bluuebunny/crossref_metadata_2025 huggingface dataset:
Structure and Fc-Effector Function of Rhesusized Variants of Human Anti-HIV-1 IgG1s
Authors: Tolbert William D. , Nguyen Dung N. , Tuyishime Marina , Crowley Andrew R. , Chen Yaozong , Jha Shalini , Goodman Derrick , Bekker Valerie , Mudrak Sarah V. , DeVico Anthony L. , Lewis George K. , Theis James F. , Pinter Abraham , Moody M. Anthony , Easterhoff David , Wiehe Kevin , Pollara Justin , Saunders Kevin O. , Tomaras Georgia D. , Ackerman Margaret , Ferrari Guido , Pazgier Marzena
Published: January 2022

Passive transfer of monoclonal antibodies (mAbs) of human origin into Non-Human Primates (NHPs), especially those which function predominantly by a Fc-effector mechanism, requires an a priori preparation step, in which the human mAb is reengineered to an equivalent NHP IgG subclass. This can be achieved by changing both the Fc and Fab sequence while simultaneously maintaining the epitope specificity of the parent antibody. This Ab reengineering process, referred to as rhesusization, can be challenging because the simple grafting of the complementarity determining regions (CDRs) into an NHP IgG subclass may impact the functionality of the mAb. Here we describe the successful rhesusization of a set of human mAbs targeting HIV-1 envelope (Env) epitopes involved in potent Fc-effector function against the virus. This set includes a mAb targeting a linear gp120 V1V2 epitope isolated from a RV144 vaccinee, a gp120 conformational epitope within the Cluster A region isolated from a RV305 vaccinated individual, and a linear gp41 epitope within the immunodominant Cys-loop region commonly targeted by most HIV-1 infected individuals. Structural analyses confirm that the rhesusized variants bind their respective Env antigens with almost identical specificity preserving epitope footprints and most antigen-Fab atomic contacts with constant regions folded as in control RM IgG1s. In addition, functional analyses confirm preservation of the Fc effector function of the rhesusized mAbs including the ability to mediate Antibody Dependent Cell-mediated Cytotoxicity (ADCC) and antibody dependent cellular phagocytosis by monocytes (ADCP) and neutrophils (ADNP) with potencies comparable to native macaque antibodies of similar specificity. While the antibodies chosen here are relevant for the examination of the correlates of protection in HIV-1 vaccine trials, the methods used are generally applicable to antibodies for other purposes.
T Cell Memory in Infection, Cancer, and Autoimmunity
Authors: Barnaba Vincenzo
Published: January 2022

Long-term immunological memory represents a unique performance of the adaptive immunity selected during evolution to support long-term survival of species in vertebrates, through protection against dangerous “invaders”, namely, infectious agents or unwanted (e.g., tumor) cells. The balance between the development of T cell memory and various mechanisms of immunoregulation (namely, T cell effector exhaustion and regulatory T cell suppression) dictates the fate in providing protection or not in different conditions, such as (acute or chronic) infection, vaccination, cancer, and autoimmunity. Here, these different environments are taken in consideration to outline the up-to-date cellular and molecular features regulating the development or damping of immunological memory and to delineate therapeutic strategies capable to improve or control it, in order to address pathological contexts, such as infection, tumor, and autoimmunity.
Real-Time Thickness Measurement of Marine Oil Spill by Fiber-Optic Surface Plasmon Resonance Sensors
Authors: Yin Huiting , Chen Shaohuang , Huang Renliang , Chang Heng , Liu Jiayue , Qi Wei , He Zhimin , Su Rongxin
Published: January 2022

Rapid detection of marine oil spills is becoming increasingly critical in the face of frequent marine oil spills. Oil slick thickness measurement is critical in the hazard assessment of such oil leaks. As surface plasmon resonance (SPR) sensors are sensitive to slight changes in refractive index, they can monitor offshore oil spills arising from significant differences in the refractive index between oil and water. This study presents a gold-film fiber-optic surface plasmon resonance (FOSPR) sensor prepared by polydopamine accelerated wet chemical plating for rapid and real-time measurement of oil slick thickness. We examined oil thickness detection at two interfaces, namely, water-oil and air-oil. Detection sensitivity of −1.373%/mm is obtained at the water-oil interface in the thickness range of 0–5 mm; detection sensitivity of −2.742%/mm is obtained at the air-oil interface in the thickness range of 0–10 mm. Temperature and salinity present negligible effects on the oil slick thickness measurement. The fabricated FOSPR sensor has the ability to detect the presence of oil as well as quantify the oil thickness. It has favorable repeatability and reusability, demonstrating the significant potential for use in the estimation of marine oil slick thickness.
Circulation Driven by Multihump Turbulent Mixing Over a Seamount in the South China Sea
Authors: Ye Ruijie , Shang Xiaodong , Zhao Wei , Zhou Chun , Yang Qingxuan , Tian Zichen , Qi Yongfeng , Liang Changrong , Huang Xiaodong , Zhang Zhiwei , Guan Shoude , Tian Jiwei
Published: January 2022

