bluuebunny/crossref_metadata_2025 huggingface dataset:
Exploring the ATR-CHK1 Pathway in the Response of Doxorubicin-induced DNA Damages in Acute Lymphoblastic Leukemia Cells
Authors: Rorà Andrea Ghelli Luserna di , Ghetti Martina , Ledda Lorenzo , Ferrari Anna , Bocconcelli Matteo , Padella Antonella , Napolitano Roberta , Fontana Maria Chiara , Liverani Chiara , Imbrogno Enrica , Bochicchio Maria Teresa , Paganelli Matteo , Robustelli Valentina , Sanogo Seydou , Cerchione Claudio , Fumagalli Monica , Rondoni Michela , Imovilli Annalisa , Musuraca Gerardo , Martinelli Giovanni , Simonetti Giorgia
Published: May 2021

Doxorubicin (Dox) is one of the most commonly used anthracyclines for the treatment of solid and hematological tumors such as B-/T-cell acute lymphoblastic leukemia (ALL). Dox compromises topoisomerase-II enzyme functionality, thus inducing structural damages during DNA replication and causes direct damages intercalating into DNA double helix. Eukaryotic cells respond to DNA damages by activating the ATM-CHK2 and/or ATR-CHK1 pathway, whose function is to regulate cell cycle progression, to promote damage repair and to control apoptosis. We evaluated the efficacy of a new drug schedule combining Dox and specific ATR (VE-821) or CHK1 (prexasertib, PX) inhibitors in the treatment of human B-/T- cell precursor ALL cell lines and primary ALL leukemic cells. We found that ALL cell lines respond to Dox activating the G2/M cell cycle checkpoint. Exposure of Dox-pretreated ALL cell lines to VE-821 or PX enhanced Dox cytotoxic effect. This phenomenon was associated with the abrogation of the G2/M cell cycle checkpoint with changes in the expression pCDK1 and cyclin B1, and cell entry in mitosis, followed by the induction of apoptosis. Indeed, the inhibition of the G2/M checkpoint led to a significant increment of normal and aberrant mitotic cells, including those showing tripolar spindles, metaphases with lagging chromosomes and massive chromosomes fragmentation. In conclusion, we found that the ATR-CHK1 pathway is involved in the response to Dox-induced DNA damages and we demonstrated that our new in vitro drug schedule that combines Dox followed by ATR/CHK1 inhibitors can increase Dox cytotoxicity against ALL cells, while using lower drug doses.
Homozygous R136S mutation in PRNP gene causes recessive inherited early onset prion disease
Authors: Ximelis Teresa , Marín-Moreno Alba , Espinosa Juan Carlos , Eraña Hasier , Charco Jorge M , Hernández Isabel , Riveira Carmen , Alcolea Daniel , González-Roca Eva , Aldecoa Iban , Molina-Porcel Laura , Parchi Piero , Rossi Marcello , Castilla Joaquín , Ruiz-García Raquel , Gelpi Ellen , Torres Juan María , Sanchez-Valle Raquel
Published: May 2021

Background: More than 40 pathogenic heterozygous PRNP mutations causing inherited prion diseases have been identified to date. Recessive inherited prion disease has not been described to date. Methods: We describe the clinical and neuropathological data of inherited early-onset prion disease caused by the rare PRNP homozygous mutation R136S. In vitro PrP Sc propagation studies were performed using recombinant-adapted Protein Mysfolding Cyclic Amplification technique. Brain material from two R136S homozygous patients were intracranially inoculated in TgMet129 and TgVal129 transgenic mice to assess the transmissibility of this rare inherited form of prion disease. Results: The index case presented symptoms of early-onset dementia beginning at the age of 49 and died at the age of 53. Neuropathological evaluation of the proband revealed abundant multicentric PrP plaques and Western blotting revealed a 6-8 kDa protease-resistant, unglycosylated PrP fragment, consistent with a Gerstmann-Sträussler-Scheinker phenotype. Her youngest sibling suffered from progressive cognitive decline, motor impairment and myoclonus with onset in her late 30s and died at the age of 48. Genetic analysis revealed the presence of the R136S mutation in homozygosis in the two affected subjects linked to homozygous methionine at codon 129. One sibling carrying the heterozygous R136S mutation, linked to homozygous methionine at codon 129, is still asymptomatic at the age of 74. The inoculation of human brain homogenates from our index case and an independent case from a Portuguese family with the same mutation in transgenic mice expressing human PrP and in vitro propagation of PrP Sc studies failed to show disease transmissibility. Conclusion: In conclusion, biallelic R136S substitution is a rare variant that produces inherited early-onset human prion disease with a Gerstmann-Sträussler-Scheinker neuropathological and molecular signature. Even if the R136S variant is predicted to be “probably damaging”, heterozygous carriers are protected, at least from an early onset providing the first evidence for a recessive pattern of inheritance in human prion diseases.
Isolation of viable Babesia bovis merozoites to study parasite invasion
Authors: Hakimi Hassan , Asada Masahito , Ishizaki Takahiro , Kawazu Shinichiro
Published: May 2021

