bluuebunny/crossref_metadata_2025 huggingface dataset:
Complement Activation Is Associated With Crescents in IgA Nephropathy
Authors: Wang Zi , Xie Xinfang , Li Jingyi , Zhang Xue , He Jiawei , Wang Manliu , Lv Jicheng , Zhang Hong
Published: September 2021

Introduction

Crescents, especially those found at a percentage greater than 50%, are often associated with rapid progression of kidney disease in IgA nephropathy (IgAN). The mechanism of crescents forming in IgAN is still unclear. In this study, we aimed to evaluate whether excess complement activation participates in the formation of crescents in IgAN.

Methods

One hundred IgAN patients with various proportions of crescents—24 with 1%–24%, 27 with 25%–49%, 21 with 50%–74% 12 with more than 75%, and 16 without crescents—were included. Urinary concentrations of mannose-binding lectin (MBL), Bb, C4d, C3a, C5a, and soluble C5b-9 (sC5b-9) were measured at the time of biopsy. Receiver operating characteristic (ROC) curves were performed to evaluate predictive ability of renal survival for urine complement activation. In addition, historical C4d, C5b-9, and C3d were stained by immunohistochemistry.

Results

IgAN patients with more than 50% crescent formation showed higher complement activation levels than the other patients (urinary C3a/creatinine (C3a/Cr): 6.7295 ng/mg, interquartile range (IQR) 1.4652–62.1086 ng/mg vs. 0.1055 ng/mg, IQR 0–1.4089 ng/mg; urinary C5a/Cr: 15.6202 ng/mg, 4.3127–66.7347 ng/mg vs. 0.3280 ng/mg, IQR 0.0859–2.4439 ng/mg; urinary sC5b-9/Cr: 98.6357 ng/mg, 8.8058–1,087.4578 ng/mg vs. 1.4262 ng/mg, 0.0916–11.0858 ng/mg, all p-values <0.001). The levels of urinary MBL and C4d representing lectin complement pathway showed a linear association with the proportion of crescents (r = 0.457 and 0.562, respectively, both p-values <0.001). Combined urine complement products could increase the predictive ability compared with crescents alone from 0.904 to 0.944 (p = 0.062) with borderline significance. Moreover, the glomerular C4d deposition rate elevated with the increase of proportions of crescents.

Conclusion

Excess complement activation may be involved in the formation of crescents, especially diffuse crescent formation, in patients with IgAN. Urinary C4d correlated with the proportion of crescents and was a potential biomarker for disease monitoring in crescentic IgAN.
Anti-Carbamylated LL37 Antibodies Promote Pathogenic Bone Resorption in Rheumatoid Arthritis
Authors: O’Neil Liam J. , Oliveira Christopher B. , Sandoval-Heglund Donavon , Barrera-Vargas Ana , Merayo-Chalico Javier , Aguirre-Aguilar Eduardo , Kaplan Mariana J. , Carmona-Rivera Carmelo
Published: September 2021

Objective

Antibodies against carbamylated proteins (anti-CarP) are associated with poor prognosis and the development of bone erosions in rheumatoid arthritis (RA). RA neutrophils externalize modified autoantigens through the formation of neutrophil extracellular traps (NETs). Increased levels of the cathelicidin LL37 have been documented in the synovium of RA patients, but the cellular source remains unclear. We sought to determine if post-translational modifications of LL37, specifically carbamylation, occur during NET formation, enhance this protein’s autoantigenicity, and contribute to drive bone erosion in the synovial joint.

Methods

ELISA and Western blot analyses were used to identify carbamylated LL37 (carLL37) in biological samples. Anti-carLL37 antibodies were measured in the serum of HLA-DRB1*04:01 transgenic mice and in human RA synovial fluid.

Results

Elevated levels of carLL37 were found in plasma and synovial fluid from RA patients, compared to healthy controls. RA NETs release carLL37 and fibroblast-like synoviocytes (FLS) internalized NET-bound carLL37 and loaded it into their MHCII compartment. HLA-DRB1*04:01 transgenic mice immunized with FLS containing NETs developed autoantibodies against carLL37. Anti-carLL37 antibodies were present in RA sera and synovial fluid and they correlated with radiologic bone erosion scores of the hands and feet in RA patients. CarLL37-IgG immune complexes enhanced the ability of monocytes to differentiate into osteoclasts and potentiated osteoclast-mediated extracellular matrix resorption.

Conclusions

NETs are a source of carLL37 leading to induction of anti-carbamylated autoantibody responses. Furthermore, carLL37-IgG immune complexes may be implicated in the bone damage characteristic of RA. These results support that dysregulated NET formation has pathogenic roles in RA.
Case Report: A Rare Case of Pembrolizumab-Induced Bullous Pemphigoid
Authors: Zhang Xiaoyan , Sui Dongjiang , Wang Dong , Zhang Lina , Wang Ruiyan
Published: September 2021