Turbulent mixing above rough topography is crucial for the vertical motions of deep water and the closure of the meridional overturning circulation. Related to prominent topographic features, turbulent mixing not only exhibits a bottom-intensified vertical structure but also displays substantial lateral variation. How turbulent mixing varies in the upslope direction and its impact on the upwelling of deep water over sloping topography remains poorly understood. In this study, the notable multihump structure of the bottom-intensified turbulent diffusivity in the upslope direction of a seamount in the South China Sea (SCS) is revealed by full-depth fine-resolution microstructure and hydrographic profiles. Numerical experiments indicate that multihump bottom-intensified turbulent mixing around a seamount could lead to multiple cells of locally strengthened circulations consisting of upwelling (downwelling) motions in (above) the bottom boundary layer (BBL) that are induced by bottom convergence (divergence) of the turbulent buoyancy flux. Accompanied by cyclonic (anticyclonic) flow, a three-dimensional spiral circulation manifests around the seamount topography. These findings regarding the turbulent mixing and three-dimensional circulation around a deep seamount provide support for the further interpretation of the abyssal meridional overturning circulation.
Experimental Study on Preparation and Performance of Concrete With Large Content of Fly Ash
Authors: Li Changyong , Geng Haibin , Zhou Siyi , Dai Manman , Sun Baoshan , Li Fenglan
Published: January 2022

Producing concrete with large content of fly ash attracts increasing attention in low carbon building materials. In this paper, the fly-ash concrete (FAC) with a content of fly ash no less than 50% total weight of binders was developed. The adaptability of fly ash used for concrete was firstly examined by testing the water requirement of normal consistency and the setting time for cement fly-ash paste, and the strengths of cement fly-ash mortar at the curing age of 7 and 28 days. The factors of water-to-binder ratio from 0.3 to 0.5, the content of fly-ash from 40% to 80%, and the excitation measures with additional Ca(OH)2 and steam curing at initial were considered. After that, the FAC was designed by adding an excessive content of fly ash to reduce the water-to-binder ratio from 0.50 to 0.26, and the content of fly-ash varied from 52% to 60%. Results show that the cement fly-ash paste presented a reduction of water requirement and an elongation of setting time with the increased content of fly ash. This provides a foundation of maintaining the workability of fresh FAC with a decreased water-to-binder ratio by adding the excessive content of fly ash. The cement fly-ash mortar had a lower early strength due to the slow reaction of fly-ash with Ca(OH)2, which could be improved by steam curing at the initial 24 h due to the excitation of fly-ash activity. At curing age of 28 days, the FAC had the expected axial compressive strength and modulus of elasticity, but the tensile strength was lower than predicted. At the curing age of 56 days, all the basic mechanical properties of FAC reached the prediction. The resistances of FAC to chloride ion penetration and carbonization were realized at a very high level as specified in codes.
Clinical Characteristics and Efficacy of Adalimumab and Low-Dose Methotrexate Combination Therapy in Patients With Vogt–Koyanagi–Harada Disease
Authors: Hiyama Tomona , Harada Yosuke , Kiuchi Yoshiaki
Published: January 2022

This retrospective study investigated the clinical characteristics and efficacy of adalimumab and low-dose methotrexate combination therapy in patients with Vogt–Koyanagi–Harada disease who were treated at Hiroshima University from February 2012 to May 2021. The patients' demographics, clinical features at administration of immunosuppressive therapy, steroid-sparing immunosuppressive therapy, side effects, and relapses were recorded. The efficacies of steroid-sparing immunosuppressive therapy (methotrexate, cyclosporine A, adalimumab, and adalimumab and methotrexate combination therapy) were analyzed. Among 62 patients, the median age at diagnosis was 47 years and the median duration of uveitis was 51 months. Systemic corticosteroid therapy was administered to 93.5% of patients (n = 58). Thirty-four patients (54.8%) were treated with steroid-sparing immunosuppressive therapy. Methotrexate and cyclosporine A were administered to 12 and 22 patients, respectively; relapse occurred in 50.0% and 22.7% of the patients, respectively. Discontinuation of cyclosporine A was required in 63.6% of patients because of side effects. Adalimumab was administered to 14 patients. Recurrence occurred in 11 patients, requiring methotrexate concomitantly. The mean dose of methotrexate at inflammatory quiescence after side effect-related dose decrease was 8.0 mg/week (0.13 mg/kg). The median duration of combination therapy without recurrence was 20 months. There were no serious adverse events during adalimumab therapy. A high relapse rate was observed in patients receiving methotrexate; a high rate of side effects requiring discontinuation was observed in patients receiving Cyclosporine A. Patients with late-stage Vogt–Koyanagi–Harada disease may achieve better control with adalimumab and methotrexate combination therapy.
Meta-Analytical Accuracy of ANCA Renal Risk Score for Prediction of Renal Outcome in Patients With ANCA-Associated Glomerulonephritis
Authors: Xia Mengdi , Yu Ruiran , Zheng Zaiqiong , Li Huan , Feng Jie , Xie Xisheng , Chen Dongming
Published: January 2022