Babesia parasite invades exclusively red blood cell (RBC) in mammalian host and induce alterations to host cell for survival. Despite the importance of Babesia in livestock industry and emerging cases in humans, their basic biology is hampered by lack of suitable biological tools. In this study, we aimed to develop a synchronization method for Babesia bovis which causes the most pathogenic form of bovine babesiosis. Initially, we used compound 2 (C2), a specific inhibitor of cyclic GMP-dependent protein kinase (PKG) and a derivative of C2, ML10. While both inhibitors were able to prevent B. bovis egress from RBC and increased percentage of binary forms, removal of inhibitors from culture did not result in a synchronized egress of parasites. Because using PKG inhibitors alone was not efficient to induce a synchronized culture, we isolated viable and invasive B. bovis merozoites and showed dynamics of merozoite invasion and development in RBCs. Using isolated merozoites we showed that BbVEAP, VESA1-export associated protein, is essential for parasite development in the RBC while has no role in invasion. Given the importance of invasion for establishment of infection, this study paves the way for finding novel antigens to be used in control strategies against bovine babesiosis.
Cumulative viral load, an indicator of virulence, is controlled by the host's immune response.
Authors: Iwasa Yoh , Hara Akane , Ozone Shihomi
Published: May 2021

A viral strain may infect a host, proliferate rapidly, become controlled by immune reactions, and eventually be eliminated from the body. The virulence, or the magnitude of harm to the host due to infection, depends on the abundance and duration of the viral strain in the body, and the importance of the damaged tissue of the host. In this study, we investigated how the cumulative viral load (time-integral of the number of infected cells) depends on various factors, such as the viral growth rate, the effectiveness of immune cells to kill infected cells, speed of immune activation, formation of memory cells, and longevity of immune cells. In addition, viruses may produce a mutant with different antigen types, escape the immune reaction targeting the original type, and inflate virulence. We derived four simple formulas for the cumulative viral load that holds in different parameter regions. We analyzed the sensitivity of the cumulative viral load to the parameters in the model. Additionally, we discussed the reported correlation between virulence and molecular evolution rate. We conclude that viral virulence can be mitigated by enhancing the speed and effectiveness of immune reactions and by reducing the viral growth rate.
Recurrent dammed-lake outburst superfloods in the Yigong river, southeastern margin of the Tibet
Authors: Hu Kaiheng , Wu Chaohua , Wei Li , Zhang Xiaopeng , Zhang Qiyuan , Liu Weiming , Yanites Brian J.
Published: May 2021

Landslide dam outburst floods have a significant impact on landform evolution in high mountainous areas. Historic landslide dams on Yigong River, southeastern Tibet, generated two outburst superfloods of > 105 m3/s in 1902 and 2000 AD. One of the slackwater deposits, newly found immediately downstream of historic dams, has been dated to 7 ka BP. One-dimensional backwater stepwise method gives an estimate of 225,000 m3/s for the peak flow related to the paleo-stage indicator of 7 ka BP. The recurrence of at least three huge landslide dam impoundments and super-outburst floods at the exit of the Yigong lake during the Holocene greatly changes the morphology of the Yigong river. Recent reports of giant landslides elsewhere on the southeastern Tibetan Plateau indicate repeated landslide dams at the same location, which counters the traditional viewpoint that landslide damming is spatially random, unlike glacial damming that persists at the same location. Repeated landslide damming may be a persistent source of outburst floods as well as impede the upstream migration of river knickpoints in the southeastern margin.
Genome Analyses Revealed Genetic Admixture and Selection Signatures in Bos indicus
Authors: Dixit S P , Bhatia A K , Ganguly Indrajit , Singh Sanjeev , Dash Soumya , Sharma Anurodh , Kumar N. Anand , Dang A K , Jayakumar S
Published: May 2021

The genomic diversity and relationship among seven diverse cattle breeds viz. Sahiwal, Tharparkar, Gir, Vechur, Ongole, Kangayam and Hariana were investigated in 132 random samples based on high density SNP array comprising > 777K SNPs. A total of 1993 SNPs (0.25% of the total) having greater power (Fst ≥ 0.20) to differentiate these cattle populations were identified, and utilized to partition genome of each animal into a predefined number of clusters. The structure of these cattle indicated shared ancestry of dairy breeds viz. Gir, Tharparkar and Sahiwal. Most of animals (> 76%) of the different populations under study except Vechur clustered into their own group of animals called breed. Vechur population contained highest rate of admixture, consistent with its crossing with other breeds. Ongole, Kangayam and Hariana shared comparatively less of their genome (≤ 15%) with other breeds. The study indicated that all seven breeds evolved from their independent ancestry but there was intermixing of these breeds in the recent past. The selection signatures identified between draft (Kangayam) and dairy breeds included several genes like FAM19A2, RAB31P, BEST3, DGKA, AHCY, PIGU and PFKP which are involved in immune response, metabolic pathway, transportation of glucose and sugars, signaling pathways, cellular processes, cell division and glycolysis regulation, respectively. Moreover, these genomic regions also harbour QTLs affecting milk performance traits. The signatures were also identified even between the dairy breeds. There were also significant differences in number of QTLs affecting production (body weight, growth rate etc.) and morphological traits (height etc.) of short stature, Vechur, compared to large sized cattle. The HMGA2 gene was present in the selection signature on chromosome 5, which may explain the differences in stature of these cattle.
Investigating the histological and structural properties of tendon gel as an artificial biomaterial using the film model method in rabbits
Authors: Shimozaki Kengo , Nakase Junsuke , Ohashi Yoshinori , Kuzumaki Toru , Yamaguchi Tatsuya , Torigoe Kojun , Tsuchiya Hiroyuki
Published: May 2021