The programmed cell death protein 1 inhibitor pembrolizumab, an immune checkpoint inhibitor, has subsequently been approved for the treatment of a wide variety of malignant tumors. Compared with conventional chemotherapy, immunotherapy is associated with a unique set of immune reactions, known collectively as immune-related adverse events. Although often mild, dermatologic toxicity can occasionally be high grade and potentially life-threatening. Here we describe a rare case of bullous pemphigoid (BP) associated with pembrolizumab. A 79-year-old male patient presented with scattered erythema, papules, blisters, and pruritus after pembrolizumab treatment. Then, the rash gradually aggravated and spread to the whole body. The extensive edematous erythema, blisters, bullae, and blood blisters were loose and easy to rupture, forming an erosive surface and with pruritus and obvious pain. The hemidesmosomal protein BP180 (type XVII collagen) was detectable in the serum, and the histological examination diagnosis was bullous pemphigoid. After 10 days of glucocorticoid (methylprednisolone, iv, 80 mg/day) treatment, new blister formation ceased. We need to increase the awareness on and facilitate the earlier identification of the cutaneous adverse effects of BP with immunotherapy so that treat can begin early in order to limit the duration and severity of toxicity.
Use of Outpatient-Derived COVID-19 Convalescent Plasma in COVID-19 Patients Before Seroconversion
Authors: Wirz Oliver F. , Röltgen Katharina , Stevens Bryan A. , Pandey Suchitra , Sahoo Malaya K. , Tolentino Lorna , Verghese Michelle , Nguyen Khoa , Hunter Molly , Snow Theo Thomas , Singh Abhay Raj , Blish Catherine A. , Cochran Jennifer R. , Zehnder James L. , Nadeau Kari C. , Pinsky Benjamin A. , Pham Tho D. , Boyd Scott D.
Published: September 2021

Background

Transfusion of COVID-19 convalescent plasma (CCP) containing high titers of anti-SARS-CoV-2 antibodies serves as therapy for COVID-19 patients. Transfusions early during disease course was found to be beneficial. Lessons from the SARS-CoV-2 pandemic could inform early responses to future pandemics and may continue to be relevant in lower resource settings. We sought to identify factors correlating to high antibody titers in convalescent plasma donors and understand the magnitude and pharmacokinetic time course of both transfused antibody titers and the endogenous antibody titers in transfused recipients.

Methods

Plasma samples were collected up to 174 days after convalescence from 93 CCP donors with mild disease, and from 16 COVID-19 patients before and after transfusion. Using ELISA, anti-SARS-CoV-2 Spike RBD, S1, and N-protein antibodies, as well as capacity of antibodies to block ACE2 from binding to RBD was measured in an in vitro assay. As an estimate for viral load, viral RNA and N-protein plasma levels were assessed in COVID-19 patients.

Results

Anti-SARS-CoV-2 antibody levels and RBD-ACE2 blocking capacity were highest within the first 60 days after symptom resolution and markedly decreased after 120 days. Highest antibody titers were found in CCP donors that experienced fever. Effect of transfused CCP was detectable in COVID-19 patients who received high-titer CCP and had not seroconverted at the time of transfusion. Decrease in viral RNA was seen in two of these patients.

Conclusion

Our results suggest that high titer CCP should be collected within 60 days after recovery from donors with past fever. The much lower titers conferred by transfused antibodies compared to endogenous production in the patient underscore the importance of providing CCP prior to endogenous seroconversion.
Multi-Tissue Methylation Clocks for Age and Sex Estimation in the Common Bottlenose Dolphin
Authors: Robeck Todd R. , Fei Zhe , Haghani Amin , Zoller Joseph A. , Li Caesar Z. , Steinman Karen J. , Dirocco Stacy , Staggs Lydia , Schmitt Todd , Osborn Steve , Montano Gisele , Rodriguez Magdalena , Horvath Steve
Published: September 2021

Accurate identification of individual ages within wild bottlenose dolphins (Tursiops truncatus) is critical for determining population health and the development of population management strategies. As such, we analyzed DNA methylation (DNAm) patterns by applying a custom methylation array (HorvathMammalMethyl40) to both blood (n= 140) and skin samples (n= 87) from known age or approximate age (0–57 years) bottlenose dolphins. We present three bottlenose dolphin specific age estimation clocks using combined blood and skin [48 CpGs,R= 0.93, median absolute error (MAE) = 2.13 years], blood only (64 CpGs, R = 0.97, error = 1.46 years) and skin only (39 CpGs,R= 0.95, error = 2.53). We characterized individual cytosines that correlate with sex and age in dolphins and developed a sex estimator based on 71 CpGs that predicts the sex of any odontocete species with 99.5% accuracy. The presented epigenetic clocks are expected to be useful for conservation efforts and for determining if anthropogenic events affect aging rates in wild populations.
Case Report: Metagenomic Next-Generation Sequencing Confirmed a Case of Central Nervous System Infection With Brucella melitensis in Non-endemic Areas
Authors: Cao Jun , Cai Qingqing , Su Wentao , Ge Zi , Zhao Hui , Zhou Xinjian , Ma Ke , Xia Zhijie
Published: September 2021

Brucellosis is a highly contagious zoonotic disease caused by bacteria that belong to the genus Brucella. It is a major endemic disease in northern China. We reported a rare case of central nervous system (CNS) infection caused by Brucella melitensis in a patient living in non-endemic areas. The medical history of the patient included chronic headache and trunk numbness. Based on the presented clinical symptoms and medical examinations, a clinical diagnosis of binocular uveo-encephalitis was made in the local hospital. The patient's symptoms were unrelieved after being treated with empiric therapy. Soon after, the patient was admitted to our hospital because of the obnubilation and coma in the trip. We ran a few examinations and sent the cerebrospinal fluid (CSF) for metagenomic next-generation sequencing (mNGS) immediately. The Magnetic resonance imaging (MRI) examination was unremarkable, and bilateral mastoid inflammation was attached. Metagenomic next-generation sequencing suggested a CNS infection caused by Brucella melitensis. Then, the results of the serum agglutination test and quantitative polymerase chain reaction assay also confirmed that. After being treated with doxycycline, rifampin, and cefatriaxone, consciousness of the patient was restored and headache diminished. Two months later, a lumbar puncture was used to check the pressure of the CSF, and the total course of treatment was more than 6 months. This case highlighted the potential value of mNGS in early clinal diagnosis. We believe that mNGS may be a complementary method for rapid identification of infection of CNS caused by the pathogen.
The Optimal Lipid Chain Length of a Membrane-Permeabilizing Lipopeptide Results From the Balance of Membrane Partitioning and Local Damage
Authors: Steigenberger Jessica , Verleysen Yentl , Geudens Niels , Martins José C. , Heerklotz Heiko
Published: September 2021

