing mouse model (Str-tumor). Both D2 dopamine receptor (DRD2) and hypoxia-inducible factor-1α (HIF1α) were highly expressed in the nucleus of Str-tumors. Treatment with trifluoperazine (TFP), a DRD2 inhibitor, elicited better antitumor effects in Str-tumors than the control group. These results indicate that DRD2 may mediate stress-induced malignant tumor progression. DRD2 interacted with von Hippel-Lindau (VHL) in the nucleus, and competitive binding of DRD2 and HIF1α to VHL resulted in reduced ubiquitination-mediated degradation of HIF1α, enhancing the epithelial-mesenchymal transition of tumor cells. TFP acted as an interface inhibitor between DRD2 and VHL to promote the degradation of HIF1α. In conclusion, DRD2 may promote the progression of malignant tumors induced by psychologic stress via activation of the oxygen-independent HIF1α pathway, and TFP may serve as a therapeutic strategy for stress management in patients with cancer.

Significance:

This work identifies DRD2 regulation of HIF1α as a mechanism underlying the progression of malignant tumors stimulated by psychologic stress and suggests that DRD2 inhibition can mitigate these stress conditions in patients.

See related commentary by Bernabé, p. 5144
FLASH Proton Radiotherapy Spares Normal Epithelial and Mesenchymal Tissues While Preserving Sarcoma Response
Authors: Velalopoulou Anastasia , Karagounis Ilias V. , Cramer Gwendolyn M. , Kim Michele M. , Skoufos Giorgos , Goia Denisa , Hagan Sarah , Verginadis Ioannis I. , Shoniyozov Khayrullo , Chiango June , Cerullo Michelle , Varner Kelley , Yao Lutian , Qin Ling , Hatzigeorgiou Artemis G. , Minn Andy J. , Putt Mary , Lanza Matthew , Assenmacher Charles-Antoine , Radaelli Enrico , Huck Jennifer , Diffenderfer Eric , Dong Lei , Metz James , Koumenis Constantinos , Cengel Keith A. , Maity Amit , Busch Theresa M.
Published: July 2021

In studies of electron and proton radiotherapy, ultrahigh dose rates of FLASH radiotherapy appear to produce fewer toxicities than standard dose rates while maintaining local tumor control. FLASH-proton radiotherapy (F-PRT) brings the spatial advantages of PRT to FLASH dose rates (>40 Gy/second), making it important to understand if and how F-PRT spares normal tissues while providing antitumor efficacy that is equivalent to standard-proton radiotherapy (S-PRT). Here we studied PRT damage to skin and mesenchymal tissues of muscle and bone and found that F-PRT of the C57BL/6 murine hind leg produced fewer severe toxicities leading to death or requiring euthanasia than S-PRT of the same dose. RNA-seq analyses of murine skin and bone revealed pathways upregulated by S-PRT yet unaltered by F-PRT, such as apoptosis signaling and keratinocyte differentiation in skin, as well as osteoclast differentiation and chondrocyte development in bone. Corroborating these findings, F-PRT reduced skin injury, stem cell depletion, and inflammation, mitigated late effects including lymphedema, and decreased histopathologically detected myofiber atrophy, bone resorption, hair follicle atrophy, and epidermal hyperplasia. F-PRT was equipotent to S-PRT in control of two murine sarcoma models, including at an orthotopic intramuscular site, thereby establishing its relevance to mesenchymal cancers. Finally, S-PRT produced greater increases in TGFβ1 in murine skin and the skin of canines enrolled in a phase I study of F-PRT versus S-PRT. Collectively, these data provide novel insights into F-PRT-mediated tissue sparing and support its ongoing investigation in applications that would benefit from this sparing of skin and mesenchymal tissues.

Significance:

These findings will spur investigation of FLASH radiotherapy in sarcoma and additional cancers where mesenchymal tissues are at risk, including head and neck cancer, breast cancer, and pelvic malignancies.
Copy Number Aberration Analysis to Predict Response to Neoadjuvant Anti-HER2 Therapy: Results from the NeoALTTO Phase III Clinical Trial
Authors: Venet David , Rediti Mattia , Maetens Marion , Fumagalli Debora , Brown David N. , Majjaj Samira , Salgado Roberto , Pusztai Lajos , Harbeck Nadia , El-Abed Sarra , Wang Yingbo , Saura Cristina , Gomez Henry , Semiglazov Vladimir Fedorovich , de Azambuja Evandro , Huober Jens , Nuciforo Paolo , Di Cosimo Serena , Piccart Martine , Loi Sherene , Rothé Françoise , Sotiriou Christos
Published: July 2021

Purpose:

The heterogeneity of response to anti-HER2 agents represents a major challenge in patients with HER2-positive breast cancer. To better understand the sensitivity and resistance to trastuzumab and lapatinib, we investigated the role of copy number aberrations (CNA) in predicting pathologic complete response (pCR) and survival outcomes in the NeoALTTO trial.

