bluuebunny/crossref_metadata_2025 huggingface dataset:
Imaging Tumor-Infiltrating Lymphocytes in Brain Tumors with [64Cu]Cu-NOTA-anti-CD8 PET
Authors: Nagle Veronica L. , Henry Kelly E. , Hertz Charli Ann J. , Graham Maya S. , Campos Carl , Parada Luis F. , Pandit-Taskar Neeta , Schietinger Andrea , Mellinghoff Ingo K. , Lewis Jason S.
Published: January 2021

Purpose:

Glioblastoma (GBM) is the most common malignant brain tumor in adults. Various immunotherapeutic approaches to improve patient survival are being developed, but the molecular mechanisms of immunotherapy resistance are currently unknown. Here, we explored the ability of a humanized radiolabeled CD8-targeted minibody to noninvasively quantify tumor-infiltrating CD8-positive (CD8+) T cells using PET.

Experimental Design:

We generated a peripheral blood mononuclear cell (PBMC) humanized immune system (HIS) mouse model and quantified the absolute number of CD8+ T cells by flow cytometry relative to the [64Cu]Cu-NOTA-anti-CD8 PET signal. To evaluate a patient-derived orthotopic GBM HIS model, we intracranially injected cells into NOG mice, humanized cohorts with multiple HLA-matched PBMC donors, and quantified CD8+ tumor-infiltrating lymphocytes by IHC. To determine whether [64Cu]Cu-NOTA-anti-CD8 images brain parenchymal T-cell infiltrate in GBM tumors, we performed PET and autoradiography and subsequently stained serial sections of brain tumor tissue by IHC for CD8+ T cells.

Results:

Nontumor-bearing NOG mice injected with human PBMCs showed prominent [64Cu]Cu-NOTA-anti-CD8 uptake in the spleen and minimal radiotracer localization to the normal brain. NOG mice harboring intracranial human GBMs yielded high-resolution PET images of tumor-infiltrating CD8+ T cells. Radiotracer retention correlated with CD8+ T-cell numbers in spleen and tumor tissue. Our study demonstrates the ability of [64Cu]Cu-NOTA-anti-CD8 PET to quantify peripheral and tumor-infiltrating CD8+ T cells in brain tumors.

Conclusions:

Human CD8+ T cells infiltrate an orthotopic GBM in a donor-dependent manner. Furthermore, [64Cu]Cu-NOTA-anti-CD8 quantitatively images both peripheral and brain parenchymal human CD8+ T cells.
Regorafenib-Avelumab Combination in Patients with Microsatellite Stable Colorectal Cancer (REGOMUNE): A Single-arm, Open-label, Phase II Trial
Authors: Cousin Sophie , Cantarel Coralie , Guegan Jean-Philippe , Gomez-Roca Carlos , Metges Jean-Philippe , Adenis Antoine , Pernot Simon , Bellera Carine , Kind Michèle , Auzanneau Céline , Le Loarer François , Soubeyran Isabelle , Bessede Alban , Italiano Antoine
Published: January 2021

Purpose:

Regorafenib is synergistic with immune checkpoint inhibition in colorectal cancer preclinical models.

Patients and Methods:

This was a single-arm, multicentric phase II trial. Regorafenib was given 3 weeks on/1 week off, 160 mg every day; avelumab 10 mg/kg i.v. was given every 2 weeks, beginning at cycle 1, day 15 until progression or unacceptable toxicity. The primary endpoint was the confirmed objective response rate under treatment, as per RECIST 1.1. The secondary endpoints included a 1-year nonprogression rate, progression-free survival (PFS), and overall survival (OS), safety and biomarkers studies performed on sequential tumor samples obtained at baseline and at cycle 2 day 1.

Results:

Forty-eight patients were enrolled in four centers. Forty-three were assessable for efficacy after central radiological review. Best response was stable disease for 23 patients (53.5%) and progressive disease for 17 patients (39.5%). The median PFS and OS were 3.6 months [95% confidence interval (CI), 1.8–5.4] and 10.8 months (95% CI, 5.9–NA), respectively. The most common grade 3 or 4 adverse events were palmar-plantar erythrodysesthesia syndrome (n = 14, 30%), hypertension (n = 11, 23%), and diarrhea (n = 6, 13%). High baseline infiltration by tumor-associated macrophages was significantly associated with adverse PFS (1.8 vs. 3.7 months; P = 0.002) and OS (3.7 months vs. not reached; P = 0.002). Increased tumor infiltration by CD8+ T cells at cycle 2, day 1 as compared with baseline was significantly associated with better outcome.

Conclusions:

The combination of regorafenib + avelumab mobilizes antitumor immunity in a subset of patients with microsatellite stable colorectal cancer. Computational pathology through quantification of immune cell infiltration may improve patient selection for further studies investigating this approach.
Radiotherapy Delivered before CDK4/6 Inhibitors Mediates Superior Therapeutic Effects in ER+ Breast Cancer
Authors: Petroni Giulia , Buqué Aitziber , Yamazaki Takahiro , Bloy Norma , Liberto Maurizio Di , Chen-Kiang Selina , Formenti Silvia C. , Galluzzi Lorenzo
Published: January 2021

Purpose:

Recent preclinical data suggest that cyclin-dependent kinase 4/6 (CDK4/6) inhibition may be harnessed to sensitize estrogen receptor–positive (ER+) breast cancer to radiotherapy. However, these findings were obtained in human ER+ breast cancer cell lines exposed to subclinical doses of CDK4/6 inhibitors with limited attention to treatment schedule. We investigated the activity of radiotherapy combined with the prototypic CDK4/6 inhibitor palbociclib placing emphasis on therapeutic schedule.