Tendon gel, a substance formed during intrinsic tendon regeneration using the film model method, could be a promising artificial biomaterial for revolutionizing tendon healing treatments. Using a rabbit model, this study aimed to detect the properties of tendon gel by investigating the histological and structural differences among tendon gels under different preservation periods. Forty mature female rabbits were divided into four groups of ten rabbits. Achilles tendon rupture models were established using the film model method to obtain tendon gels. A tensile stress was applied to the tendon gel to promote maturation. Although the day-3 and -5 tendon gels were histologically more immature than the day-10 and -15 ones prior to the application of tensile stress, type I collagen fibers equivalent to those of normal tendons were observed in all groups after the tensile process. According to surface and molecular structural evaluations, day-3 tendon gels following tensile process were molecularly cross-linked, and thick collagen fibers similar to those present in normal tendons were observed. Structural maturation observed in day-3 tendon gels caused by traction was hardly observed in day-5, -10, and -15 tendon gels. Hence, the day-3 tendon gel was considered as a novel biomaterial with the best regenerative potential.
Clinical Outcomes and Prognostic Factors of Fractionated Stereotactic Radiation Therapy for Large Brain Metastases as a Potential Alternative to Surgery
Authors: Ogawa Hiroaki , Ito Kei , Karasawa Katsuyuki
Published: May 2021

Introduction: We investigated the outcomes and prognostic factors for fractionated stereotactic radiation therapy (FSRT) for large brain metastases and evaluated whether FSRT could negate the need for surgery, which is the mainstream treatment for large brain metastases.Methods: Patients with brain metastases measuring ≥2 cm treated with FSRT were retrospectively examined. Patients undergoing FSRT postoperatively were excluded. Local failure, intracranial failure, and adverse events were evaluated.Results: Overall, 106 lesions in 98 patients were evaluated. Performance status was 0–1, 2–4, and unknown in 79, 25, and 2 patients, respectively. The median maximum tumor diameter was 25 mm, and the median prescription dose was 35 Gy in 3 fractions. The median follow-up period after FSRT was 7 months. The 1-year rates of local failure, intracranial failure, and overall survival were 13.0%, 57.8%, and 48.0%, respectively. In multivariate analysis, the maximum dose for target ≥135 Gy (biological equivalent dose of a/b of 10 Gy) and good performance status were independent positive prognostic factors for local failure. Sixteen patients (16.3%) were treated with whole-brain radiotherapy after FSRT owing to multiple intracranial recurrences, while surgery was performed for three patients (3.1%) owing to local recurrence.Conclusions: FSRT for large brain metastases achieved good local control and only 3% of patients needed surgery after FSRT, suggesting that FSRT is a potential alternative to surgery. In FSRT, a higher maximum tumor dose was useful for local control.
Cost Comparison from a Patient Perspective for Intracranial Stereotactic Radiation Therapy
Authors: Prasad Rahul N. , Yildiz Vedat O , Patel Tejash , Royce Trevor J. , Palmer Joshua David
Published: May 2021

IntroductionFinancial toxicity is a damaging consequence of oncologic therapy addressable through improved price transparency. The US government recently mandated that hospitals publish a “chargemaster,” or list of “standard charges” for provided services. Patients often travel to tertiary centers for intracranial stereotactic radiotherapy (SRT), but cost comparison is complicated by multiple delivery systems and fractionation schemes. We hypothesized that publicly listed prices vary widely between comparable SRT modalities and by institution.MethodsThrough online query, we obtained chargemasters for clinical National Cancer Institute (NCI)-designated centers. Technical charges for Gamma Knife (GK), single fraction linear-accelerator stereotactic radiosurgery (SRS), and 3-fraction fractionated stereotactic radiation therapy (FSRT) were obtained by billing code and keyword searches. Prices were adjusted by the Medicare geographic cost price index (GPCI). Pairwise comparisons were conducted to compare prices between modalities and geographic regions. Price association between modalities and relationships with cost index were examined using Spearman correlations.Results62 chargemasters were obtained, and 58 listed SRT prices. Median prices varied widely (GK-$49,529; FSRT-$31,834; SRS-$22,915) with large interquartile ranges. Adjusting for GPCI, GK (p = .0003) and FSRT (p = .001) were significantly more expensive than SRS, and no difference in price was noted between regions. FSRT price was positively correlated with GPCI (p = .033) but other modalities were not. Modality prices were positively correlated (all p < .001).ConclusionsPublished prices for SRT vary by delivery system, fractionation, and by institution. Differences are poorly explained by variable cost of living. These inefficiencies expose patients already at high risk for financial toxicity to unnecessary costs.
Multi-Objective Optimization of Process Parameters in TIG-MIG Welded AISI 1008 Steel For Improved Structural Integrity
Authors: ABIMA CYNTHIA SAMUEL , AKINLABI STEPHEN AKINWALE , Madushele Nkosinathi , FATOBA Olawale Samuel , AKINLABI ESTHER TITILAYO
Published: May 2021

This study investigates a parametric multi-objective optimization of the Tungsten Inert Gas-Metal Inert Gas (TIG-MIG) hybrid welding of AISI 1008 mild steel joints. A combined grey relational system theory and the Taguchi method was used for process optimization towards achieving a set of process parameter that maximizes both ultimate tensile strength and 0.2% yield strength for structural applications. An L-9 orthogonal array based on the Taguchi method was adopted for the experimental design matrix. Grey relational grading system was used to establish a single grade for the responses. Mathematical models for first and second-order regression were developed and optimum process parameters combination that optimizes the response were obtained. From the results, the gas flow rate had the most significant influence on the responses with a percentage contribution of 39.77%. Also, the second-order regression models had a higher coefficient of determination (R2) compared to the first-order regression for the two responses and thus, represents the best fit for the process. The grey relational grade was improved by 0.0489 through process optimization. The interactive effects of process parameters and their effects on the responses are also illustrated by response surface plots. This study shows the effectiveness of the grey relational grading system in achieving a multi-objective optimization for the TIG-MIG welding process.
New Oxidovanadium(IV) Mixed Ligand Complexes: Antidibetic, Anticancer activities and Cytotoxicity Study Using MTT Assay
Authors: Gayakwad Sonaji , Wankhede Dnyaneshwar , Ragole Vikas , Maulage Satish
Published: May 2021