Experimental Design:

The neoadjuvant phase III NeoALTTO trial enrolled 455 patients with HER2-positive early-stage breast cancer. DNA samples from 269 patients were assessed for genome-wide copy number profiling. Recurrent CNAs were found with GISTIC2.0.

Results:

CNA estimates were obtained for 184 patients included in NeoALTTO. Among those, matched transcriptome and whole-exome data were available for 154 and 181 patients, respectively. A significant association between gene copy number and pCR was demonstrated for ERBB2 amplification. Nevertheless, ERBB2 amplification ceased to be predictive once ERBB2 expression level was considered. GISTIC2.0 analysis revealed 159 recurrent CNA regions. Lower copy number levels of the 6q23-24 locus predicted absence of pCR in the whole cohort and in the estrogen receptor–positive subgroup. 6q23-24 deletion was significantly more frequent in TP53 wild-type (WT) compared with TP53-mutated, resulting in copy number levels significantly associated with lack of pCR only in the TP53 WT subgroup. Interestingly, a gene-ontology analysis highlighted several immune processes correlated to 6q23-24 copy number.

Conclusions:

Our analysis identified ERBB2 copy number as well as 6q23-24 CNAs as predictors of response to anti–HER2-based treatment. ERBB2 expression outperformed ERBB2 amplification. The complexity of the 6q23-24 region warrants further investigation.
A Phase I Study of the Combination of Pexidartinib and Sirolimus to Target Tumor-Associated Macrophages in Unresectable Sarcoma and Malignant Peripheral Nerve Sheath Tumors
Authors: Manji Gulam A. , Van Tine Brian A. , Lee Shing M. , Raufi Alexander G. , Pellicciotta Ilenia , Hirbe Angela C. , Pradhan Jaya , Chen Andrew , Rabadan Raul , Schwartz Gary K.
Published: July 2021

Purpose:

To evaluate the safety and tolerability in phase I first-in-human combination therapy with pexidartinib, an inhibitor of colony-stimulating factor-1 receptor, and sirolimus, an mTOR inhibitor, to target tumor-associated macrophage (TAM) polarization in soft tissue sarcomas (STS).

Patients and Methods:

This multicenter phase I study used the time-to-event continual reassessment method (TITE-CRM) to study the combination of sirolimus, doses ranging from 2 to 6 mg, with pexidartinib, doses ranging from 600 to 1,000 mg, both provided continuously on a 28-day cycle, in patients with advanced sarcoma. A total of 24 patients [8 malignant peripheral nerve sheath tumor, 3 tenosynovial giant cell tumor (TGCT), 5 leiomyosarcoma, and 8 with other sarcoma subtypes] were enrolled. The median age was 46 years, 56% were male, and 61% had >2 prior lines of therapy.

Results:

The recommended phase II dose was 2 mg of sirolimus combined with 1,000 mg of pexidartinib daily. Of the 18 evaluable subjects, 5 experienced dose-limiting toxicities (2 elevated aspartate aminotransferase/alanine aminotransferase, 2 elevated sirolimus trough levels, and 1 grade 5 dehydration). Most common grade 2 or higher treatment-related adverse events included anemia, fatigue, neutropenia, and lymphopenia. Clinical benefit was observed in 12 of 18 (67%) evaluable subjects with 3 partial responses (all in TGCT) and 9 stable disease. Tissue staining indicated a decreased proportion of activated M2 macrophages within tumor samples with treatment.

Conclusions:

Pexidartinib can be safely administered with sirolimus. These findings support further investigation of this combination to determine clinical efficacy. Clinicaltrials.gov identifier NCT02584647.
Multimorbidity and Regional Volumes of the Default Mode Network in Brain Aging
Authors: Wang Jen-Hung , Soo Goh Joshua Oon , Chang Yu-Ling , Chen Shu-Cin , Li Yu-Ying , Yu Yu-Ping , Lo Raymond Y.
Published: July 2021