Experimental Design:

We combined radiotherapy and palbociclib in various doses and therapeutic schedules in human and mouse models of ER+ and ER-negative (ER−) breast cancer, including an immunocompetent mouse model that recapitulates key features of human luminal B breast cancer in women. We assessed proliferation, cell death, cell-cycle control, and clonogenic survival in vitro, as well as tumor growth, overall survival, and metastatic dissemination in vivo.

Results:

Radiotherapy and palbociclib employed as standalone agents had partial cytostatic effects in vitro, correlating with suboptimal tumor control in vivo. However, while palbociclib delivered before focal radiotherapy provided minimal benefits as compared with either treatment alone, delivering focal radiotherapy before palbociclib mediated superior therapeutic effects, even in the absence of p53. Such superiority manifested in vitro with enhanced cytostasis and loss of clonogenic potential, as well as in vivo with improved local and systemic tumor control.

Conclusions:

Our preclinical findings demonstrate that radiotherapy delivered before CDK4/6 inhibitors mediates superior antineoplastic effects compared with alternative treatment schedules, calling into question the design of clinical trials administering CDK4/6 inhibitors before radiotherapy in women with ER+ breast cancer.
Adaptor Protein ShcD/SHC4 Interacts with Tie2 Receptor to Synergistically Promote Glioma Cell Invasion
Authors: Tilak Manali , Alural Begüm , Wismer Sarah E. , Brasher Megan I. , New Laura A. , Sheridan Steven D. , Perlis Roy H. , Coppolino Marc G. , Lalonde Jasmin , Jones Nina
Published: January 2021

Gliomas are characterized by diffuse infiltration of tumor cells into surrounding brain tissue, and this highly invasive nature contributes to disease recurrence and poor patient outcomes. The molecular mechanisms underlying glioma cell invasion remain incompletely understood, limiting development of new targeted therapies. Here, we have identified phosphotyrosine adaptor protein ShcD as upregulated in malignant glioma and shown that it associates with receptor tyrosine kinase Tie2 to facilitate invasion. In human glioma cells, we find that expression of ShcD and Tie2 increases invasion, and this significant synergistic effect is disrupted with a ShcD mutant that cannot bind Tie2 or hyperphosphorylate the receptor. Expression of ShcD and/or Tie2 further increases invadopodia formation and matrix degradation in U87 glioma cells. In a coculture model, we show that U87-derived tumor spheroids expressing both ShcD and Tie2 display enhanced infiltration into cerebral organoids. Mechanistically, we identify changes in focal adhesion kinase phosphorylation in the presence of ShcD and/or Tie2 in U87 cells upon Tie2 activation. Finally, we identify a strong correlation between transcript levels of ShcD and Tie2 signaling components as well as N-cadherin in advanced gliomas and those with classical or mesenchymal subtypes, and we show that elevated expression of ShcD correlates with a significant reduction in patient survival in higher grade gliomas with mesenchymal signature. Altogether, our data highlight a novel Tie2–ShcD signaling axis in glioma cell invasion, which may be of clinical significance.

Implications:

ShcD cooperates with Tie2 to promote glioma cell invasion and its elevated expression correlates with poor patient outcome in advanced gliomas.
Loss of Aryl Hydrocarbon Receptor Promotes Colon Tumorigenesis in ApcS580/+; KrasG12D/+ Mice
Authors: Han Huajun , Davidson Laurie A. , Hensel Martha , Yoon Grace , Landrock Kerstin , Allred Clinton , Jayaraman Arul , Ivanov Ivan , Safe Stephen H. , Chapkin Robert S.
Published: January 2021

The mutational genetic landscape of colorectal cancer has been extensively characterized; however, the ability of “cooperation response genes” to modulate the function of cancer “driver” genes remains largely unknown. In this study, we investigate the role of aryl hydrocarbon receptor (AhR), a ligand-activated transcription factor, in modulating oncogenic cues in the colon. We show that intestinal epithelial cell–targeted AhR knockout (KO) promotes the expansion and clonogenic capacity of colonic stem/progenitor cells harboring ApcS580/+; KrasG12D/+ mutations by upregulating Wnt signaling. The loss of AhR in the gut epithelium increased cell proliferation, reduced mouse survival rate, and promoted cecum and colon tumorigenesis in mice. Mechanistically, the antagonism of Wnt signaling induced by Lgr5 haploinsufficiency attenuated the effects of AhR KO on cecum and colon tumorigenesis.

Implications:

Our findings reveal that AhR signaling plays a protective role in genetically induced colon tumorigenesis at least by suppressing Wnt signaling and provides rationale for the AhR as a therapeutic target for cancer prevention and treatment.
Complete Oculomotor Palsy after Influenza Vaccination in a Young Healthy Adult: A Case Report
Authors: Kim Bo Young , Yung Youngbok , Kim Geun Soo , Park Hea Ree , Lee Jae Jung , Song Pamela , Cho Joong-Yang
Published: January 2021

Influenza vaccines are known to have a few neurological complications, such as Guillain-Barre syndrome, chronic inflammatory demyelinating polyneuropathy, and acute disseminated encephalomyelitis. However, oculomotor palsy caused by influenza vaccination is extremely rare. We present a case report of a 25-year-old woman without any medical history who developed complete oculomotor palsy 2 weeks after influenza vaccination. Other possible causes of oculomotor nerve palsy, such as stroke, compressive lesions, infections, and autoimmune disorders, were eliminated by blood tests, cerebrospinal fluid examination, and imaging studies. Hence, influenza vaccine was considered as the likely cause.
Lung Sestamibi Uptake on Myocardial Perfusion Imaging and Outcomes in Chronic Kidney Disease
Authors: Bian Julia , Herzog Charles A. , Rangaswami Janani , Wald Ron , Stratman Jennifer A. , Asif Arif , Sidhu Mandeep S. , Bangalore Sripal , Mathew Roy O.
Published: January 2021