Pseudodesmin A (PSD) is a cyclic lipodepsipeptide produced by Pseudomonas that kills certain bacteria at MIC1/2 in the single micromolar range, probably by permeabilizing their cellular membranes. Synthetic PSD variants, where the native decanoic (C10) acyl chain is varied in length from C4 to C8 and C12 to C14 carbons, were described to be not or less active against a panel of gram-positive strains, as compared to native PSD-C10. Here, we test the membrane-permeabilizing activity of PSD-C4 through PSD-C14 in terms of calcein release from liposomes, which is characterized in detail by the fluorescence-lifetime based leakage assay. Antagonistic concentrations and their chain length dependence agree well for liposome leakage and antimicrobial activity. The optimal chain length is governed by a balance between membrane partitioning (favoring longer chains) and the local perturbation or “damage” inflicted by a membrane-bound molecule (weakening for longer chains). Local perturbation, in turn, may involve at least two modes of action. Asymmetry stress between outer and inner leaflet builds up as the lipopeptides enter the outer leaflet and when it reaches a system-specific stability threshold, it causes a transient membrane failure that allows for the flip of some molecules from the outer to the inner leaflet. This cracking-in may be accompanied by transient, incomplete leakage from the aqueous cores of the liposomes observed, typically, for some seconds or less. The mismatch of the lipopeptide with the lipid leaflet geometry, expressed for example in terms of a spontaneous curvature, has two effects. First, it affects the threshold for transient leakage as described. Second, it controls the rate of equilibrium leakage proceeding as the lipopeptide has reached sufficient local concentrations in both leaflets to form quasi-toroidal defects or pores. Both modes of action, transient and equilibrium leakage, synergize for intermediate chain lengths such as the native, i.e., for PSD-C10. These mechanisms may also account for the reported chain-length dependent specificities of antibiotic action against the target bacteria.
Extraction of Chitin From Shrimp Shell by Successive Two-Step Fermentation of Exiguobacterium profundum and Lactobacillus acidophilus
Authors: Xie Jingwen , Xie Wancui , Yu Jing , Xin Rongyu , Shi Zhenping , Song Lin , Yang Xihong
Published: September 2021

As an environmentally friendly and efficient method, successive two-step fermentation has been applied for extracting chitin from shrimp shells. To screen out the microorganisms for fermentation, a protease-producing strain, Exiguobacterium profundum, and a lactic acid-producing strain, Lactobacillus acidophilus, were isolated from the traditional fermented shrimp paste. Chitin was extracted by successive two-step fermentation with these two strains, and 85.9 ± 1.2% of protein and 95 ± 3% of minerals were removed. The recovery and yield of chitin were 47.82 and 16.32%, respectively. Fourier transform infrared spectroscopy, X-ray diffraction, and scanning electron microscopy (SEM) were used to characterize the chitin. The crystallinity index was 54.37%, and the degree of deacetylation was 3.67%, which was lower than that of chitin extracted by the chemical method. These results indicated that successive two-step fermentation using these two bacterial strains could be applied to extract chitin. This work provides a suitable strategy for developing an effective method to extract chitin by microbial fermentation.
Quantifying Airborne Dispersal Route of Corynespora cassiicola in Greenhouses
Authors: Zhao Qian , Shi Yanxia , Wang Yuhong , Xie Xuewen , Li Lei , Guo Liyun , Chai Ali , Li Baoju
Published: September 2021

Target leaf spot (TLS), caused byCorynespora cassiicola, is an emerging and high-incidence disease that has spread rapidly on the global scale. Aerospores released by infected plants play a significant role in the epidemiology of cucumber TLS disease; however, no data exist concerning the infectiousness and particle size ofC. cassiicolaaerospores, and the experimental evidence for the aerospores transmission was lacking. In the present study, highly effective approaches to collect and quantify aerospores were developed for exposure chamber and greenhouse studies. Quantifiable levels ofC.cassiicolaaerospores were detected in 27 air samples from nine naturally infested greenhouses, ranging from 198 to 5,969 spores/m3. TheC. cassiicolastrains isolated from air samples were infective to healthy cucumber plants. Exposure chambers were constructed to study the characteristics ofC. cassiicolaaerospores released by artificially infested cucumber plants. The particle size ofC. cassiicolaranged predominately from 2.1 to 4.7 μm, accounting for 71.97% of the total amount. In addition, the transmission dynamics ofC. cassiicolaaerospores from donor cucumber plants to recipient cucumber plants were confirmed in exposure chambers and greenhouses. The concentration ofC. cassiicolaaerospores was positively associated with cucumber TLS disease severity. This study suggested that aerospore dispersal is an important route for the epidemiology of plant fungal disease, and these data will contribute to the development of new strategies for the effective alleviation and control of plant diseases.
Shifts in Soil Structure, Biological, and Functional Diversity Under Long-Term Carbon Deprivation
Authors: George Paul B. L. , Fidler David B. , Van Nostrand Joy D. , Atkinson Jonathan A. , Mooney Sacha J. , Creer Simon , Griffiths Robert I. , McDonald James E. , Robinson David A. , Jones Davey L.
Published: September 2021