Introduction: The default mode network (DMN) is selectively vulnerable in brain aging. Little is known about the effect of multimorbidity as a whole onto the brain structural integrity. Objective: We aimed to investigate the association between multimorbidity and the structural integrity of DMN. Methods: We enrolled senior volunteers aged between 60 and 80 years in Hualien County during 2014–2018 and conducted in-person interview to collect information on chronic diseases. Fasting blood glucose and glycated hemoglobin (HbA1c) were tested. We assessed multimorbidity burden by the cumulative illness rating scale-geriatric (CIRS-G). MRI brain scans were standardized to measure the regional volume within the DMN. In a cross-sectional design, we employed stepwise regression models to evaluate the effects of age, sex, hyperglycemia, and multimorbidity on the DMN. Results: A total of 170 volunteers were enrolled with a mean age of 66.9 years, female preponderance (71%), an average mini-mental state examination score of 27.6, a mean HbA1c of 6.0, and a mean CIRS-G total score (TS) of 7.2. We found that older age was associated with reduced volumes in the hippocampus, left rostral anterior cingulate cortex, right posterior cingulate, right isthmus, precuneus, and right supramarginal. Higher levels of HbA1c and fasting glucose were associated with a reduced volume in the hippocampus only. A higher CIRS-G-TS was associated with reduced volumes in the left posterior cingulate cortex and right supramarginal gyrus; while a higher CIRS-G severity index was associated with a smaller right precuneus and right supramarginal. Conclusions: In the DMN, hippocampal volume shows vulnerability to aging and hyperglycemia, whereas the posterior cingulate, supramarginal, and precuneus cortices may be the key sites to reflect the total effects of multimorbidity.
A Histopathological Evaluation of Ovarian Hyperstimulation Syndrome on Reproductive and Vital Organs and the Role of the VEGF-PKA Pathway in a Mouse Model
Authors: Karabulut Seda , Korkmaz Oya , Erdem Altun Ceren , Keskin Ilknur
Published: July 2021

Ovarian hyperstimulation syndrome (OHSS) is one of the most common and iatrogenic complications of in vitro fertilization therapy, which is an exaggerated response to excess hormones resulting in the development of a large number of maturing follicles. Although the complications of and reasons for the condition are well known, the overall histopathological effects on systemic organs and the extent of the damage have not been fully elucidated. Besides, the mechanism that underlies the situation is not very well known. The aim of the present work was to analyse the histopathological effects of OHSS on reproductive (uterus and ovary) and vital organs (liver and kidney) and the possible role of the VEGF-PKA pathway in triggering the condition. Balb/c mice were used to establish an OHSS model. The OHSS group were injected with overdose PMSG while the normal responder group were injected with an optimal dose. Histopathological evaluation was utilised in the liver, kidney, ovary, and uterus stained with hematoxylin and eosin, Masson’s trichrome, and periodic acid-Schiff stain. The expression profiles of VEGF (vascular endothelial growth factor), PKA (protein kinase A), and p-PKA (an activated form of PKA) were detected with immunohistochemistry and Western blotting. OHSS was demonstrated to have a negative histopathological effect on all of the organs analysed. These effects were associated with an overall increase in the expression levels of VEGF, PKA, and p-PKA. OHSS has a serious histopathological negative effect on the systemic and reproductive organs and is proven to affect overall health, and thus should be considered a dangerous complication during ART techniques. The activation of the VEGF-PKA pathway, which is indicated by the expression levels of VEGF, PKA, and p-PKA, is demonstrated to accompany this complication, which should be further elucidated to understand the mechanisms underlying the condition.
Anosmia as a Screening Tool for COVID-19 Infection: A Prospective Cohort Study
Authors: AlHamadani Esra , Zia Sania , AlRahma Ali , AlNajjar Firas
Published: July 2021

Objectives: Several studies promoted anosmia as a possible isolated symptom for coronavirus disease 2019 (COVID-19). No studies used feasible methods of smell testing that the public would use to address the accuracy of these claims. Methods: This is a single-center study conducted between April 2020 and June 2020. The sense of smell was tested in vitally stable suspected COVID-19 patients with no/mild upper respiratory tract infection symptoms prior to nasopharyngeal swabbing for reverse-transcriptase polymerase chain reaction. Patients were instructed to close their eyes. Each nostril was tested separately while the other was blocked with the patient’s index finger. Patients inhaled from 2 concealed vials (coffee and strawberry essence) consecutively, kept within 30 cm of the nostril for 60 s. Patients who could not identify both odors with both nostrils were recorded as “anosmia.” Results: Out of 346 eligible subjects, 43 had anosmia of which 26 (60%) tested COVID-19 positive. χ2 test showed a p value <0.001. The test showed a sensitivity of 30% (95% confidence interval [CI] 21%, 41%) and specificity 94% (95% CI 90%, 96%). Logistic regression revealed an odds ratio of 5.9 (95% CI 3.0, 12) p value <0.001. Conclusion: Given the low sensitivity (30%) of this method in detecting COVID-19 infection, we conclude that this method is not a useful screening tool for COVID-19 infection. The moderate negative predictive value (80%) is nongeneralizable.
CYP24A1 and SLC34A1 Pathogenic Variants Are Uncommon in a Canadian Cohort of Children with Hypercalcemia or Hypercalciuria
Authors: Rousseau-Nepton Isabelle , Jones Glenville , Schlingmann Karlpiet , Kaufmann Martin , Zuijdwijk Caroline S. , Khatchadourian Karine , Gupta Indra R. , Pacaud Danièle , Pinsk Maury N. , Mokashi Arati , Nour Munier A. , Alexander R. Todd , Rodd Celia J.
Published: July 2021