Background and Objectives: In patients with CKD and end-stage kidney disease (ESKD), cardiac stress testing has low sensitivity and specificity for coronary disease. Alternate markers that are derived during the stress testing may enhance the predictive characteristic of stress testing. The objective was to examine the predictive characteristic of lung-to-heart ratio (LHR) in patients with CKD and ESKD. Design, Setting, Participants, and Measurements: Retrospective parallel cohort of ESKD and CKD not on dialysis (CKD-ND) who underwent stress testing with nuclear myocardial perfusion imaging utilizing sestamibi tracer and regadenoson. Stress LHR was calculated by the processing software and reported. Patients were analyzed by tertile of LHR (≤0.28, 0.29–0.32, ≥0.33). The primary outcome was a composite of all-cause mortality, hospitalization for myocardial infarction or unstable angina, or revascularization. Results: There were 144 CKD-ND and 145 ESKD patients. Patients with ESKD had greater comorbidity burden than CKD-ND. Stress tests were more often performed for pre-operative risk assessment among ESKD versus CKD-ND (53.8 vs. 5.6%, p < 0.001). ESKD patients more likely had ischemia identified on stress testing (19.3 vs. 8.3%, p = 0.001). Mean LHR was 0.31 (Standard deviation – SD: 0.09) and was similar across CKD-ND stages and ESKD. Primary outcome in the lowest (23%) and highest (33.3%) LHR tertile was higher than the middle tertile (12.8%); p = 0.005. This finding was similar between CKD-ND and ESKD and persisted in multivariable analysis. Conclusions: LHR ≤0.28 and ≥0.33 are independently associated with higher risk for death in patients with CKD-ND and ESKD. Future studies are warranted to understand the association of extreme LHR values and outcomes in this high-risk population.
Van Neck Disease: A Rare Case
Authors: Narayanan Sukesh Ammanath , Chandy Lazar J. , Kandathil Julio Chacko
Published: January 2021

Hyperostosis of the ischiopubic synchondrosis, van Neck disease, is a rare skeletal abnormality in children. Asymmetric and delayed closure of this cartilaginous joint is considered as a normal phenomenon. The symptomatic presentation of this pathology often mimics other closely related conditions like stress fracture, infection, or tumor. We are presenting a case of van Neck disease in the nondominant limb of an eleven-year-old boy.
Transient Receptor Potential Melastatin 7 Promotes Vascular Adventitial Fibroblasts Phenotypic Transformation and Inflammatory Reaction Induced by Mechanical Stretching Stress via p38 MAPK/JNK Pathway
Authors: Liu Jiachen , Chen Laijiang , Huang Jun , Guo Shujie , Zhu Dingliang , Gao Pingjin
Published: January 2021

Remodeling of the arteries is one of the pathological bases of hypertension. We have previously shown that transient receptor potential melastatin 7 (TRPM7) aggravates the vascular adventitial remodeling caused by pressure overload in the transverse aortic constriction (TAC) model. In this study, we sought to explore the functional expression and downstream signaling of TRPM7 in vascular adventitial fibroblasts (AFs) stimulated by mechanical stretching stress (MSS). The expression of TRPM7 was upregulated with a concomitant translocation to the cytoplasm in the AFs stimulated with 20% MSS. Meanwhile, the expression of α-smooth muscle actin (α-SMA), a marker of transformation from AFs to myofibroblasts (MFs) was also increased. Moreover, AF-conditioned medium caused a significant migration of macrophages after treatment with MSS and contained high levels of monocyte chemotactic protein-1 (MCP-1), interleukin-6 (IL-6), interleukin-8 (IL-8), and tumor necrosis factor-α (TNF-α). Pharmacological and RNA interference approaches using the TRPM7 inhibitor 2-aminoethoxydiphenyl borate (2-APB) and speciﬁc anti-TRPM7 small interfering RNA (si­RNA-TRPM7) abrogated these changes significantly. Further exploration uncloaked that inhibition of TRPM7 reduced the phosphorylation of p38 MAP kinase (p38MAPK) and c-Jun N-terminal kinase (JNK) in the AFs stimulated with MSS. Furthermore, inhibition of the phosphorylation of p38MAPK or JNK could also alleviate the MSS-induced expression of α-SMA and secretion of inflammatory factors. These observations indicate that activated TRPM7 participates in the phenotypic transformation and inflammatory action of AFs in response to MSS through the p38MAPK/JNK pathway and suggest that TRPM7 may be a potential therapeutic target for vascular remodeling caused by hemodynamic changes in hypertension.
Research Priorities in Atrial Fibrillation Screening
Authors: Benjamin Emelia J. , Go Alan S. , Desvigne-Nickens Patrice , Anderson Christopher D. , Casadei Barbara , Chen Lin Y. , Crijns Harry J.G.M. , Freedman Ben , Hills Mellanie True , Healey Jeff S. , Kamel Hooman , Kim Dong-Yun , Link Mark S. , Lopes Renato D. , Lubitz Steven A. , McManus David D. , Noseworthy Peter A. , Perez Marco V. , Piccini Jonathan P. , Schnabel Renate B. , Singer Daniel E. , Tieleman Robert G. , Turakhia Mintu P. , Van Gelder Isabelle C. , Cooper Lawton S. , Al-Khatib Sana M.
Published: January 2021