Background: To evaluate the diagnostic accuracy of antineutrophil cytoplasmic antibody (ANCA) renal risk score (ARRS) for prediction of renal outcome in patients with ANCA-associated glomerulonephritis (ANCA-GN).

Methods: We searched PubMed, EMBASE, Ovid, Web of Science, the Cochrane Library, and ClinicalTrials.gov for studies, which used ARRS to predict end-stage renal disease (ESRD) in patients with ANCA-GN. Two reviewers independently screened articles for inclusion, assessed the quality of studies with both an adapted Quality Assessment of Diagnostic Accuracy Studies 2 (QUADAS-2) tool. We calculated the combined patients with ESRD in the ARRS categories and presented the summary and individual estimates based on the ARRS categories. Then, the sensitivity, specificity, diagnostic odds ratio (DOR), positive/negative likelihood ratio, and the area under the receiver operating characteristic (AUROC) curves of the pooled data for ARRS were used to assess the accuracy of the “above the low-risk threshold” (ARRS ≥ 2) and “high-risk grade” (ARRS ≥ 8) for renal outcome of patients with ANCA-GN. The hierarchical summary ROC (HSROC) was used to verify the accuracy value. The clinical utility of ARRS was evaluated by the Fagan plot. Heterogeneity was explored using meta-regression and subgroup analysis.

Results: A total of 12 distinct cohorts from 11 articles involving 1,568 patients with ANCA-GN were analyzed. The cumulative patients with ESRD at the maximum follow-up of 60 months was 5% (95% CI: 0.02–0.07; p < 0.001) for ANCA-GN with low ARRS (0–1 points) and significantly increased to 22% (95% CI: 0.15–0.29; p < 0.001) medium ARRS (2–7 points). The combined cumulative patients with ESRD was 59% (95% CI: 0.49–0.69; p < 0.001) high ARRS (8–11 points). The pooled sensitivity of ARRS ≥ 2 in predicting ESRD was 98% with a specificity of 30% and a DOR of 15.08 and the mean AUROC value was 0.82. The pooled sensitivity of ARRS ≥ 8 in predicting ESRD was 58% with a specificity of 86% and a DOR of 7.59. The meta-regression and subgroup analysis indicated that variation in the geographic regions, study design, index risk, follow-up time, age of patient, publication year, and number of patient could be the potential sources of heterogeneity in the diagnosis of ARRS ≥ 8.

Conclusion: This meta-analysis emphasized the good performance of the ARRS score in predicting the renal outcome in patients with ANCA-GN. However, these findings should be verified by future large-scale prospective studies.
Clinical Relevance of Absolute BK Polyoma Viral Load Kinetics in Patients With Biopsy Proven BK Polyomavirus Associated Nephropathy
Authors: Omić Haris , Kläger Johannes Phillip , Herkner Harald , Aberle Stephan W. , Regele Heinz , Weseslindtner Lukas , Schrag Tarek Arno , Bond Gregor , Hohenstein Katharina , Watschinger Bruno , Werzowa Johannes , Strassl Robert , Eder Michael , Kikić Željko
Published: January 2022

Introduction: The absolute BK viral load is an important diagnostic surrogate for BK polyomavirus associated nephropathy (PyVAN) after renal transplant (KTX) and serial assessment of BK viremia is recommended. However, there is no data indicating which particular viral load change, i.e., absolute vs. relative viral load changes (copies/ml; percentage of the preceding viremia) is associated with worse renal graft outcomes.

Materials and Methods: In this retrospective study of 91 biopsy proven PyVAN, we analyzed the interplay of exposure time, absolute and relative viral load kinetics, baseline risk, and treatment strategies as risk factors for graft loss after 2 years using a multivariable Poisson-model.

Results: We compared two major treatment strategies: standardized immunosuppression (IS) reduction (n = 53) and leflunomide (n = 30). The median viral load at the index biopsy was 2.15E+04 copies/ml (interquartile range [IQR] 1.70E+03–1.77E+05) and median peak viremia was 3.6E+04 copies/ml (IQR 2.7E+03–3.3E+05). Treatment strategies and IS-levels were not related to graft loss. After correction for baseline viral load and estimated glomerular filtration rate (eGFR), absolute viral load decrease/unit remained an independent risk factor for graft loss [incidence rate ratios [IRR] = 0.77, (95% CI 0.61–0.96), p = 0.02].