Soil organic matter is composed of a variety of carbon (C) forms. However, not all forms are equally accessible to soil microorganisms. Deprivation of C inputs will cause changes in the physical and microbial community structures of soils; yet the trajectories of such changes are not clear. We assessed microbial communities using phospholipid fatty acid profiling, metabarcoding, CO2 emissions, and functional gene microarrays in a decade-long C deprivation field experiment. We also assessed changes in a range of soil physicochemical properties, including using X-ray Computed Tomography imaging to assess differences in soil structure. Two sets of soils were deprived of C inputs by removing plant inputs for 10 years and 1 year, respectively. We found a reduction in diversity measures, after 10 years of C deprivation, which was unexpected based on previous research. Fungi appeared to be most impacted, likely due to competition for scarce resources after exhausting the available plant material. This suggestion was supported by evidence of bioindicator taxa in non-vegetated soils that may directly compete with or consume fungi. There was also a reduction in copies of most functional genes after 10 years of C deprivation, though gene copies increased for phytase and some genes involved in decomposing recalcitrant C and methanogenesis. Additionally, soils under C deprivation displayed expected reductions in pH, organic C, nitrogen, and biomass as well as reduced mean pore size, especially in larger pores. However, pore connectivity increased after 10 years of C deprivation contrary to expectations. Our results highlight concurrent collapse of soil structure and biodiversity following long-term C deprivation. Overall, this study shows the negative trajectory of continuous C deprivation and loss of organic matter on a wide range of soil quality indicators and microorganisms.
Semantic Congruence Drives Long-Term Memory and Similarly Affects Neural Retrieval Dynamics in Young and Older Adults
Authors: Alejandro Ricardo J. , Packard Pau A. , Steiger Tineke K. , Fuentemilla Lluis , Bunzeck Nico
Published: September 2021

Learning novel information can be promoted if it is congruent with already stored knowledge. This so-called semantic congruence effect has been broadly studied in healthy young adults with a focus on neural encoding mechanisms. However, the impacts on retrieval, and possible impairments during healthy aging, which is typically associated with changes in declarative long-term memory, remain unclear. To investigate these issues, we used a previously established paradigm in healthy young and older humans with a focus on the neural activity at a final retrieval stage as measured with electroencephalography (EEG). In both age groups, semantic congruence at encoding enhanced subsequent long-term recognition memory of words. Compatible with this observation, semantic congruence led to differences in event-related potentials (ERPs) at retrieval, and this effect was not modulated by age. Specifically, congruence modulated old/new ERPs at a fronto-central (Fz) and left parietal (P3) electrode in a late (400–600 ms) time window, which has previously been associated with recognition memory processes. Importantly, ERPs to old items also correlated with the positive effect of semantic congruence on long-term memory independent of age. Together, our findings suggest that semantic congruence drives subsequent recognition memory across the lifespan through changes in neural retrieval processes.
Predictors of Early Neurological Deterioration in Stroke Due to Vertebrobasilar Occlusion
Authors: Koh Seungyon , Lee Sung Eun , Jung Woo Sang , Choi Jin Wook , Lee Jin Soo , Hong Ji Man , Lee Seong-Joon
Published: September 2021

Background and Aims: This study explores the predictors of early neurological deterioration (END) in patients with vertebrobasilar occlusion (VBO) in both primary endovascular therapy (EVT) and medical management (MM) groups.

Methods: Patients diagnosed with VBO from 2010 to 2018 were included. Comparative and multivariate analyses were used to identify predictors of all-cause END in the EVT group, and END due to ischemia progression (END-IP) in the MM group.

Results: In 174 patients with VBO, 43 had END. In the primary EVT group (N = 66), 17 all-cause END occurred. Distal basilar occlusion (odds ratio (OR), 14.5 [95% confidence interval (CI), 1.4–154.4]) and reperfusion failure (eTICI < 2b67 (OR, 5.0 [95% CI, 1.3–19.9]) were predictive of END in multivariable analysis. In the MM group (N=108), 17 END-IP occurred. Higher systolic blood pressure (SBP) at presentation (per 10 mmHg increase, OR, 1.5 [95% CI, 1.1–2.0]), stroke onset-to-door time <24 h (OR, 5.3 [95% CI, 1.1–2.0]), near-total occlusions (OR, 4.9 [95% CI, 1.2–19.6]), lower posterior circulation-Alberta Stroke Program Early CT scores (OR, 1.6 [95% CI, 1.0–2.5]), and lower BATMAN collateral scores (OR, 1.6 [95% CI, 1.1–2.2]) were predictive of END-IP.

Conclusions: In patients with stroke due to VBO, potential predictors of END can be identified. In the primary EVT group, failure to achieve reperfusion and distal basilar occlusion were associated with all-cause END. In the MM group, higher SBP at presentation, onset-to-door time less than 24 h, incomplete occlusions, larger infarct cores, and poorer collaterals were associated with END-IP.
Pure Thalamic Infarct: 8-Year Follow-Up Study in a Hospital in China
Authors: Liang He , Sarma Anand Karthik , Wang Zhenxing , Mo Ming , Lin Jianwen , Ji Xunming , Chen Dong , Liu Yi
Published: September 2021

Pure thalamic infarct is a rare lacunar stroke type, with little known about long-term outcomes. This 8-year, single-center, retrospective study evaluated the clinical background, etiology, Trial of ORG 10172 in Acute Stroke Treatment (TOAST) classification, and 8-year follow-up results in 27 patients with pure thalamic infarcts identified by MR diffusion-weighted imaging in Dalian, China. All patients presented chief complaints of limb weakness or sensory disturbances. Hypertension (24/27, 88.9%), diabetes (12/27, 44.4%), atrial fibrillation (1/27, 3.7%), hyperlipidemia (10/27, 37%), hyperhomocysteinemia (6/27, 22.2%), smoking history (10/27, 37%; 9/15, 60% for men; 1/12, 8.3% for women), and excessive alcohol consumption history (7/27, 25.9%; 7/15, 46.7% for men; 0 for women) were observed in our patient population. Based on TOAST classification, 1 patient had large artery atherosclerosis (7.14%), 23 had small vessel occlusion (SVO; 85.2%), and 3 patients were unidentified due to lack of cerebral angiography. The thalamic blood supply classification were as follows: 23 (85.2%), inferolateral territory; 1 (3.7%), tuberothalamic territory; 2 (7.4%), combination of tuberothalamic and paramedian arteries; 1 (3.7%), combination of inferolateral and paramedian arteries; 0, posterior choroidal arteries. During the 8-year follow-up, 3 patients died of colon cancer, multi-organ failure, and kidney failure, respectively; 7 presented with a recurrent stroke; while 10 recovered well with their risk factors under control. In conclusion, our cohort of pure thalamic infarcts were mainly due to SVO (TOAST), with hypertension as the main risk factor, and the inferolateral artery as the most implicated arterial territory. Less severe outcome or stroke recurrence are identified in long-term follow-up of pure thalamic infarcts. Other comorbidities would be cause of death in aged patients.
Machine Learning in Modeling of Mouse Behavior
Authors: Gharagozloo Marjan , Amrani Abdelaziz , Wittingstall Kevin , Hamilton-Wright Andrew , Gris Denis
Published: September 2021