Five new (HQ-1 to HQ-5) oxidovanadium(IV) mixed ligand complexes using 8-hydroxyquinoline as primary ligand and amino acids like L-cystein, L-alanine, L-phenylalanine, L-threonine and L-serine as secondary ligands in 1:1:1 ratio were synthesized. All the complexes were characterized using various characterization techniques such as elemental analysis, IR, electronic, mass spectra, thermal (TGA/DTA) and powder XRD analysis, molar conductance and magnetic susceptibility measurements. Based on the results obtained all the complexes were proposed to have square pyramidal geometry. All the complexes were screened for their antibacterial activities against E. coli and antifungal activities against C. albicans. In vitro antidibetic activities of all the complexes were studied by screening them for a-amylase inhibition activities. The complexes HQ-4 and HQ-5 were also screened for their anticancer activities against human cancer cells HepG2 using MTT assay.
Multimodal Imaging of the Distal Interphalangeal-joint Synovio-entheseal Complex in Psoriatic Arthritis (MIDAS): a Cross-sectional Study on the Diagnostic Accuracy of Different Imaging Modalities Comparing Psoriatic Arthritis to Psoriasis and Osteoarthritis
Authors: Guldberg-Møller Jørgen , Mogensen Mette , Ellegaard Karen , Zavareh Ali , Wakefield Richard J. , Tan Ai Lyn , Boesen Mikael , Dehmeshki Jamshid , Kubassova Olga , Dreyer Lene , Henriksen Marius , Kristensen Lars Erik
Published: May 2021

BackgroundNo gold-standard diagnostic test for psoriatic arthritis (PsA) exists. The diagnosis relies on different patterns of symptom involvement which can mimic other arthritides such as hand osteoarthritis (OA). We aimed to investigate if ultrasound (US), magnetic resonance imaging (MRI) and X-Ray applied to the distal interphalangeal (DIP)-joint and synovio-entheseal complex (SEC) can be used to discriminate between patients with PsA, skin psoriasis (PsO) and OA.MethodsIn this prospective, cross-sectional study, patients with DIP-joint PsA and nail involvement (n=50), PsO with nail involvement (n=12); and OA (n=13); were consecutively recruited. Risk ratios (RR) and odds ratios were calculated for US, MRI and X-ray findings of the DIP-joint and SEC between diagnoses.ResultsNew bone formation (NBF) assessed by US and MRI was a hallmark of OA, reducing the risk of having PsA (RR 0.52 (CI95% 0.43 to 0.63) and 0.64 (CI95% 0.56 to 0.74). The OA group was different from PsA and PsO on all MRI semiquantitative and X-ray outcomes reflected in a much lower RR of having PsA; RR ranging from 0.20 (CI95% 0.13 to 0.31) for MRI bone marrow oedema to 0.85 (CI95% 0.80 to 0.90) in X-ray entheseal bone-change. No outcome in US, MRI or X-ray was associated with a higher risk of PsA versus PsO, although the damage grade was higher in PsA.ConclusionsThe differentiation between PsA, PsO, and OA using US, MRI and X-ray is possible based on the grade of structural disease involvement using semiquantitative OMERACT US scores, MRI PsAMRIS score and X-ray score. A high grade of US, MRI and X-ray NBF and MRI bone marrow oedema reduce the RR of having PsA compared to OA. In demarcating PsA from PsO patients, it is of significance if they present with X-ray enthesitis and a high degree of US erosions and NBF or MRI synovitis-, tenosynovitis-, erosion score or bone marrow oedema.
Licorice Extracts Inhibits growth of Non-Small Cell Lung Cancer by Down-Regulating CDK4-Cyclin D1 Complex and Increasing CD8+ T Cell Infiltration
Authors: Huang Ruifei , Zhu Jinglin , Yang Ruijie , Xiao Yue , Yan Jiangna , Zheng Chunli , Xiao Wei , Huang Chao , Wang Yonghua
Published: May 2021

Background: Targeting tumor microenvironment (TME) may provide therapeutic activity and selectivity in treating cancers. Therefore, an improved understanding of the mechanism by which drug targeting TME would enable more informed and effective treatment measures. Glycyrrhiza uralensis Fisch (GUF, licorice), a widely used herb medicine, which has shown promising immunomodulatory activity and anti-tumor activity. However, the molecular mechanism of this biological activity has not been fully elaborated.Methods: Here, potential active compounds and specific targets of licorice that trigger the antitumor immunity were predicted with a systems pharmacology strategy. Flow cytometry technique was used to detect cell cycle profile and CD8+ T cell infiltration of licorice treatment. And anti-tumor activity of licorice was evaluated in C57BL/6 mice.Results: We reported the G0/G1 growth phase cycle arrest of tumor cells induced by licorice that is related with the down-regulation of CDK4-Cyclin D1 complex, which subsequently led to increased protein abundance of PD-L1. Further, in vivo studies demonstrated that mitigation the outgrowth of NSCLC tumor induced by licorice was reliant on increased antigen presentation and improved CD8+ T cell infiltration.Conclusions: Briefly, our findings improved understanding of the anti-tumor effects of licorice with the systems pharmacology strategy, thereby promoting the development of natural products in the prevention or treatment of cancers.Trial registration: Not applicable
The effect of loop diuretics on 28-day mortality of patients with acute respiratory distress syndrome
Authors: Zhang Rui , Chen Hui , Gao Zhiwei , Liang Meihao , Qiu Haibo , Yang Yi , Liu Ling
Published: May 2021