Conclusion: This study provides evidence for the prognostic importance of absolute BK viremia kinetics as a dynamic parameter indicating short-term graft survival independently of other established risk factors.
Colistin Resistance in Monophasic Isolates of Salmonella enterica ST34 Collected From Meat-Derived Products in Spain, With or Without CMY-2 Co-production
Authors: Vázquez Xenia , García Vanesa , Fernández Javier , Bances Margarita , de Toro María , Ladero Víctor , Rodicio Rosaura , Rodicio M. Rosario
Published: January 2022

Colistin is a last-resort antibiotic in fighting severe infections caused by multidrug resistant Gram negative pathogens in hospitals. Zoonotic bacteria acquire colistin resistance in animal reservoirs and mediate its spread along the food chain. This is the case of non-typhoid serovars of Salmonella enterica. Colistin-resistant S. enterica in foods represents a threat to human health. Here, we assessed the prevalence of colistin-resistance in food-borne isolates of S. enterica (2014–2019; Asturias, Spain), and established the genetic basis and transferability of this resistance. Five out of 231 isolates tested (2.2%) were resistant to colistin. Four of them, belonging to the European monophasic ST34 clone of S. Typhimurium, were characterized in the present study. They were collected from pork or pork and beef meat-derived products, either in 2015 (three isolates) or 2019 (one isolate). Molecular typing with XbaI-PFGE and plasmid profiling revealed distinct patterns for each isolate, even though two of the 2015 isolates derived from the same sample. The MICs of colistin ranged from 8 to 16 mg/L. All isolates carried the mcr-1.1 gene located on conjugative plasmids of the incompatibility groups IncX4 (2015 isolates) or IncHI2 (2019 isolate). Apart from colistin resistance, the four isolates carried chromosomal genes conferring resistance to ampicillin, streptomycin, sulfonamides and tetracycline [blaTEM–1, strA-strB, sul2, and tet(B)] and heavy metals, including copper and silver (silESRCFBAGP and pcoGE1ABCDRSE2), arsenic (arsRSD2A2BCA1D1) ± mercury (merEDACPTR), which are characteristically associated with the European ST34 monophasic clone. The 2019 isolate was also resistant to other antibiotics, comprising third generation cephalosporins and cephamycins. The latter phenotype was conferred by the blaCMY–2 gene located on an IncI1-I(α)-ST2 plasmid. Results in the present study identified meat-derived products as a reservoir of a highly successful clone harboring transferable plasmids which confer resistance to colistin and other clinically important antibiotics. An important reduction in the number of food-borne S. enterica detected during the period of the study, together with the low frequency of colistin resistance, underlines the success of One Health initiatives, such as those implemented at the UE, to control zoonotic bacteria along the food chain and to halt the spread of antimicrobial resistance.
SARS-CoV-2 Causes Mitochondrial Dysfunction and Mitophagy Impairment
Authors: Shang Chao , Liu Zirui , Zhu Yilong , Lu Jing , Ge Chenchen , Zhang Cuiling , Li Nan , Jin Ningyi , Li Yiquan , Tian Mingyao , Li Xiao
Published: January 2022

Mitochondria, which is essential for adequate innate immune response, energy metabolism and mitochondria reactive oxygen species (ROS) production, might be in the cross fire of Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and host cell defense. However, little is known about interactions between mitochondria and SARS-CoV-2. We performed fluorescent microscopy and found an enrichment of SARS-CoV-2 replication products double stranded RNA (dsRNA) within mitochondria. The entry process of dsRNA might be mediated by Tom20 as observed by reduced mitochondrial localization of SARS-CoV-2 dsRNA in Tom20 knockdown cells. Importantly, decreased mitochondrial localization of dsRNA, as well as mitochondrial membrane stabilizers mdivi-1 and cyclosporin A, inhibited viral load in cells. Next, we detected mitochondrial dysfunction caused by SARS-CoV-2 infection, including mitochondrial membrane depolarization, mitochondrial permeability transition pore opening and increased ROS release. In response to mitochondrial damage, we observed an increase in expression and mitochondrial accumulation of Pink1 and Parkin proteins, as well as Pink-1-mediated recruitment of P62 to mitochondria, suggesting initiated mitophagy for mitochondrial quality control and virus clearance. Nevertheless, we observed that mitophagy was inhibited and stayed in early stage with an unchanged Hsp60 expression post SARS-CoV-2 infection. This might be one of the anti-autophagy strategies of SARS-CoV-2 and we used co-immunoprecipitation to found that SARS-CoV-2 infection inhibited P62 and LC3 binding which plays a critical role in selective envelopment of substrates into autophagosomes. Our results suggest that mitochondria are closely involved in SARS-CoV-2 replication and mitochondrial homeostasis is disrupted by SARS-CoV-2 in the virus-cell confrontation.
Selective and Inverse U-Shaped Curve Alteration of the Retinal Nerve in Amyotrophic Lateral Sclerosis: A Potential Mirror of the Disease
Authors: Zhang Yixuan , Liu Xiangyi , Fu Jiayu , Zhang Yuanjin , Yang Xue , Zhang Shuo , Fan Dongsheng
Published: January 2022