Clinically recognized atrial fibrillation (AF) is associated with higher risk of complications, including ischemic stroke, cognitive decline, heart failure, myocardial infarction, and death. It is increasingly recognized that AF frequently is undetected until complications such as stroke or heart failure occur. Hence, the public and clinicians have an intense interest in detecting AF earlier. However, the most appropriate strategies to detect undiagnosed AF (sometimes referred to as subclinical AF) and the prognostic and therapeutic implications of AF detected by screening are uncertain. Our report summarizes the National Heart, Lung, and Blood Institute’s virtual workshop focused on identifying key research priorities related to AF screening. Global experts reviewed major knowledge gaps and identified critical research priorities in the following areas: (1) role of opportunistic screening; (2) AF as a risk factor, risk marker, or both; (3) relationship between AF burden detected with long-term monitoring and outcomes/treatments; (4) designs of potential randomized trials of systematic AF screening with clinically relevant outcomes; and (5) role of AF screening after ischemic stroke. Our report aims to inform and catalyze AF screening research that will advance innovative, resource-efficient, and clinically relevant studies in diverse populations to improve the diagnosis, management, and prognosis of patients with undiagnosed AF.
Impaired Endothelial Function in Patients With Postural Tachycardia Syndrome
Authors: Chopoorian Abby H. , Wahba Amr , Celedonio Jorge , Nwazue Victor , Smith Emily C. , Garland Emily M. , Paranjape Sachin , Okamoto Luis E. , Black Bonnie K. , Biaggioni Italo , Raj Satish R. , Gamboa Alfredo
Published: January 2021

The purpose of this study is to evaluate endothelial function in postural tachycardia syndrome (PoTS), a poorly understood chronic condition characterized by a state of consistent orthostatic tachycardia (delta heart rate ≥30 beats per minute) upon standing without orthostatic hypotension. Nineteen patients with PoTS and 9 healthy controls were studied after 3 days of a fixed, caffeine-free, normal sodium (150 milliequivalents/day) diet. All participants underwent autonomic function testing, including sinus arrhythmia, valsalva maneuver, hyperventilation, cold pressor, handgrip, and a standing test with catecholamine measurements, followed by endothelial function testing. We analyzed 3 measures of endothelial function: percent brachial flow-mediated dilation, digital pulsatile arterial tonometry, and postischemic percent leg blood flow. Flow-mediated dilation was significantly lower in patients with PoTS (6.23±3.54% for PoTS) than in healthy controls (10.6±4.37% for controls versus,
P
=0.014). PoTS and controls had similar digital pulsatile arterial tonometry (1.93±0.40 arbitrary units for controls versus 2.13±0.63 arbitrary units for PoTS). PoTS had similar but suggestive percent leg blood flow to controls (313±158% for PoTS versus 468±236% for controls,
P
=0.098). Patients with PoTS have significantly reduced flow-mediated dilation compared with healthy controls, suggesting that PoTS is characterized by endothelial dysfunction in conduit arteries.

Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01308099.
Influence of Pregnancy on Hemorrhage Risk in Women With Cerebral and Spinal Cavernous Malformations
Authors: Joseph Nycole K. , Kumar Shivram , Brown Robert D. , Lanzino Giuseppe , Flemming Kelly D.
Published: January 2021

Background and Purpose:

Pregnancy as a hemorrhage risk factor in women with cavernous malformations (CMs) is controversial. We describe prospective hemorrhage risk in women who become pregnant after an established CM diagnosis.

Methods:

Beginning in 2015, we recruited consecutive patients with radiologically confirmed CM of the brain or spinal cord to participate in a prospective registry. Participants underwent a baseline and annual medical record review, imaging review, and annual surveys to ascertain pregnancies, deliveries, and neurological complications. We collected prospective hemorrhage data on reproductive age women. We calculated prospective hemorrhage rates on childbearing age patients based on the number of hemorrhages occurring post-CM diagnosis during pregnancy and nonpregnancy, divided by the years of follow-up and censored at last follow-up, age 46, or surgery in sporadic-form CM. The hemorrhage rates were compared and the 95% CI presented with a
P
value of <0.05.

Results:

Of 160 women, 90 presented with CM under the age of 46 (average age 31.6 years; 25.6% familial form; 46.7% with hemorrhage; 24.4% brain stem location). These 90 patients had 136 pregnancies before CM diagnosis; 36 pregnancies occurred at or after the diagnosis of CM. Four patients had a hemorrhage while pregnant or postpartum leading to the first CM diagnosis. During 402.6 years of follow-up while not pregnant, 42 hemorrhages occurred prospectively yielding a 10.4% per year (95% CI, 7.5–14.0) risk of hemorrhage while not pregnant. No hemorrhages occurred during 32 prospective pregnancies (26 live births including 1 twinset and 7 nonviable fetuses) after CM diagnosis during 26.9 years of pregnancy time yielding a rate of 0% per year (95% CI, 0–13.6). We found no statistical difference in the rates of hemorrhage during pregnant and nonpregnant time (
P
=0.09). No hemorrhage occurred during delivery.