Background Diuretics have been widely used in critically ill patients while it remains uncertain whether it could reduce mortality of patients with acute respiratory distress syndrome (ARDS). The study aimed to investigate the association between diuretics and 28-day mortality of ARDS patients.Methods This is a secondary analysis of the NHLBI ARDS Network’s FACTT. Patients enrolled in FACTT who did not receive renal replacement therapy within the first 48 hours after enrollment were included. Marginal structural Cox model (MSCM) was used to investigate any association between diuretics and 28-day mortality after correction of both baseline and time-fixed variables. Latent class model (LCA) and subgroup analysis were performed to detect which kind of patents could benefit from diuretics.Results In total, 932 patients were enrolled including 558 in the diuretics group and 374 in the no diuretics group within the first 48 hours. The 28-day mortality was lower in the diuretics group (15.1% vs. 28.1%, p < 0.001). MSCM revealed that diuretics use was related to an improved 28-day mortality (HR 0.78; 95%CI 0.62–0.99; p = 0.04). LCA identified three subtypes, and diuretics were associated with reduced mortality in subtype3, which were characterized by worse renal function and higher CVP. Subgroup analysis indicated survival advantage among patients who are female, sepsis induced ARDS, and those with PaO2/FiO2 < = 150 mmHg, MAP > = 65 mmHg.Conclusion Loop diuretics are associated with reduced 28-day mortality of ARDS patients, after controlling for time-varying confounders. Randomized trials are required to verify the results.
Evaluating Two Respiratory Correction Methods for Abdominal PET/MRI Imaging
Authors: Ruan Weiwei , Liu Fang , Sun Xun , Hu Fan , Wu Tingfan , Zhang Yongxue , Lan Xiaoli
Published: May 2021

Background: To evaluate two respiratory correction methods for abdominal PET/MRI images, further to analyse the effects on standard uptake values (SUVs) of respiratory motion correction. 17 patients with 25 abdominal lesions on 18F-FDG PET/CT were scanned with PET/MRI. PET images were reconstructed using end-expiratory respiratory gating and multi-bin respiratory gating. Meanwhile, full data and the first 3 minutes and 20 seconds of data acquired both without respiratory gating were reconstructed for evaluation. Five parameters, including the SUVmax and SUVmean in the lesions, the SUVmean and standard deviation (SD) in the background, and the signal-to-noise ratio (SNR) were calculated, and used for statistical comparisons. The differences in multi-bin respiratory gating and reconstruction of full data, relative to the reconstruction of the first 3 minutes and 20 seconds of data acquired, were calculated. Results: Compared with PET/CT, the longer scanning time of abdominal PET/MRI makes respiratory motion correction necessary. The multi-bin respiratory gating correction could reduce the PET image blur and increase the SUVmax (11.98%) and SUVmean (13.12%) of the lesions significantly (p = 0.00), which was much more effective than end-expiratory respiratory gating for abdominal PET/MRI. There was no significant difference in the increase in SUVmax between multi-bin respiratory gating correction and associated count loss with the correction (p=0.39), which was rarely reported by previous studies.Conclusion: The multi-bin respiratory gating is proposed as the default reconstruction method for abdominal PET/MRI. However, the respiratory gating correction with the PET counts loss would induce the falsely improvement for SUVmax of lesions.
Physiotherapy Interventions Including Frequent Changes of the Body Position and Stimulation to Physical Activity for Infants Hospitalised with Bronchiolitis: A Feasibility Study of a Randomised Control Trial
Authors: Marforio Sonja Andersson , Josenby Annika Lundkvist , Hansen Christine , Hansson Eva Ekvall
Published: May 2021

Background: The effect of a treatment that includes frequent changes of the body position for infants with bronchiolitis has not been evaluated, although it is often used in Swedish hospitals. Because of this, a randomised control trial (RCT) has begun with the aim to evaluate this treatment, comparing the effect of an individualised physiotherapy intervention, a non-individualised intervention, and a control group receiving standard care. The objective of this internal pilot study was to address uncertainties concerning the ongoing RCT and to determine whether the trial is feasible or not, possibly with adjustments to the protocol.Methods: Descriptive analyses of the recruitment, retention, data supply for the primary end point and the usability of the primary outcome measure were performed. A safety analysis was conducted by an independent analysis group. Results: Ninety-one infants were included, 33 (36.3%), 28 (30.8%), and 30 (33.0%) in the respective allocation groups. Fifty-nine (64.8%) were boys. The median age was 2.5 (min-max: 0.2-23.7) months. They remained in the study for a median of 46 hours (min-max: 2-159). The recruitment rate was 19%. The data supply for the primary end point and for the primary outcome measure was lower than anticipated in the original sample size calculation. Difficulties concerning utilising the primary outcome measure were identified. The safety analysis detected no risks of harm related to participation in the study.Conclusions: It is feasible to continue the RCT with modifications of the analysis plan. Participation in the study was not associated with any safety risks.Trial registration: ClinicalTrials.gov NCT03575091. Registered 2 July 2018. Retrospectively registered, https://clinicaltrials.gov/ct2/show/NCT03575091?term=NCT03575091&rank=1
Low Dose DMSO Treatment Induces Oligomerization and Accelerates Aggregation of α-Synuclein
Authors: Reimer Lasse , Haikal Caroline , Gram Hjalte , Ruesink Harm , Baun Andreas , Gewering Theresa , Moeller Arne , Li Jia-Yi , Jensen Poul Henning
Published: May 2021