Objectives: Biallelic pathogenic variants in CYPA24A1 and SLC34A1 are causes of idiopathic infantile hypercalcemia. Pathogenic variants in both may also give rise to hypercalciuria with nephrocalcinosis or nephrolithiasis without previous hypercalcemia (renal group). Our objective was to examine the frequency of CYP24A1 or SLC34A1 variants in children with early hypercalcemia or late-onset hypercalciuria. Method: Forty-one children from 7 centers across Canada were recruited. Local investigations were undertaken. The serum was evaluated by liquid chromatography tandem-mass spectrometry for the ratio of 25-hydroxyvitamin D3 to 24,25-dihydroxyvitamin D3, (25-OH-D3:24,25-(OH)2D3), an elevation pathognomonic for the loss of function of the CYP24A1 enzyme. Mutational analyses were undertaken. Family cascade screening was performed if pathogenic variants were detected in probands. Results: Twenty-nine children had early-onset hypercalcemia; none had elevated 25-OH-D3:24,25-(OH)2D3 or variants. Interestingly, 2 of 12 in the renal group had elevated 25-OH-D3:24,25-(OH)2D3 and presented as preadolescents. In case 1, cascade testing revealed a sibling and parent with asymptomatic pathogenic variants in CYP24A1. Four CYP24A1 pathogenic variants were identified in these 2 probands: 3 have been described in European populations, and 1 is a rare variant in exon 7 (c931delC) that is likely pathogenic. No SLC34A1 pathogenic variants were detected. Conclusion: In Canada, pathogenic variants in CYP24A1 appear to manifest with late-onset hypercalciuria and its sequelae. The 25-OH-D3:24,25-(OH)2D3 ratio is an excellent tool for screening for biallelic pathogenic variants in CYP24A1. We confirm that cascade testing is important for these variants.
Lorlatinib Induces Durable Disease Stabilization in a Pancreatic Cancer Patient with a ROS1 p.L1950F Mutation: Case Report
Authors: Velthaus Janna-Lisa , Iglauer Peter , Simon Ronald , Bokemeyer Carsten , Bannas Peter , Beumer Niklas , Imbusch Charles D. , Goekkurt Eray , Loges Sonja
Published: July 2021

Introduction: The prognosis of pancreatic cancer has improved only modestly in recent years. This is partly due to the lack of development in precision oncology including immune oncology in this entity. Rearrangements of the proto-oncogene tyrosine protein kinase ROS1 gene represent driver alterations found especially in lung cancer. Tyrosine kinase inhibitors (TKI) with activity against ROS1 including lorlatinib substantially improved the outcome of this patient population. Anecdotal evidence reports treatment of pancreatic cancer harboring ROS1 fusions with ROS1 TKI, but data concerning treatment of patients with ROS1 point mutations are lacking. Case Presentation: This case describes a pancreatic cancer patient harboring a ROS1 point mutation that occurred without an underlying ROS1 rearrangement and thus not in the resistance situation. The heavily pretreated patient showed a strong decrease of the tumor biomarkers (CA19-9 and CEA) and radiologically a durable stable disease to the targeted treatment with lorlatinib, thereby achieving a progression-free survival of 12 months. Conclusion: Our data are the first to show a clinical benefit from targeted treatment with ROS1 TKI in a cancer patient with a thus far undescribed ROS1 point mutation without a concomitant ROS1 rearrangement. Furthermore, they indicate that ROS1 could be an oncogenic driver in pancreatic cancer. This subgroup could be eligible for targeted treatments, which may contribute to the urgently needed improvement in patient outcome.
Short-Term Effects of Dexamethasone versus Betamethasone on Ultrasonic Measures of Fetal Well-Being: Cohort from a Blinded, Randomized Trial
Authors: Henry Amanda , Mahajan Aditi , Crowther Caroline A. , Lainchbury Anne , Roberts Lynne , Shand Antonia W. , Welsh Alec W.
Published: July 2021