Conclusions:

Our prospective data suggest that pregnancy does not increase the risk of hemorrhage in women with a known brain or spinal cord CM and that vaginal delivery is safe in appropriate candidates.
Evolutionary Robotics Controllers with Proprioception Facilitated by Neural-Network-Based Simulators
Authors: Phillips Antin , du Plessis Mathys C.
Published: January 2021

Taking inspiration from the navigation ability of humans, this study investigated a method of providing robotic controllers with a basic sense of position. It incorporated robotic simulators into robotic controllers to provide them with a mechanism to approximate the effects their actions had on the robot. Controllers with and without internal simulators were tested and compared. The proposed controller architecture was shown to outperform the regular controller architecture. However, the longer an internal simulator was executed, the more inaccurate it became. Thus, the performance of controllers with internal simulators reduced over time unless their internal simulator was periodically corrected.
Review of Australian species of Plectranthias Bleeker and Selenanthias Tanaka (Teleostei: Serranidae: Anthiadinae), with descriptions of four new species
Authors: GILL ANTHONY C. , POGONOSKI JOHN J. , MOORE GLENN I. , JOHNSON JEFFREY W.
Published: January 2021

Australian species of the anthiadine genera Plectranthias and Selenanthias are reviewed. Twenty-two species of Plectranthias and two species of Selenanthias are recorded from Australian waters: Plectranthias sp. 1 from a seamount north of Middleton Reef and Norfolk Ridge, Tasman Sea; P. alleni Randall from off southwest Western Australia; P. azumanus (Jordan & Richardson) from off southwest Western Australia; P. bennetti Allen & Walsh from Holmes Reef, Coral Sea; P. cruentus Gill & Roberts from Lord Howe Island, and possibly off Stradbroke Island, Queensland; P. ferrugineus n. sp. from the North West Shelf and Arafura Sea; P. fourmanoiri Randall from Christmas Island and Holmes Reef, Coral Sea; P. grahami n. sp. from off central New South Wales, Tasman Sea; P. inermis Randall from Christmas Island; P. japonicus (Steindachner) from the Arafura Sea and North West Shelf; P. kamii Randall from the Coral Sea, Lord Howe Island and Christmas Island; P. lasti Randall & Hoese from the North West Shelf and off Marion Reef, Queensland; P. longimanus (Weber) from the Timor Sea, Great Barrier Reef, Coral Sea and southern Queensland; P. maculicauda (Regan) from southeastern Australia; P. mcgroutheri n. sp. from the North West Shelf; P. megalophthalmus Fourmanoir & Randall from northeast of the Whitsunday Islands, Queensland; P. melanesius Randall from southeastern Queensland and a seamount north of Middleton Reef; P. moretonensis n. sp. from off Stradbroke Island, Queensland; P. nanus Randall from the Cocos (Keeling) Islands, Christmas Island, Great Barrier Reef and Coral Sea; P. retrofasciatus Fourmanoir & Randall from the Great Barrier Reef; P. robertsi Randall & Hoese from off Queensland, Coral Sea; P. winniensis (Tyler) from the Great Barrier Reef and Coral Sea; Selenanthias analis Tanaka from the North West Shelf and Arafura Sea; and S. barroi (Fourmanoir) from west of Lihou Reef, Coral Sea. Five of the species represent new records for Australia: P. azumanus, P. kamii, P. megalophthalmus, P. melanesius and S. barroi. Previous records of P. megalophthalmus from the North West Shelf are based on misidentified specimens of P. lasti. Records of P. wheeleri from the North West Shelf are based on specimens here identified as P. mcgroutheri n. sp. A record of P. yamakawai Yoshino from Christmas Island is based on a misidentified specimen of P. kamii. Plectranthias retrofasciatus was previously recorded from the Great Barrier Reef as P. pallidus Randall & Hoese, here shown to be a junior synonym of P. retrofasciatus. Video-based records of P. kelloggi from the Great Barrier Reef appear to be based on P. retrofasciatus. Identification keys, diagnoses, character summaries, photographs and Australian distribution information are presented for all species. Full descriptions are provided for the new species and for those newly recorded from Australia.
Molecular mapping of a novel lesion mimic gene (lm4) associated with enhanced resistance to stripe rust in bread wheat
Authors: Liu Rong , Lu Jing , Zheng Shigang , Du Mei , Zhang Chihong , Wang Minxiu , Li Yunfang , Xing Jiayi , Wu Yu , Zhang Lei
Published: January 2021

Background

Lesion mimics (LMs) are disease-like symptoms that occur randomly on plant green leaves in the absence of pathogens. A previous study showed that LMs are related to enhanced resistance to a broad spectrum of diverse pathogen races and programmed cell death (PCD). Stripe rust is a globally epidemic fungal disease that can substantially reduce the quality and yield of crops. The development of resistant cultivars is an economical and environmentally friendly way to enhance the adaptability and yield stability of crops instead of the use of fungicide applications.

Results

In this study, a novel LM gene affording Pst resistance was identified and mapped with molecular markers developed for marker-assisted selection (MAS)-based wheat breeding. In this study, a novel LM gene named lm4, which is closely linked (8.06 cM) to SSR markers Xgwm210 and Xgwm455, was identified by using a Yanzhan 1/Neixiang 188 RIL population. The genetic distance of lm4 was then narrowed such that it was flanked by SSR markers with 0.51 cM and 0.77 cM intervals. Two SSR markers, lm4_01_cib and lm4_02_cib, were developed based on the content in the Chinese Spring genome database and wheat 660 K SNP results; these markers can be used to conduct MAS of LMs in wheat. The results also showed that lm4 significantly improved the resistance of stripe rust in wheat.

Conclusions

Therefore, lm4 is associated with stripe rust resistance, which may provide theoretical support for future crop disease-resistance breeding and for understanding the plant apoptosis mechanism.
Global transcriptome changes of elongating internode of sugarcane in response to mepiquat chloride
Authors: Chen Rongfa , Fan Yegeng , Zhou Huiwen , Mo Shanping , Zhou Zhongfeng , Yan Haifeng , Luo Ting , Huang Xing , Weng Mengling , Lakshmanan Prakash , Li Yangrui , Qiu Lihang , Wu Jianming
Published: January 2021

Background

Mepiquat chloride (DPC) is a chemical that is extensively used to control internode growth and create compact canopies in cultured plants. Previous studies have suggested that DPC could also inhibit gibberellin biosynthesis in sugarcane. Unfortunately, the molecular mechanism underlying the suppressive effects of DPC on plant growth is still largely unknown.