Dimethyl sulfoxide (DMSO) is a highly utilized small molecule that serves many purposes in scientific research. DMSO offers unique polar, aprotic and amphiphilic features, which makes it an ideal solvent for a wide variety of both polar and nonpolar molecules. Furthermore, DMSO is often used as a cryoprotectant in cell-based research. However, recent reports suggest that DMSO, even at low concentration, might interfere with important cellular processes, and cause macromolecular changes to proteins where a shift from α-helical to β-sheet structure can be observed. To investigate how DMSO might influence current research, we assessed biochemical and cellular impacts of DMSO treatment on the structure of the aggregation-prone protein α-synuclein, which plays a central role in the etiology of Parkinson’s disease, and other brain-related disorders, collectively termed the synucleinopathies. Here, we found that addition of DMSO increased the particle-size of α-synuclein, and accelerated the formation of seeding-potent fibrils in a dose-dependent manner. Moreover, as evident through aggregation specific antibody recognition and a bimolecular fluorescence complementation assay, cells exposed to DMSO experienced increased aggregation of α-synuclein. However, no observable α-synuclein abnormalities nor neuronal survival was affected by oral DMSO-treatment in either C57BL/6- or α-synuclein transgenic F28 mice. In summary, we demonstrate that low concentrations of DMSO makes 𝛼-synuclein susceptible to undergo aggregation both in vitro and in cells. This may affect experimental outcomes when studying α-synuclein in the presence of DMSO, and should call for careful consideration when such experiments are planned.
The LORIS MyeliNeuroGene Rare Disease Database for Natural History Studies and Clinical Trial Readiness
Authors: Spahr Aaron , Rosli Zaliqa , Legault Mélanie , Tran Luan , Fournier Simon , Toutounchi Helia , Darbelli Lama , Madjar Cecile , Lucia Cassandra , St-Jean Marie-Lou , Das Samir , Evans Alan Charles , Bernard Geneviève
Published: May 2021

Background: Rare diseases are estimated to affect 150-350 million people worldwide. With advances in next generation sequencing, the number of known disease-causing genes has increased significantly, opening the door for therapy development. Rare disease research has therefore pivoted from gene discovery to the exploration of potential therapies. With impending clinical trials on the horizon, researchers are in urgent need of natural history studies to help them identify surrogate markers, validate outcome measures, define historical control patients, and design therapeutic trials. Results: We customized a browser-accessible multi-modal (e.g. genetics, imaging, behavioral, patient-determined outcomes) database to increase cohort sizes, identify surrogate markers, and foster international collaborations. Ninety data entry forms were developed including family, perinatal, developmental history, clinical examinations and diagnostic investigations, neurological evaluations (i.e. spasticity, dystonia, ataxia, etc.), disability measures, parental stress, and quality of life. A customizable clinical letter generator was created to assist in continuity of patient care. Conclusions: Small cohorts and underpowered studies are a major challenge for rare disease research. This online, rare disease database will be accessible from all over the world, making it easier to share and disseminate data. We have outlined the methodology to become Title 21 Code of Federal Regulations Part 11 Compliant, which is a requirement to use electronic records as historical controls in clinical trials in the United States. Food and Drug Administration compliant databases will be life-changing for patients and families when historical control data is used for emerging clinical trials. Future work will leverage these tools to delineate the natural history of several rare diseases and we are confident that this database will be used on a larger scale to improve care for patients affected with rare diseases.
Cadmium (Cd) Reduction Bacteria From Northern Coast Sediment Indramayu, Indonesia
Authors: Ihsan Yudi , Pribadi Tri , Fellatami Kalysta
Published: May 2021

Cadmium (Cd) is one of the metals that contaminates Karangsong and has found several bacteria that can reduce cadmium (Cd). The purposes of this research are to obtain the type of bacteria and obtain an evolutionary relationship of cadmium (Cd) reduction bacteria from sediments in Karangsong Beach, Indramayu. The method used in this research is an exploratory method and the resulting data is analyzed descriptively. The molecular identification method uses 16S rRNA gene which is a universal primer for bacteria. The bacterial sequences obtained were analyzed with GenBank data from the NCBI website. The results showed that two bacterial isolates were identical to the Pseudoalteromonas issachenkonii strain KMM 3549 (Acc. No. NR 025139.1) with 77% identity value and 100% evolutionary relationship value and Pseudoalteromonas tetraodonis GFC strain IAM 14160 (Acc. No. NR 041787.1) with identity values 97% and evolutionary value 99%.
2,7-Naphthyridine based colorimetric and fluorescent “Turn Off” chemosensors for selective detection of Ni(II) in aqueous media
Authors: Ashraf Abida , Islam Muhammad , Shafiq Zahid , Ahsan Muhammad Tayyeb , Yaqub Muhammad
Published: May 2021