Introduction: Alterations in the visual pathway involving the retina have been reported in amyotrophic lateral sclerosis (ALS) but they lack consistency and subgroup analysis. We aimed to assess the retinal nerve fiber layer (RNFL) and retinal ganglion cells (RGCs) alterations in different stages of ALS patients and their association with ALS progression parameters.

Methods: The study population consisted of 70 clinically diagnosed ALS patients and 55 age, sex matched controls. All of them underwent ophthalmic assessments and optical coherence tomography imaging. Four quadrants of the peripapillary RNFL and ganglion cell/inner plexiform complex (GCIP) were observed and automatically measured. Early-stage distal motor neuron axon dysfunction in ALS was detected by compound muscle action potential (CMAP) of the distal limbs within 12 months. The ALS disease parameters included the ALSFRS-R score and the disease progression rate (ΔFS).

Results: Generally compared with controls, the nasal (p = 0.016) quadrant of the RNFL was thicker in ALS patients. When controlling for age and ΔFS, the RNFL(r = 0.37, p = 0.034) and GCIP(r = 0.40, p = 0.021) were significantly thickened as disease progressed within 12 months, while the RNFL declined with time after one year (r = −0.41, p = 0.037). ALS patients was subclassified into thickened RNFL (T-RNFL, >95th percentile of normal), impaired RNFL (I-RNFL, <5th percentile of normal) and normal RNFL. There were significant differences in the GCIP among the three groups (p < 0.001). In the T-RNFL group (n = 18), the RNFL was negatively correlated with the abductor pollicis brevis-CMAP amplitude within 12 months (r = −0.56, p = 0.01). Patients within 12 months in this group progressed faster than others (p = 0.039). In the normal RNFL group (n = 22), 13 patients were diagnosed beyond 12 months, whose ΔFS was remarkably lower (p = 0.007). In I-RNFL group (n = 30), the early stage patients (<12 months) had significant higher ΔFS (p = 0.006). One patient was with SOD1 pathogenic variant (p.A5V).

Conclusion: Alterations of retinal nerve were not consistent in ALS patients with diverse phenotypes and progression rates. Generally speaking, the RNFL thickened during the first year and then gradually declined, which is related to but preceding the thickness change of the RGCs. Patients with a significant RNFL thinning in the early stage may have a faster progression rate. The inverse U-shaped curve transformation might be in accordance with early-stage motor neuron axonopathy.
Microemulsion Based Nanostructures for Drug Delivery
Authors: Arredondo-Ochoa Teresita , Silva-Martínez Guillermo A.
Published: January 2022

Most of the active pharmaceutical compounds are often prone to display low bioavailability and biological degradation represents an important drawback. Due to the above, the development of a drug delivery system (DDS) that enables the introduction of a pharmaceutical compound through the body to achieve a therapeutic effect in a controlled manner is an expanding application. Henceforth, new strategies have been developed to control several parameters considered essential for enhancing delivery of drugs. Nanostructure synthesis by microemulsions (ME) consist of enclosing a substance within a wall material at the nanoscale level, allowing to control the size and surface area of the resulting particle. This nanotechnology has shown the importance on targeted drug delivery to improve their stability by protecting a bioactive compound from an adverse environment, enhanced bioavailability as well as controlled release. Thus, a lower dose administration could be achieved by minimizing systemic side effects and decreasing toxicity. This review will focus on describing the different biocompatible nanostructures synthesized by ME as controlled DDS for therapeutic purposes.
Spatialization of Time in the Entorhinal-Hippocampal System
Authors: Houser Troy M.
Published: January 2022

The functional role of the entorhinal-hippocampal system has been a long withstanding mystery. One key theory that has become most popular is that the entorhinal-hippocampal system represents space to facilitate navigation in one’s surroundings. In this Perspective article, I introduce a novel idea that undermines the inherent uniqueness of spatial information in favor of time driving entorhinal-hippocampal activity. Specifically, by spatializing events that occur in succession (i.e., across time), the entorhinal-hippocampal system is critical for all types of cognitive representations. I back up this argument with empirical evidence that hints at a role for the entorhinal-hippocampal system in non-spatial representation, and computational models of the logarithmic compression of time in the brain.
Application of Artificial Intelligence in Diagnosis of Craniopharyngioma
Authors: Qin Caijie , Hu Wenxing , Wang Xinsheng , Ma Xibo
Published: January 2022