Results

In the present study, we first obtained high-quality long transcripts from the internodes of sugarcane using the PacBio Sequel System. A total of 72,671 isoforms, with N50 at 3073, were generated. These long isoforms were used as a reference for the subsequent RNA-seq. Afterwards, short reads generated from the Illumina HiSeq 4000 platform were used to compare the differentially expressed genes in both the DPC and the control groups. Transcriptome profiling showed that most significant gene changes occurred after six days post DPC treatment. These genes were related to plant hormone signal transduction and biosynthesis of several metabolites, indicating that DPC affected multiple pathways, in addition to suppressing gibberellin biosynthesis. The network of DPC on the key stage was illustrated by weighted gene co-expression network analysis (WGCNA). Among the 36 constructed modules, the top positive correlated module, at the stage of six days post spraying DPC, was sienna3. Notably, Stf0 sulfotransferase, cyclin-like F-box, and HOX12 were the hub genes in sienna3 that had high correlation with other genes in this module. Furthermore, the qPCR validated the high accuracy of the RNA-seq results.

Conclusion

Taken together, we have demonstrated the key role of these genes in DPC-induced growth inhibition in sugarcane.
Reconciling relationships with physical activity: a qualitative study of women’s postnatal physical activity decision-making
Authors: Liva Sarah Jane , Hall Wendy Anne , Oliffe John
Published: January 2021

Background

Challenges with engaging in postnatal physical activity can negatively affect the health of women and their families. This study investigated women’s physical activity decision-making processes and strategies to support their physical activity as part of a healthy postpartum transition.

Methods

Thirty healthy women with infants aged 2.5–12 months completed 3-day activity diaries and an individual interview. Using Glaser and Charmaz’s grounded theory methodology, the core category, reconciling relationships with physical activity, was constructed, which explained women’s processes of postnatal physical activity decision-making.

Results

Through reconciling relationships with physical activity, women discerned the types of physical activity they were comfortable pursuing at various points in the postpartum transition. Based on the meaning physical activity held for participants and their views about risks, supports, and resources, women gauged their capacity and the workability of their physical activity desires. Most women were uncertain of their capacity (physical, emotional) to return to physical activity and viewed the achievement of several or all of their desired physical activities as unworkable. Only a small group of women fully pursued the desirable physical activities they viewed as important for their well-being. Women adjusted the strategies they used to achieve physical activity when their expectations of capacity and workability did not align with their experiences. Some women lacked access to resources or supportive messaging about postpartum physical activity and downgraded their physical activity pursuit after negative personal physical or childcare experiences.

Conclusions

Women can benefit from discussions about physiological birth recovery and navigating community and peer resources to support physical activity access and the safe return to physical activity following birth.
The utility of simultaneous CT-guided localization for multiple pulmonary nodules using microcoil before video-assisted thoracic surgery
Authors: Xu Yanyan , Ma Lingchuan , Sun Hongliang , Huang Zhenguo , Zhang Zhenrong , Xiao Fei , Ma Qianli , Lin Jie , Xie Sheng
Published: January 2021

Background

To evaluate the feasibility and safety of microcoil in simultaneous localization for multiple pulmonary nodules before video-assisted thoracic surgery (VATS).

Methods

Twenty-eight consecutive patients (26 two-nodule, 2 three-nodule; 58 nodules in total; Group A) underwent simultaneous CT-guided localization of multiple pulmonary nodules before VATS using microcoil. Successful targeting, localization, and VATS were defined as implantation of microcoil at the target site on CT image which was obtained immediately after the marking procedure, visualization of nodule location, and complete resection of the target nodule with adequate margin, respectively. Meanwhile, the clinical characteristics, localization procedure-related variables of the nodules and procedure-related complications in group A were also assessed and compared with those in a control group (221 single-localization procedures in 221 patients; Group B).

Results

Similar rates of successful targeting, localization and VATS were observed in group A and B (96.6% vs. 98.2%; 91.4% vs. 91.0%; 100% vs. 99.1%). Although the rate of overall complications (including localized pneumothorax and intrapulmonary hemorrhage) was a bit higher in group A than that in group B (32.8% vs. 30.8%, p = 0.771), only minor complications were observed in the subjects of the two groups with no need for further treatment. In addition, the duration of simultaneous localization procedures was significantly longer than that of single localization (24 ± 7.5 vs.13 ± 6 min, p < 0.001).

Conclusions

CT-guided simultaneous microcoil localization for multiple pulmonary nodules before VATS was clinically feasible and safe with acceptable increase in the procedure time. Compared with localization for a single pulmonary nodule, simultaneous microcoil localizations for multiple nodules were prone to pneumothorax and hemorrhage. However, no statistically significant differences were observed between the two groups.
Short-term outcomes after minimally invasive versus open pancreaticoduodenectomy in elderly patients: a propensity score-matched analysis
Authors: Yin Shih-Min , Liu Yueh-Wei , Liu Yu-Yin , Yong Chee-Chien , Wang Chih-Chi , Li Wei-Feng , Yeh Cheng-Hsi
Published: January 2021

Background

To date, the evidence on the safety and benefits of minimally invasive pancreatoduodenectomy (MIPD) in elderly patients is still controversy. This study aim to compare the risk and benefit between MIPD and open pancreatoduodenectomy (OPD) in elderly patients.