A highly selective and sensitive 2,7-naphthyridine based colorimetric, reversible, pH independent and fluorescence “Turn Off” chemosensors (L1-L4) for detection of Ni2+ are being reported in aqueous media. The synthesized sensors are highly efficient in detecting Ni2+ even in the presence of other metal ions that commonly co-exist with nickel. The receptors (L1-L4) showed a distinct color change from yellow to red by addition of Ni2+ with spectral changes in bands at 535–550 nm. The detection limit of Ni2+ for (L1-L4) are in the range of 0.2–0.5 µM which is 2–5 times lower than the permissible value of Ni2+ (1.2 µM) in drinking water defined by EPA. The binding mode of interactions of L1-L4 for Ni2+ were found to be 2:1 through job’s plot and ESI-MS analysis. Moreover the receptors can be used to quantify Ni2+ in real water samples and formation of test strips by dip-stick method increases the practical applicability of Ni2+ test for “in-the-field” measurement of Ni2+. Importantly the sensing potential of these derivatives have been tuned by the nature of substituents i.e. electron donating (CH3) and electron attracting (F, OCF3), which showed that L4 is highly efficient in sensing of Ni2+ even at minute level.
Prevalence of Extensively Drug-resistant Tuberculosis in a Chinese Multidrug-resistant TB Cohort after Redefinition
Authors: Pang Yu , yao cong , guo ping hai , li qiang , zhang xia xu , shang yuan yuan , wang feng yu , xue tan zhong , wang lu , li liang
Published: May 2021

Objectives: Recently, the definition of extensively drug-resistant TB (XDR-TB) has been revised. In this study, we conducted a descriptive study to determine the prevalence of XDR-TB in a Chinese multidrug-resistant TB (MDR-TB) cohort. Methods: Broth microdilution method was performed to determine in vitro susceptibilities of Mycobacterium tuberculosis (MTB) isolates to (FQs), bedaquiline (BDQ) and linezolid (LZD). The putative drug target genes conferring drug resistance were screened by DNA sequencing. Results: A total of 411 MDR-TB isolates were included from 13 pilots in China. LZD and BDQ resistance were noted in 30 (7.1%) and 10 (2.4%) isolates. On the basis of latest definitions, 114 (26.8%) were MDR-TB, 282 (66.4%) were pre-XDR-TB, and 29 (6.8%) were XDR-TB. Among 311 FQ-resistant isolates, 265 harbored genetic mutations within QRDRs. The most common mutations were observed at codon 94 of gyrA, accounting for 47.2% of FQ-resistant MTB isolates. Only mutations within Rv0678 gene were found to confer BDQ resistance in our cohort, conferring 40.0% of BDQ resistance. For LZD resistance, 53.3% of LZD-resistant isolates carried genetic mutations in rplC or 23S rRNA. The most frequent mutation was Cys154Arg in the rplC gene. In addition, we recorded two MDR-TB patients with resistant to both BDQ and LZD, of which one patient experienced continuous positive culture of MTB despite inclusion of efficacious moxifloxacin. Conclusion: our results demonstrate that the low prevalence of XDR-TB holds great promise for MDR-TB treatment with WHO-endorsed regimens containing BDQ-LZD combination, whereas the high prevalence of FQ-resistance in MDR-TB patients warrants national attention.
Social Withdrawal and Neurocognitive Correlates in Schizophrenia
Authors: De Donatis Domenico , Porcelli Stefano , De Ronchi Diana , Pich Emilio Merlo , Kas Martien J , Bilderbeck Amy , Serretti Alessandro
Published: May 2021

Background: Social withdrawal constitutes a clinical manifestation of social dysfunction in SCZ that has a high impact on the quality of life of patients. Poor neurocognitive performance has been associated with poor functional outcome in SCZ in past studies. Nonetheless, the likely association between neurocognition and social withdrawal has never been investigated. The aim of our study was to investigate in a large and heterogeneous sample of SCZ patients cross-sectional associations between neurocognitive domains and social withdrawal. Methods: The sample included 761 SCZ patients who completed the baseline visit in the CATIE study. Neurocognition was assessed by a comprehensive battery of tests resulting in 5 domain scores and a composite score. Social withdrawal was measured by a specific item of the Heinrichs-Carpenter Quality of Life Scale. Bivariate correlations, ANOVA and multiple regression analysis were conducted using STATISTICA software package (StatSoft, Inc. Tulsa, OK, USA). Statistical significance was tested at p value < 0.05. Results: Social withdrawal was associated with a lower score in the neurocognitive composite score and in “Verbal memory”, “Processing speed” and “Working memory” scores. “Verbal memory” score showed the strongest association with social withdrawal. 8% of the total variance of social withdrawal was explained by these three cognitive domains and additional clinical and socio-demographic factors (education years, PANSS positive symptoms score, employment). Conclusions: Our study showed that in a large and real-world representative sample of SCZ patients, social withdrawal was associated with neurocognitive deficits involving verbal memory, processing speed and working memory domains. Our results confirmed the wide heterogeneity and specificity of the correlation between neurocognitive domains and indicators of functional outcome in SCZ, underlining the role of certain neurocognitive abilities in social withdrawal.
Knowledge of End-of-life Wishes by Physicians and Caregivers in Cancer Patients
Authors: Calvache Jose A , Moreno Socorro , Prue Gillian , Reid Joanne , Ahmedzai Sam , Arango-Gutierrez Angelica , Ardila Liliana , Arroyo Lucia I , de Vries Esther
Published: May 2021