Mouse behavior is a primary outcome in evaluations of therapeutic efficacy. Exhaustive, continuous, multiparametric behavioral phenotyping is a valuable tool for understanding the pathophysiological status of mouse brain diseases. Automated home cage behavior analysis produces highly granulated data both in terms of number of features and sampling frequency. Previously, we demonstrated several ways to reduce feature dimensionality. In this study, we propose novel approaches for analyzing 33-Hz data generated by CleverSys software. We hypothesized that behavioral patterns within short time windows are reflective of physiological state, and that computer modeling of mouse behavioral routines can serve as a predictive tool in classification tasks. To remove bias due to researcher decisions, our data flow is indifferent to the quality, value, and importance of any given feature in isolation. To classify day and night behavior, as an example application, we developed a data preprocessing flow and utilized logistic regression (LG), support vector machines (SVM), random forest (RF), and one-dimensional convolutional neural networks paired with long short-term memory deep neural networks (1DConvBiLSTM). We determined that a 5-min video clip is sufficient to classify mouse behavior with high accuracy. LG, SVM, and RF performed similarly, predicting mouse behavior with 85% accuracy, and combining the three algorithms in an ensemble procedure increased accuracy to 90%. The best performance was achieved by combining the 1DConv and BiLSTM algorithms yielding 96% accuracy. Our findings demonstrate that computer modeling of the home-cage ethome can clearly define mouse physiological state. Furthermore, we showed that continuous behavioral data can be analyzed using approaches similar to natural language processing. These data provide proof of concept for future research in diagnostics of complex pathophysiological changes that are accompanied by changes in behavioral profile.
Alterations in Sensorimotor and Mesiotemporal Cortices and Diffuse White Matter Changes in Primary Progressive Multiple Sclerosis Detected by Adiabatic Relaxometry
Authors: Filip Pavel , Dufek Michal , Mangia Silvia , Michaeli Shalom , Bareš Martin , Schwarz Daniel , Rektor Ivan , Vojtíšek Lubomír
Published: September 2021

Background: The research of primary progressive multiple sclerosis (PPMS) has not been able to capitalize on recent progresses in advanced magnetic resonance imaging (MRI) protocols.

Objective: The presented cross-sectional study evaluated the utility of four different MRI relaxation metrics and diffusion-weighted imaging in PPMS.

Methods: Conventional free precession T1 and T2, and rotating frame adiabatic T1ρ and T2ρ in combination with diffusion-weighted parameters were acquired in 13 PPMS patients and 13 age- and sex-matched controls.

Results: T1ρ, a marker of crucial relevance for PPMS due to its sensitivity to neuronal loss, revealed large-scale changes in mesiotemporal structures, the sensorimotor cortex, and the cingulate, in combination with diffuse alterations in the white matter and cerebellum. T2ρ, particularly sensitive to local tissue background gradients and thus an indicator of iron accumulation, concurred with similar topography of damage, but of lower extent. Moreover, these adiabatic protocols outperformed both conventional T1 and T2 maps and diffusion tensor/kurtosis approaches, methods previously used in the MRI research of PPMS.

Conclusion: This study introduces adiabatic T1ρ and T2ρ as elegant markers confirming large-scale cortical gray matter, cerebellar, and white matter alterations in PPMS invisible to other in vivo biomarkers.
Early Chronic Memantine Treatment-Induced Transcriptomic Changes in Wild-Type and Shank2-Mutant Mice
Authors: Yoo Ye-Eun , Lee Seungjoon , Kim Woohyun , Kim Hyosang , Chung Changuk , Ha Seungmin , Park Jinsu , Chung Yeonseung , Kang Hyojin , Kim Eunjoon
Published: September 2021

Shank2 is an excitatory postsynaptic scaffolding protein strongly implicated in autism spectrum disorders (ASDs). Shank2-mutant mice with a homozygous deletion of exons 6 and 7 (Shank2-KO mice) show decreased NMDA receptor (NMDAR) function and autistic-like behaviors at juvenile [∼postnatal day (P21)] and adult (>P56) stages that are rescued by NMDAR activation. However, at ∼P14, these mice show the opposite change – increased NMDAR function; moreover, suppression of NMDAR activity with early, chronic memantine treatment during P7–21 prevents NMDAR hypofunction and autistic-like behaviors at later (∼P21 and >P56) stages. To better understand the mechanisms underlying this rescue, we performed RNA-Seq gene-set enrichment analysis of forebrain transcriptomes from wild-type (WT) and Shank2-KO juvenile (P25) mice treated early and chronically (P7–21) with vehicle or memantine. Vehicle-treated Shank2-KO mice showed upregulation of synapse-related genes and downregulation of ribosome- and mitochondria-related genes compared with vehicle-treated WT mice. They also showed a transcriptomic pattern largely opposite that observed in ASD (reverse-ASD pattern), based on ASD-related/risk genes and cell-type–specific genes. In memantine-treated Shank2-KO mice, chromatin-related genes were upregulated; mitochondria, extracellular matrix (ECM), and actin-related genes were downregulated; and the reverse-ASD pattern was weakened compared with that in vehicle-treated Shank2-KO mice. In WT mice, memantine treatment, which does not alter NMDAR function, upregulated synaptic genes and downregulated ECM genes; memantine-treated WT mice also exhibited a reverse-ASD pattern. Therefore, early chronic treatment of Shank2-KO mice with memantine alters expression of chromatin, mitochondria, ECM, actin, and ASD-related genes.
Free-Living Energy Balance Behaviors Are Associated With Greater Weight Loss During a Weight Loss Program
Authors: Myers Anna , Camidge Diana , Croden Fiona , Gibbons Catherine , Stubbs R. James , Blundell John , Finlayson Graham , Buckland Nicola
Published: September 2021