Methods

From 2016 to 2020, we retrospective enrolled 26 patients underwent MIPD and other 119 patients underwent OPD. We firstly compared the baseline characteristics, 90-day mortality and short-term surgical outcomes of MIPD and OPD. Propensity score matching was applied for old age patient (≥ 65-year-old vs. < 65-year-old) for detail safety and feasibility analysis.

Results

Patients received MIPD is significantly older, had poor performance status, less lymph node harvest, longer operation time, less postoperative hospital stay (POHS) and earlier drain removal. After 1:2 propensity score matching analysis, elderly patients in MIPD group had significantly poor performance status (P = 0.042) compared to OPD group. Patients receiving MIPD had significantly shorter POHS (18 vs. 25 days, P = 0.028), earlier drain removal (16 vs. 21 days, P = 0.012) and smaller delay gastric empty rate (5.9 vs. 32.4% P = 0.036). There was no 90-day mortality (0% vs. 11.8%, P = 0.186) and pulmonary complications (0% vs. 17.6%, P = 0.075) in MIPD group, and the major complication rate is comparable to OPD group (17.6% vs. 29.4%, P = 0.290).

Conclusion

For elderly patients, MIPD is a feasible and safe option even in patients with inferior preoperative performance status. MIPD might also provide potential advantage for elderly patients in minimizing pulmonary complication and overall mortality over OPD.
User testing a patient information resource about potential complications of vaginally inserted synthetic mesh
Authors: Angelova Nikolina , Taylor Louise , McKee Lorna , Fearns Naomi , Mitchell Tracey
Published: January 2021

Background

Vaginal mesh implants are medical devices used in a number of operations to treat stress urinary incontinence and pelvic organ prolapse. Although many of these operations have delivered good outcomes, some women have experienced serious complications that have profoundly affected their quality of life. To ensure that evolving patient information is up-to-date, accurate and appropriate, the Transvaginal Mesh Oversight Group ‘user-tested’ a newly developed Scottish patient resource, the first to focus exclusively on the issue of complications. The aim of this research was to gather feedback on usability, content, language and presentation to inform the development of the resource from a user perspective.

Methods

The experience of using the patient resource was captured through semi-structured interviews that followed a ‘think-aloud’ protocol. The interviewer observed each participant as they went through the resource, asking questions and making field notes. Participants’ comments were then categorised using a validated model of user experience and subsequently analysed thematically.

Results

Thirteen people participated in the user testing interviews, including women with lived experience of mesh implants (n = 7), a convenience sample of staff working for Healthcare Improvement Scotland (n = 5) and a patient’s carer (n = 1). The majority of participants considered the resource as clear and helpful. Respondents reported that some presentational aspects promoted usability and understandability, including the use of a font that is easy to read, bullet lists, coloured headings and simple language. Barriers included the reliance on some technical language and an explicit anatomical diagram. Participants endorsed the valuable role of health professionals as co-mediators of patient information.

Conclusions

The findings illustrate the value of undertaking in-depth user-testing for patient information resources before their dissemination. The study highlighted how the direct guidance or navigation of a patient information resource by a health professional could increase its salience and accuracy of interpretation by patients, their families and carers. These insights may also be useful to other developers in improving patient information.
Yellow loosestrife (Lysimachia vulgaris var. davurica) ameliorates liver fibrosis in db/db mice with methionine- and choline-deficient diet-induced nonalcoholic steatohepatitis
Authors: Son Yang-Ju , Jung Da Seul , Shin Ji Min , Kim Myungsuk , Yoo Gyhye , Nho Chu Won
Published: January 2021

Background

Nonalcoholic steatohepatitis (NASH), a liver disease caused by a nonalcoholic fatty liver, is increasing in incidence worldwide. Owing to the complexity of its pathogenic mechanisms, there are no therapeutic agents for this disease yet. The ideal drug for NASH needs to concurrently decrease hepatic lipid accumulation and exert anti-inflammatory, antifibrotic, and antioxidative effects in the liver. Because of their multipurpose therapeutic effects, we considered that medicinal herbs are suitable for treating patients with NASH.

Methods

We determined the efficacy of the alcoholic extract of Lysimachia vulgaris var. davurica (LV), an edible medicinal herb, for NASH treatment. For inducing NASH, C57BLKS/J lar-Leprdb/Leprdb (db/db) male mice were fed with a methionine-choline deficient (MCD) diet ad libitum. After 3 weeks, the LV extract and a positive control (GFT505) were administered to mice by oral gavage for 3 weeks with a continued MCD diet as needed.

Results

In mice with diet-induced NASH, the LV extract could relieve the disease symptoms; that is, the extract ameliorated hepatic lipid accumulation and also showed antioxidative and anti-inflammatory effects. The LV extract also activated nuclear factor E2-related factor 2 (Nrf2) expression, leading to the upregulation of antioxidants and detoxification signaling. Moreover, the extract presented remarkable efficacy in alleviating liver fibrosis compared with GFT505. This difference was caused by significant LV extract-mediated reduction in the mRNA expression of fibrotic genes like the alpha-smooth muscle actin and collagen type 3 alpha 1. Reduction of fibrotic genes may thus relate with the downregulation of transforming growth factor beta (TGFβ)/Smad signaling by LV extract administration.

Conclusions

Lipid accumulation and inflammatory responses in the liver were alleviated by feeding LV extract to NASH-induced mice. Moreover, the LV extract strongly prevented liver fibrosis by blocking TGFβ/Smad signaling. Hence, LV showed sufficient potency for use as a therapeutic agent against NASH.
Hsa_circ_0010235 functions as an oncogenic drive in non-small cell lung cancer by modulating miR-433-3p/TIPRL axis
Authors: Zhang Furui , Cheng Ruirui , Li Ping , Lu Chunya , Zhang Guojun
Published: January 2021

Background

Non-small cell lung cancer (NSCLC) is a threat to human health. Circular RNAs (circRNAs) have been proved to function in NSCLC development. In this study, the role of circRNA hsa_circ_0010235 in NSCLC progression and the possible molecular mechanism were explored.