Objectives: To describe communication regarding cancer patient’s end-of-life (EoL) wishes by physicians and caregivers.Methods: An online questionnaire and telephone-based surveys were performed with physicians and caregivers respectively in three teaching hospitals in Colombia who had been involved in the EoL care of cancer patients. Results: For 138 deceased patients we obtained responses from physicians and caregivers. In 32% physicians reported they spoke to the caregiver and in 17% with the patient regarding EoL decisions. In most cases with absence of a conversation, physicians indicated the treatment option was “clearly the best for the patient” or that it was “not necessary to discuss treatment with the patient”.Twenty-six percent of the caregivers indicated that someone from the medical team spoke with the patient about treatment, and in 67% who had a conversation, caregivers felt that the provided information was unclear or incomplete. Physicians and caregivers were unaware if the patient had any advance care directive (ACD) in 65% and 51% of cases, respectively, with a very low absolute agreement (34%).Conclusion: There is a lack of open conversations regarding EoL in patients with advanced cancer with their physicians and caregivers in Colombia. Communication strategies are urgently needed.
Dormancy Induces the Formation of Persisters in the Candida Albicans-staphylococcus Epidermidis Mixed Species Biofilm
Authors: Yang jichen , Xiang Bingquan , Wang Wei , Rao Sunyin , Cao Run , Xiao Shouyong , Cui Xin , Huang Yunchao , ye lianhua
Published: May 2021

Background: Persisters make biofilm infections difficult to cure, the low content of persisters in biofilm and the difficulty of obtaining them are outstanding problems in research, finding a reliable method to obtain a sufficient amount of persisters is the key to research. Methods: In this study, C.albicans strain ATCC10231 and S.epidermidis ATCC35984 were used to culture mixed biofilms on the surface of a titanium metal coupon. Tetracycline, gentamicin, 5-fluorocytosine(5-Fc), caspofungin, rifampicin, fluconazole and carbonyl cyanide m-chlorophenylhydrazone (CCCP) were used to induce the dormancy of biofilms to produce persisters. Ciprofloxacin and amphotericin B were used to kill the non dormant bacteria, and then the persisters were screened. Results:The study showed that dormancy induced by tetracycline and 5-Fc could significantly increase the persister levels of S.epidermidis and C.albicans, respectively. After the induced persisters were re-cultured, there was no significant change in antibiotic sensitivity compared with before induction.Scanning electron microscope(SEM) observations showed that after dormancy induction, the surface morphology of C.albicans in the mixed biofilm showed convex changes, and the volume of S.epidermidis decreased. Confocal laser scanning microscope (CLSM)observation showed that the mixed biofilm with high content of persisters did not dissolve under the killing of antibiotics, and the biofilm with low content of persisters dissolved in large area. Conclusions: Induction of dormancy is a reliable method for the formation of persistent bacteria in C.albicans-S.epidermidis mixed biofilm.
Exercise Improves Bone Formation by Upregulating the Wnt3a/β-catenin Signalling Pathway in Type 2 Diabetic Mice
Authors: Chen Xianghe , Yang Kang , Sun Peng , Zhao Renqing , Liu Bo , Lu Pengcheng
Published: May 2021

Bone formation in type 2 diabetes mellitus (T2DM) is inhibited by decreased bone formation capacity. Exercise can significantly improve bone metabolism; however, the effect and mechanism of exercise on bone formation in T2DM is not known. In this study, we used the method of a high-fat diet and injecting STZ to build a T2DM mouse model, and the mice were treated with swimming and downhill running for 8 weeks. Their body weights were obtained using an electronic scale. Their bone length and wet weights were measured by Vernier callipers and an electronic balance. The bone microstructure of the distal femur was analysed by Alizarin red staining of paraffin sections and micro-CT. An ALP dye was used to detect the changes in ALP activity in the mouse skull and osteoblasts. Alizarin red staining was applied to stain the osteoblasts produced by BMSCs. The mRNA expression of related factors were detected by RT-PCR. Our results showed that the body weights of T2DM mice were significantly increased by exercise. When the Wnt3a/β-catenin pathway in the bones of T2DM mice is inhibited, their bone formation ability is significantly reduced, resulting in the degradation of the bone tissue morphology and structure. Except for the significant increase in body weight and Runx2 mRNA expression, swimming had no significant effect on bone formation-related indicators in T2DM mice. However, downhill running could significantly increase their body weight, while the tibia length, wet weight, and the trabecular morphological structure of the distal femur and the indexes of bone histomorphology were significantly improved by activating the Wnt3a/β-catenin pathway. Compared with swimming, downhill running can activate the Wnt pathway to improve bone formation ability, thereby improving bone histomorphology. These findings suggest that exercise promotes OB differentiation, osteogenic capacity and enhances bone formation metabolism by regulating Wnt3a/β-catenin signalling in T2DM mice.
Prolonged Loss of Consciousness in Parkinson’s Disease
Authors: Morimatsu Mitsunori
Published: May 2021

Background: Loss of consciousness is fairly common in Parkinson’s disease (PD), which occurs as syncope associated with postural hypotension based on autonomic dysfunction, or as sleep disorder which consists of excessive daytime sleepiness (EDS) and sleep attacks. In my experience, prolonged loss of consciousness lasting for several hours that is neither EDS nor ordinary sleep attacks can occur in PD patients and indeed seems to be a symptom unique to PD.Case presentation: Eight patients with PD are reported who showed episodes of loss of consciousness lasting for 4-24 h that appeared to be deep sleep or a coma, and could not be roused even by strong painful stimuli. After four hours or more, they spontaneously resumed consciousness without sequelae.Discussion and conclusions: According to the International Classification of Sleep Disorders - Third edition (ICSD-3), “hypersomnia due to a medical disorder,” a synonym of EDS, and “narcolepsy, type 2”, a synonym of sleep attacks are the representatives of sleep disorder in PD. However, the diagnostic criteria of these two disorders in ICSD-3 differ from the prolonged loss of consciousness in my cases. As it has brought great concern to family members, medical staff, and emergent hospital personnel, we must pay more attention to this type of loss of consciousness.