Introduction: Free-living movement (physical activity [PA] and sedentary behavior [SB]) and eating behaviors (energy intake [EI] and food choice) affect energy balance and therefore have the potential to influence weight loss (WL). This study explored whether free-living movement and/or eating behaviors measured early (week 3) in a 14-week WL programme or their change during the intervention are associated with WL in women.

Methods: In the study, 80 women (M ± SD age: 42.0 ± 12.4 years) with overweight or obesity [body mass index (BMI): 34.08 ± 3.62 kg/m2] completed a 14 week WL program focused primarily on diet (commercial or self-led). Body mass (BM) was measured at baseline, and again during week 2 and 14 along with body composition. Free-living movement (SenseWear Armband) and eating behavior (weighed food diaries) were measured for 1 week during week 3 and 12. Hierarchical multiple regression analyses examined whether early and early-late change in free-living movement and eating behavior were associated with WL. The differences in behavior between clinically significant weight losers (CWL; ≥5% WL) and non-clinically significant weight losers (NWL; ≤ 3% WL) were compared.

Results: The energy density of food consumed [β = 0.45, p < 0.001] and vigorous PA [β = −0.30, p < 0.001] early in the intervention (regression model 1) and early-late change in light PA [β = −0.81 p < 0.001], moderate PA [β = −1.17 p < 0.001], vigorous PA [β = −0.49, p < 0.001], total energy expenditure (EE) [β = 1.84, p < 0.001], and energy density of food consumed [β = 0.27, p = 0.01] (regression model 2) significantly predicted percentage change in BM. Early in the intervention, CWL consumed less energy dense foods than NWL [p = 0.03]. CWL showed a small but significant increase in vigorous PA, whereas NWL showed a slight decrease in PA [p = 0.04].

Conclusion: Both early and early-late change in free-living movement and eating behaviors during a 14 week WL program are predictors of WL. These findings demonstrate that specific behaviors that contribute to greater EE (e.g., vigorous PA) and lower EI (e.g., less energy-dense foods) are related to greater WL outcomes. Interventions targeting these behaviors can be expected to increase the effectiveness of WL programs.
Circulating Tumor Cells in Desmoid Tumors: New Perspectives
Authors: Braun Alexcia C. , Campos Fernando A. B. , Abdallah Emne A. , Ruano Anna P. C. , Medina Tiago da S. , Tariki Milena S. , Pinto Fabio F. E. , de Mello Celso A. L. , Chinen Ludmilla T. D.
Published: September 2021

Introduction

Desmoid tumor (DT) is a rare neoplasm with high local recurrence rates, composed of fibroblastic cells that are characterized by the expression of key molecules, including the intermediate filament vimentin, cyclooxygenase-2 (COX-2), and nuclear β-catenin, and lack of epithelial markers. Circulating tumor cells (CTCs) isolated from the peripheral blood of patients with sarcomas and other neoplasms can be used as early biomarkers of tumor invasion and dissemination. Moreover, CTCs can also re-colonize their tumors of origin through a process of “tumor self-seeding.”

Objectives

We aimed to identify CTCs in the peripheral blood of patients with DT and evaluate their expression of β-catenin, transforming growth factor receptor I (TGF-βRI), COX-2, and vimentin proteins.

Material and Methods

We conducted a prospective study of patients with initial diagnosis or relapsed DT with measurable disease. Blood samples from each patient were processed and filtered by ISET® (Rarecells, France) for CTC isolation and quantification. The CTC expression of β-catenin, COX-2, TGF-βRI, and vimentin was analyzed by immunocytochemistry (ICC).

Results

A total of 18 patients were included, and all had detectable CTCs. We found a concordance of β-catenin expression in both CTCs and primary tumors in 42.8% (6/14) of cases by using ICC and immunohistochemistry, respectively.

Conclusions

Our study identified a high prevalence of CTCs in DT patients. Concordance of β-catenin expression between primary tumor and CTCs brings new perspectives to assess the dynamics of CTCs in the blood compartment, opening new avenues for studying the biology and behavior of DT. In addition, these results open the possibility of using CTCs to predict DT dynamics at the time of disease progression and treatment. Further studies with larger sample sizes are needed to validate our findings.
Addition of Induction or Consolidation Chemotherapy in Definitive Concurrent Chemoradiotherapy Versus Concurrent Chemoradiotherapy Alone for Patients With Unresectable Esophageal Cancer: A Systematic Review and Meta-Analysis
Authors: Wang Jianing , Xiao Linlin , Wang Shuai , Pang Qingsong , Wang Jun
Published: September 2021

Background

Concurrent chemoradiotherapy (CCRT) has become the standard of care in esophageal carcinoma patients who are not surgical candidates. The efficacy of induction chemotherapy (IC) or consolidation chemotherapy (CCT) for unresectable esophageal cancer (EC) treated with CCRT is unclear. We performed a systematic review and meta-analysis of published papers to evaluate the potential benefit of IC or CCT for patients with EC.