Craniopharyngioma is a congenital brain tumor with clinical characteristics of hypothalamic-pituitary dysfunction, increased intracranial pressure, and visual field disorder, among other injuries. Its clinical diagnosis mainly depends on radiological examinations (such as Computed Tomography, Magnetic Resonance Imaging). However, assessing numerous radiological images manually is a challenging task, and the experience of doctors has a great influence on the diagnosis result. The development of artificial intelligence has brought about a great transformation in the clinical diagnosis of craniopharyngioma. This study reviewed the application of artificial intelligence technology in the clinical diagnosis of craniopharyngioma from the aspects of differential classification, prediction of tissue invasion and gene mutation, prognosis prediction, and so on. Based on the reviews, the technical route of intelligent diagnosis based on the traditional machine learning model and deep learning model were further proposed. Additionally, in terms of the limitations and possibilities of the development of artificial intelligence in craniopharyngioma diagnosis, this study discussed the attentions required in future research, including few-shot learning, imbalanced data set, semi-supervised models, and multi-omics fusion.
Roadmap Guided Direct Percutaneous Vertebral Artery Puncture for Mechanical Thrombectomy of Acute Basilar Artery Occlusion: A Technical Case Report and Review of the Literature
Authors: Nawabi Jawed , Bohner Georg , Siebert Eberhard
Published: January 2022

Access techniques for mechanical thrombectomy normally include percutaneous puncture of the common femoral or, more recently, the radial artery. Although target vessel catheterization may frequently not be devoid of difficulties via both routes, the vast majority of mechanical thrombectomy (MT) cases can be successfully managed. However, in a significant minority of cases, a stable target vessel access cannot be reached resulting in futile recanalization procedures and detrimental outcomes for the patients. As such, in analogy to direct carotid puncture for anterior circulation MT, direct vertebral artery (VA) puncture (DVP) is a direct cervical approach, which can constitute the only feasible access to the posterior circulation in highly selected cases. So far, due to the rarity of DVP, only anecdotal evidence from isolated case reports is available and this approach raises concerns with regard to safety issues, feasibility, and technical realization. We present a case in which bail-out access to the posterior circulation was successfully obtained through a roadmap-guided lateral direct puncture of the V2 segment of the cervical VA and give an overview of technical nuances of published DVP approaches for posterior circulation MT.
Reconsidering Ventriculoperitoneal Shunt Surgery and Postoperative Shunt Valve Pressure Adjustment: Our Approaches Learned From Past Challenges and Failures
Authors: Yamada Shigeki , Ishikawa Masatsune , Nakajima Madoka , Nozaki Kazuhiko
Published: January 2022

Treatment for idiopathic normal pressure hydrocephalus (iNPH) continues to develop. Although ventriculoperitoneal shunt surgery has a long history and is one of the most established neurosurgeries, in the 1970s, the improvement rate of iNPH triad symptoms was poor and the risks related to shunt implantation were high. This led experts to question the surgical indication for iNPH and, over the next 20 years, cerebrospinal fluid (CSF) shunt surgery for iNPH fell out of favor and was rarely performed. However, the development of programmable-pressure shunt valve devices has reduced the major complications associated with the CSF drainage volume and appears to have increased shunt effectiveness. In addition, the development of support devices for the placement of ventricular catheters including preoperative virtual simulation and navigation systems has increased the certainty of ventriculoperitoneal shunt surgery. Secure shunt implantation is the most important prognostic indicator, but ensuring optimal initial valve pressure is also important. Since over-drainage is most likely to occur in the month after shunting, it is generally believed that a high initial setting of shunt valve pressure is the safest option. However, this does not always result in sufficient improvement of the symptoms in the early period after shunting. In fact, evidence suggests that setting the optimal valve pressure early after shunting may cause symptoms to improve earlier. This leads to improved quality of life and better long-term independent living expectations. However, in iNPH patients, the remaining symptoms may worsen again after several years, even when there is initial improvement due to setting the optimal valve pressure early after shunting. Because of the possibility of insufficient CSF drainage, the valve pressure should be reduced by one step (2–4 cmH2O) after 6 months to a year after shunting to maximize symptom improvement. After the valve pressure is reduced, a head CT scan is advised a month later.
Effects of Linguistic Distance on Second Language Brain Activations in Bilinguals: An Exploratory Coordinate-Based Meta-Analysis
Authors: Cargnelutti Elisa , Tomasino Barbara , Fabbro Franco
Published: January 2022