Methods

Expression of hsa_circ_0010235, miRNA (miR)-433-3p and TOR signaling pathway regulator-like (TIPRL) was examined by quantitative real-time PCR (qRT-PCR). Cell viability and clonogenicity were detected by cell counting kit-8 (CCK-8) assay and colony formation assay, respectively. Flow cytometry was performed to monitor cell apoptosis and cell cycle distribution. Western blot assay was employed to evaluate the protein levels of TIPRL, light chain 3 (LC3)-II/I and p62. Cell metastasis was assessed by Transwell and wound healing assays. The targeted relationship between miR-433-3p and hsa_circ_0010235 or TIPRL was confirmed by dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Furthermore, the role of hsa_circ_0010235 in vivo was investigated by xenograft assay.

Results

Hsa_circ_0010235 and TIPRL were highly expressed in NSCLC tissues and cells, while miR-433-3p was downregulated. Depletion of hsa_circ_0010235 or gain of miR-433-3p repressed proliferation and autophagy but promoted apoptosis in NSCLC cells. Hsa_circ_0010235 sponged miR-433-3p to upregulate TIPRL expression, so as to affect NSCLC development. Hsa_circ_0010235 knockdown also blocked tumor growth in vivo.

Conclusion

Hsa_circ_0010235 knockdown suppressed NSCLC progression by regulating miR-433-3p/TIPRL axis, affording a novel mechanism of NSCLC progression.
Mice with cleavage-resistant N-cadherin exhibit synapse anomaly in the hippocampus and outperformance in spatial learning tasks
Authors: Asada-Utsugi M. , Uemura K. , Kubota M. , Noda Y. , Tashiro Y. , Uemura T. M. , Yamakado H. , Urushitani M. , Takahashi R. , Hattori S. , Miyakawa T. , Ageta-Ishihara N. , Kobayashi K. , Kinoshita M. , Kinoshita A.
Published: January 2021

N-cadherin is a homophilic cell adhesion molecule that stabilizes excitatory synapses, by connecting pre- and post-synaptic termini. Upon NMDA receptor (NMDAR) activation by glutamate, membrane-proximal domains of N-cadherin are cleaved serially by a-disintegrin-and-metalloprotease 10 (ADAM10) and then presenilin 1(PS1, catalytic subunit of the γ-secretase complex). To assess the physiological significance of the initial N-cadherin cleavage, we engineer the mouse genome to create a knock-in allele with tandem missense mutations in the mouse N-cadherin/Cadherin-2 gene (Cdh2R714G, I715D, or GD) that confers resistance on proteolysis by ADAM10 (GD mice). GD mice showed a better performance in the radial maze test, with significantly less revisiting errors after intervals of 30 and 300 s than WT, and a tendency for enhanced freezing in fear conditioning. Interestingly, GD mice reveal higher complexity in the tufts of thorny excrescence in the CA3 region of the hippocampus. Fine morphometry with serial section transmission electron microscopy (ssTEM) and three-dimensional (3D) reconstruction reveals significantly higher synaptic density, significantly smaller PSD area, and normal dendritic spine volume in GD mice. This knock-in mouse has provided in vivo evidence that ADAM10-mediated cleavage is a critical step in N-cadherin shedding and degradation and involved in the structure and function of glutamatergic synapses, which affect the memory function.
Streamlining the institutional review board process in pragmatic randomized clinical trials: challenges and lessons learned from the Aspirin Dosing: A Patient-centric Trial Assessing Benefits and Long-Term Effectiveness (ADAPTABLE) trial
Authors: Marquis-Gravel Guillaume , Robertson Holly , Jones W. Schuyler , Riley Danielle , Ford Daniel E. , Crenshaw David , Joosten Yvonne A. , Rudov Lindsey , Hernandez Adrian F. , Hess Rachel
Published: January 2021

Background

New considerations during the ethical review processes may emerge from innovative, yet unfamiliar operational methods enabled in pragmatic randomized controlled trials (RCT), potentially making institutional review board (IRB) evaluation more complex. In this manuscript, key components of the pragmatic “Aspirin Dosing: A Patient-Centric Trial Assessing Benefits and Long-term Effectiveness (ADAPTABLE)” randomized trial that required a reappraisal of the IRB submission, review, and approval processes are discussed.

Main text

ADAPTABLE is a pragmatic, multicenter, open-label RCT evaluating the comparative effectiveness of two doses of aspirin widely used for secondary prevention (81 mg and 325 mg) in 15,000 patients with an established history of atherosclerotic cardiovascular disease. The electronic informed consent form is completed online by the participants at the time of enrollment, and endpoint ascertainment is conducted through queries of electronic health records.

IRB challenges encountered regarding centralized IRB evaluation, electronic informed consent, patient engagement, and risk determination in ADAPTABLE are described in this manuscript. The experience of ADAPTABLE encapsulates how pragmatic protocol components intended to facilitate the study conduct have been tempered by unexpected, yet justified concerns raised by local IRBs. How the lessons learned can be applied to future similar pragmatic trials is delineated.

Conclusion

Development of engaging communication channels between IRB and study personnel in pragmatic randomized trials as early as at the time of protocol design allows to reduce issues with IRB approval. Integrations of the lessons learned in ADAPTABLE regarding the IRB process for centralized IRBs, informed consent, patient engagement, and risk determination can be emulated and will be instrumental in future pragmatic studies.