Methods

Eligible studies of IC followed by CCRT (IC-CCRT) vs. CCRT alone or CCRT followed by CCT (CCRT-CCT) vs. CCRT alone were retrieved through extensive searches of the PubMed, Science Direct, Embase, and Cochrane Library databases from the establishment of the database to July 31, 2021. Data such as 1-, 2-, 3-, and 5-year overall survival (OS), local recurrence rate (LRR), and distant metastasis rate (DMR) were collected for meta-analysis to evaluate the efficacy of IC/CCT.

Results

Four studies of IC-CCRT vs. CCRT including 836 EC patients and six studies of CCRT-CCT vs. CCRT including 1,339 patients with esophageal squamous cell carcinoma (ESCC) were finally identified in our analysis. Both IC-CCRT group [hazard ratio (HR) 0.446, 95% CI 0.286–0.693; p < 0.001] and CCRT-CCT group (HR 0.542, 95% CI 0.410–0.716; p < 0.001) exhibited statistically significant improvement in 1-year OS rate compared to that of CCRT, while the 2-year OS rate of IC-CCRT (HR 0.803, 95% CI 0.589–1.095; p = 0.166) or CCRT-CCT (HR 0.783, 95% CI 0.600–1.022; p = 0.072) was similar with that of CCRT. And the 3-year OS rate between IC-CCRT and CCRT was similar (HR 1.065, 95% CI 0.789–1.439; p = 0.680). However, comparing with CCRT alone, the CCRT-CCT group had lower DMR [odds ratio (OR) 1.562, 95% CI 1.090–2.240; p = 0.015] and higher 3-year OS rate (HR 0.786, 95% CI 0.625–0.987; p = 0.039). Besides, no differences were observed between the CCRT-CCT and CCRT groups in 5-year OS rate (HR 0.923, 95% CI 0.706–1.205; p = 0.555) and LRR (OR 0.899, 95% CI 0.686–1.179; p = 0.441).

Conclusion

The study revealed the short-time survival benefit of additional IC or CCT compared to CCRT alone for patients with unresectable EC, and CCRT followed by CCT could significantly reduce the risk of distant metastases.
CT Radiomics for the Preoperative Prediction of Ki67 Index in Gastrointestinal Stromal Tumors: A Multi-Center Study
Authors: Zhao Yilei , Feng Meibao , Wang Minhong , Zhang Liang , Li Meirong , Huang Chencui
Published: September 2021

Purpose

This study established and verified a radiomics model for the preoperative prediction of the Ki67 index of gastrointestinal stromal tumors (GISTs).

Materials and Methods

A total of 344 patients with GISTs from three hospitals were divided into a training set and an external validation set. The tumor region of interest was delineated based on enhanced computed-tomography (CT) images to extract radiomic features. The Boruta algorithm was used for dimensionality reduction of the features, and the random forest algorithm was used to construct the model for radiomics prediction of the Ki67 index. The receiver operating characteristic (ROC) curve was used to evaluate the model’s performance and generalization ability.

Results

After dimensionality reduction, a feature subset having 21 radiomics features was generated. The generated radiomics model had an the area under curve (AUC) value of 0.835 (95% confidence interval(CI): 0.761–0.908) in the training set and 0.784 (95% CI: 0.691–0.874) in the external validation cohort.

Conclusion

The radiomics model of this study had the potential to predict the Ki67 index of GISTs preoperatively.
Analysis of EPID Transmission Fluence Maps Using Machine Learning Models and CNN for Identifying Position Errors in the Treatment of GO Patients
Authors: Dai Guyu , Zhang Xiangbin , Liu Wenjie , Li Zhibin , Wang Guangyu , Liu Yaxin , Xiao Qing , Duan Lian , Li Jing , Song Xinyu , Li Guangjun , Bai Sen
Published: September 2021

Purpose

To find a suitable method for analyzing electronic portal imaging device (EPID) transmission fluence maps for the identification of position errors in the in vivo dose monitoring of patients with Graves’ ophthalmopathy (GO).

Methods

Position errors combining 0-, 2-, and 4-mm errors in the left-right (LR), anterior-posterior (AP), and superior-inferior (SI) directions in the delivery of 40 GO patient radiotherapy plans to a human head phantom were simulated and EPID transmission fluence maps were acquired. Dose difference (DD) and structural similarity (SSIM) maps were calculated to quantify changes in the fluence maps. Three types of machine learning (ML) models that utilize radiomics features of the DD maps (ML 1 models), features of the SSIM maps (ML 2 models), and features of both DD and SSIM maps (ML 3 models) as inputs were used to perform three types of position error classification, namely a binary classification of the isocenter error (type 1), three binary classifications of LR, SI, and AP direction errors (type 2), and an eight-element classification of the combined LR, SI, and AP direction errors (type 3). Convolutional neural network (CNN) was also used to classify position errors using the DD and SSIM maps as input.

Results

The best-performing ML 1 model was XGBoost, which achieved accuracies of 0.889, 0.755, 0.778, 0.833, and 0.532 in the type 1, type 2-LR, type 2-AP, type 2-SI, and type 3 classification, respectively. The best ML 2 model was XGBoost, which achieved accuracies of 0.856, 0.731, 0.736, 0.949, and 0.491, respectively. The best ML 3 model was linear discriminant classifier (LDC), which achieved accuracies of 0.903, 0.792, 0.870, 0.931, and 0.671, respectively. The CNN achieved classification accuracies of 0.925, 0.833, 0.875, 0.949, and 0.689, respectively.