In this quantitative meta-analysis, we used the activation likelihood estimation (ALE) approach to address the effects of linguistic distance between first (L1) and second (L2) languages on language-related brain activations. In particular, we investigated how L2-related networks may change in response to linguistic distance from L1. Thus, we examined L2 brain activations in two groups of participants with English as L2 and either (i) a European language (European group, n = 13 studies) or (ii) Chinese (Chinese group, n = 18 studies) as L1. We further explored the modulatory effect of age of appropriation (AoA) and proficiency of L2. We found that, irrespective of L1-L2 distance—and to an extent—irrespective of L2 proficiency, L2 recruits brain areas supporting higher-order cognitive functions (e.g., cognitive control), although with group-specific differences (e.g., the insula region in the European group and the frontal cortex in the Chinese group). The Chinese group also selectively activated the parietal lobe, but this did not occur in the subgroup with high L2 proficiency. These preliminary results highlight the relevance of linguistic distance and call for future research to generalize findings to other language pairs and shed further light on the interaction between linguistic distance, AoA, and proficiency of L2.
Case Report: Bilateral Deep Brain Stimulation Implantation on Different Targets for a Parkinson's Disease Patient With a Bullet in the Brain
Authors: Tian Yu , Wang Jiaming , Shi Xin , Feng Zhaohai , Jiang Lei , Hao Yujun
Published: January 2022

Patients requiring deep brain stimulation due to intracerebral metallic foreign substances have not been reported elsewhere in the world. Additionally, the long-term effects of metallic foreign bodies on deep brain stimulation (DBS) are unknown. A 79-year-old man with a 5-year history of Parkinson's disease (PD) reported that, 40 years ago, while playing with a pistol, a metallic bullet was accidentally discharged into the left brain through the edge of the left eye, causing no discomfort other than blurry vision in the left eye. DBS was performed due to the short duration of efficacy for oral medication. Because the bullet was on the left subthalamic nucleus (STN) electrode trajectory and the patient's right limb was primarily stiff, the patient received globus pallidus interna (GPi)-DBS implantation in the left hemisphere and STN-DBS implantation in the right hemisphere. During a 6-month postoperative follow-up, the patient's PD symptoms were effectively managed with no noticeable discomfort.
Finite Element Modeling of Magnitude and Location of Brain Micromotion Induced Strain for Intracortical Implants
Authors: Al Abed Ali , Amatoury Jason , Khraiche Massoud
Published: January 2022

Micromotion-induced stress remains one of the main determinants of life of intracortical implants. This is due to high stress leading to tissue injury, which in turn leads to an immune response coupled with a significant reduction in the nearby neural population and subsequent isolation of the implant. In this work, we develop a finite element model of the intracortical probe-tissue interface to study the effect of implant micromotion, implant thickness, and material properties on the strain levels induced in brain tissue. Our results showed that for stiff implants, the strain magnitude is dependent on the magnitude of the motion, where a micromotion increase from 1 to 10 μm induced an increase in the strain by an order of magnitude. For higher displacement over 10 μm, the change in the strain was relatively smaller. We also showed that displacement magnitude has no impact on the location of maximum strain and addressed the conflicting results in the literature. Further, we explored the effect of different probe materials [i.e., silicon, polyimide (PI), and polyvinyl acetate nanocomposite (PVAc-NC)] on the magnitude, location, and distribution of strain. Finally, we showed that strain distribution across cortical implants was in line with published results on the size of the typical glial response to the neural probe, further reaffirming that strain can be a precursor to the glial response.
Clinical Progress of PD-1/L1 Inhibitors in Breast Cancer Immunotherapy
Authors: Chen Fei , Chen Naifei , Gao Yangyang , Jia Lin , Lyu Zheng , Cui Jiuwei
Published: January 2022

Breast cancer is a major killer of women’s health worldwide. While breast cancer is thought to have lower immunogenicity compared with other solid tumors, combination therapy is able to improve the immunogenicity of the tumor and sensitize breast cancer cells to immunotherapy. Immunotherapy represented by immune checkpoint inhibitors (ICIs) has been largely explored in the field of breast cancer, including both early and advanced disease. Immunotherapy for triple-negative breast cancer (TNBC) has been the most studied, and the PD-L1 inhibitor atezolizumab combined with nab-paclitaxel has been used in the first-line treatment of TNBC. Immunotherapeutic data for human epidermal growth factor receptor-positive and hormone receptor-positive breast cancer are also accumulating. This review summarizes the clinical trial data of ICIs or ICI-containing therapies in different types and stages of breast cancer.
PUTH Grading System for Urinary Tumor With Supradiaphragmatic Tumor Thrombus: Different Surgical Techniques for Different Tumor Characteristics
Authors: Liu Zhuo , Li Yuxuan , Zhang Yu , Zhao Xun , Ge Liyuan , Tang Shiying , Hong Peng , Zhang Shudong , Tian Xiaojun , Wang Shumin , Liu Cheng , Zhang Hongxian , Ma Lulin
Published: January 2022

Purpose

To explore the different treatment strategies for urinary tumors with Mayo IV thrombus.