Introduction: Maternal corticosteroid administration for anticipated preterm birth is common; however, the corticosteroid effect on fetal ultrasound and cardiotocograph (CTG) remains contested. This study aimed to evaluate short-term ultrasound and CTG impact of (a) dexamethasone versus betamethasone (b) pooled corticosteroid effect. Methods: Substudy of blinded randomized trial of dexamethasone versus betamethasone (given <34 weeks). Umbilical artery (UA), middle cerebral artery (MCA), ductus venosus (DV), and uterine artery Doppler, myocardial performance index (MPI), biophysical profile (BPP), and CTG measured pre-corticosteroid then 1, 2, 4, and 7 days post-corticosteroid. Results: Of 47 fetuses (39 singleton; 4 dichorionic, diamniotic twins; and 4 monochorionic, diamniotic twins) in the February 2012–2013 period, 24 received dexamethasone and 23 betamethasone at average gestation 29.8 ± 2.9 weeks. Thirteen pregnancies (30%) had pre-corticosteroid fetal concerns (estimated weight <10th centile and/or abnormal UA/MCA Doppler). Few significant differences were seen post-corticosteroid: DV pulsatility index and right MPI initially decreased 15–20%, and average BPP decreased slightly on days 1–2. There were no major differential effects of dexamethasone versus betamethasone. Discussion/Conclusion: No substantive post-corticosteroid effects were seen for most ultrasound/CTG measures in fetuses with heightened preterm birth risk but predominantly normal pre-corticosteroid measures. Clinically, this suggests avoiding overreliance on individual measures for delivery decisions post-corticosteroid; equally, multiple/marked ultrasound changes suggest true pathology and not corticosteroid effect.
Exclusive Neurogenic Bladder and Fecal Incontinency in an Achondroplasic Child Successfully Treated with Lumbar Foraminal Decompression
Authors: Giordano Flavio , Lenge Matteo , Donati Pierarturo , Mongardi Lorenzo , Di Giacomo Gianpiero , Mura Regina , Taverna Maria , Cini Chiara , Peraio Simone , Poggi Giovanni , Tuccinardi Germana , Giglio Sabrina , Genitori Lorenzo
Published: July 2021

Introduction: Achondroplasia is a genetic disorder characterized by defects in the development of endochondral bone resulting in skeletal abnormalities like stenosis of the foramen magnum and of the spine, shortened limb bones, and macrocephaly. Congenital spinal stenosis is frequent and due to premature fusion of the pedicles to the laminae. Case Presentation: We report a case of neurogenic bladder and fecal incontinence due to lumbar stenosis successfully treated with L1–L5 partial laminectomy and foraminotomy in a 7-year-old achondroplasic child. Discussion/Conclusion: To our knowledge, this is the first case report of exclusive neurogenic bladder and fecal incontinence in an achondroplasic child. Neurogenic bladder and fecal incontinence without motor impairment may be early and exclusive clinical findings of lumbar stenosis in children with achondroplasia.
Gut Microbiota and Pathophysiology of Depressive Disorder
Authors: Kunugi Hiroshi
Published: July 2021

Background: Accumulating evidence has suggested that the bi-directional communication pathway, the microbiota-gut-brain axis, plays an important role in the pathophysiology of many neuropsychiatric diseases including major depressive disorder (MDD). This review outlines current evidence and promising findings related to the pathophysiology and treatment of MDD. Summary: There are at least 4 key biological molecules/systems underlying the pathophysiology of MDD: central dopamine, stress responses by the hypothalamic-pituitary-adrenal axis and autonomic nervous system, inflammation, and brain-derived neurotrophic factor. Animal experiments in several depression models have clearly indicated that gut microbiota is closely related to these molecules/systems and administration of probiotics and prebitotics may have beneficial effects on them. Although the results of microbiota profile of MDD patients varied from a study to another, multiple studies reported that bacteria which produce short-chain fatty acids such as butyrate and those protective against metabolic diseases (e.g., Bacteroidetes) were reduced. Clinical trials of probiotics have emerged, and the majority of the studies have reported beneficial effects on depression symptoms and related biological markers. Key Messages: The accumulating evidence suggests that research on the microbiota-gut-brain axis in major depressive disorder (MDD) is promising to elucidate the pathophysiology and to develop novel treatment of MDD, although there is still a long distance yet to reach the goals.