Conclusion

ML models and CNN using combined DD and SSIM maps can analyze EPID transmission fluence maps to identify position errors in the treatment of GO patients. Further studies with large sample sizes are needed to improve the accuracy of CNN.
circRPS16 Promotes Proliferation and Invasion of Hepatocellular Carcinoma by Sponging miR-876-5p to Upregulate SPINK1
Authors: Lin Shuwen , Lin Ye , Wu Zhongshi , Xia Wuzheng , Miao Chenglong , Peng Tianyi , Zhao Zhen , Ji Chenggang , Mo Zhikang , Liu Xi , Jian Zhixiang
Published: September 2021

The roles of serine protease inhibitor Kazal type 1 (SPINK1) in multiple types of cancers have been significantly documented. However, its specific roles in hepatocellular carcinoma (HCC) remain to be investigated. This study found that SPINK1 is upregulated in HCC and its upregulation correlates with poor prognosis. Besides, functional assays revealed that SPINK1 promotes cell proliferation, cell cycle, and invasion in vitro. Through bioinformatics analysis, we speculate that circRPS16 regulates SPINK1 expression by sponging miR-876-5p. This was further verified by the dual-luciferase reporter and fluorescent in situ hybridization (FISH) assays. Subsequently, rescue assays verified that circRPS16 promotes cell proliferation, cell cycle, and invasion through miR-876-5p. Importantly, silencing circRPS16 inhibited tumor growth by downregulating SPINK1 expression in vivo. Collectively, our results confirm that SPINK1 is a downstream target of circRPS16. Besides, circRPS16 and SPINK1 are oncogenic factors in HCC progression; they provide novel diagnostic and therapeutic targets for HCC patients.
Erythropoietin Produces a Dual Effect on Carotid Body Chemoreception in Male Rats
Authors: Arias-Reyes Christian , Laouafa Sofien , Zubieta-DeUrioste Natalia , Joseph Vincent , Bairam Aida , Schneider Gasser Edith M. , Soliz Jorge
Published: September 2021

Erythropoietin (EPO) regulates respiration under conditions of normoxia and hypoxia through interaction with the respiratory centers of the brainstem. Here we investigate the dose-dependent impact of EPO in the CB response to hypoxia and hypercapnia. We show, in isolated “en bloc” carotid body (CB) preparations containing the carotid sinus nerve (CSN) from adult male Sprague Dawley rats, that EPO acts as a stimulator of CSN activity in response to hypoxia at concentrations below 0.5 IU/ml. Under hypercapnic conditions, EPO did not influence the CSN response. EPO concentrations above 0.5 IU/ml decreased the response of the CSN to both hypoxia and hypercapnia, reaching complete inhibition at 2 IU/ml. The inhibitory action of high-dose EPO on the CSN activity might result from an increase in nitric oxide (NO) production. Accordingly, CB preparations were incubated with 2 IU/ml EPO and the unspecific NO synthase inhibitor (L-NAME), or the neuronal-specific NO synthase inhibitor (7NI). Both NO inhibitors fully restored the CSN activity in response to hypoxia and hypercapnia in presence of EPO. Our results show that EPO activates the CB response to hypoxia when its concentration does not exceed the threshold at which NO inhibitors masks EPO’s action.
Effects of Corticosteroid Treatment on Mycophenolic Acid Exposure in Renal Transplant Patients—Results From the SAILOR Study
Authors: Nourbakhsh Nima , Ekberg Jana , Skov Karin , Peters Christian Daugaard , Øzbay Aygen , Lindner Per , Buus Niels Henrik
Published: September 2021

Background: Mycophenolic acid (MPA) is a potent immunosuppressive agent used in solid organ transplantation. MPA exhibits large interindividual variation in dose-normalized plasma concentrations but is nevertheless usually prescribed as a fixed dose without use of therapeutic drug monitoring (TDM). Data on the effect of corticosteroid (CS) treatment on MPA concentrations during concomitant tacrolimus treatment remains sparse.

Methods: Data is based on TDM of MPA area under the concentration curve (AUC) in 210 renal transplant recipients participating in the prospective, randomized, controlled, multi-center trial (SAILOR) where a steroid-free immunosuppressive regimen with mycophenolate mofetil (MMF) and low-dose tacrolimus was compared with a conventional prednisolone-based treatment regimen. Multilevel mixed-effects linear regression post-hoc analyses of MPA AUC was performed.

Results: Median MPA AUC at baseline (within the first 2 weeks post-transplant) in patients taking 2 g MMF daily was 53 mg*h/L (interquartile range: 43–69 mg*h/L, min: 24—max: 117 mg*h/L). Between-patient variation in MPA AUC was up to 5-fold on the same MMF dose. Patients in the steroid-free group had 12.5% lower (95% CI; 3.2–20.9%, p = 0.01) MPA AUC levels at baseline compared to the steroid treated group. During follow-up (14 days–2 years post-transplant) there were no significant differences in MPA AUC between the groups with MPA AUC being 4.2% lower (95% CI: −4.8%−12,5%, p = 0.35) in the steroid-free vs standard treatment group in restricted analysis after multivariate adjustment for tacrolimus trough level, body weight, time after transplantation and MMF dose. MMF dose was positively correlated with MPA AUC (p < 0.001) whereas body weight was negatively correlated with MPA AUC (p < 0.001). MPA AUC was 0.4% (95% CI: 0.2–0.6%, p < 0.001) lower per 1 kg increase in weight. Tacrolimus trough levels had no significant effect on MPA AUC.

Conclusion: Immunosuppression with CS during concomitant tacrolimus treatment was shortly after transplantation associated with a significantly higher MPA exposure but the effect was small and not maintained during follow-up. Low body weight was associated with higher MPA exposure, which suggests a potential for weight adjusted MMF dosing.