Materials and Methods

We retrospectively analyzed the patients with Mayo IV thrombus in Peking University Third Hospital from January 2014 to April 2021. We used the Peking University Third Hospital (PUTH) grading system to classify urinary tumors with supradiaphragmatic thrombus. PUTH-A referred to the filled thrombus whose tip just reached above the diaphragm, or the thrombus entering the right atrium (< 2cm). PUTH-B referred to the filled thrombus entering the right atrium (> 2cm), or the thrombus invading the wall of the inferior pericardial vena cava. Detailed techniques were described for various scenarios. Clinicopathological data and perioperative outcomes were reported. Group difference statistical analysis was performed.

Results

A total of 26 cases of urinary tumors with supradiaphragmatic IVC thrombus (Mayo grade IV) underwent treatment were enrolled in this study. 19 patients in the PUTH-A group received the open approach without sternotomy and cardiopulmonary bypass. Seven patients in the PUTH-B group received open thoracotomy assisted by cardiopulmonary bypass. No intraoperative death occurred. After 56 months of follow-up, 46.2% (12 of 26) patients died of all causes. Estimated 1-year, 2-year, and 3-year overall survival were 72.0% (95% CI, 54.4%-89.6%), 58.2% (95% CI, 38.0%-78.4%), and 52.4% (95% CI, 31.2%-73.6%), respectively.

Conclusions

We introduced the PUTH grading system for the characteristics of urinary tumors with supradiaphragmatic tumor thrombus, and selected different surgical techniques according to different classifications. This grading system was relatively feasible and effective.
Notch2 Increases the Resistance to Venetoclax-Induced Apoptosis in Chronic Lymphocytic Leukemia B Cells by Inducing Mcl-1
Authors: Fiorcari Stefania , Maffei Rossana , Atene Claudio Giacinto , Mesini Nicolò , Maccaferri Monica , Leonardi Giovanna , Martinelli Silvia , Paolini Ambra , Nasillo Vincenzo , Debbia Giulia , Potenza Leonardo , Luppi Mario , Marasca Roberto
Published: January 2022

Chronic lymphocytic leukemia (CLL) has experienced a clinical revolution—thanks to the discovery of crucial pathogenic mechanisms. CLL is still an incurable disease due to intrinsic or acquired resistance of the leukemic clone. Venetoclax is a Bcl-2 inhibitor with a marked activity in CLL, but emerging patterns of resistance are being described. We hypothesize that intrinsic features of CLL cells may contribute to drive mechanisms of resistance to venetoclax. We analyzed the expression of Interferon Regulatory Factor 4 (IRF4), Notch2, and Mcl-1 in a cohort of CLL patients. We evaluated CLL cell viability after genetic and pharmaceutical modulation of Notch2 expression in patients harboring trisomy 12. We tested venetoclax in trisomy 12 CLL cells either silenced or not for Notch2 expression or in combination with an inhibitor of Mcl-1, AMG-176. Trisomy 12 CLL cells were characterized by low expression of IRF4 associated with high levels of Notch2 and Mcl-1. Notch2 and Mcl-1 expression determined protection of CLL cells from spontaneous and drug-induced apoptosis. Considering the involvement of Mcl-1 in venetoclax resistance, our data demonstrated a contribution of high levels of Notch2 and Mcl-1 in a reduced response to venetoclax in CLL cells carrying trisomy 12. Furthermore, reduction of Mcl-1 expression by silencing Notch2 or by treatment with AMG-176 was able to restore the response of CLL cells to venetoclax. The expression of Notch2 identifies a subset of CLL patients, mainly harboring trisomy 12, characterized by high levels of Mcl-1. This biological mechanism may compromise an effective response to venetoclax.
Comparison of Long-Term Survival Outcomes of T4a and T4b Colorectal Cancer
Authors: Lim Ji Ha , Huh Jung Wook , Lee Woo Yong , Yun Seong Hyeon , Kim Hee Cheol , Cho Yong Beom , Park Yoon Ah , Shin Jung Kyong
Published: January 2022

Background

Although T4b is known to have worse oncologic outcomes, it is unclear whether it truly shows a worse prognosis. This study aims to compare the survival differences between T4a and T4b.

Methods

Patients who were pathologically diagnosed with T3 and T4 colorectal adenocarcinoma from 2010 to 2014 were included (T3, n = 1822; T4a, n = 424; T4b, n = 67). Overall survival (OS) and cancer-specific survival (CSS) were compared between T4a and T4b using the Kaplan-Meier method and log-rank test.

Results

In stage II, T4a had better OS and CSS than T4b (5-year OS, 89.5% vs. 72.6%; 5-year CSS, 94.4% vs. 81.7%, all p < 0.05), however, in stage III, there were no significant differences in survivals between groups (all p > 0.05). In multivariable analysis, T classification was not an independent risk factor for OS (p > 0.05). However, for CSS, when respectively compared to T3, T4b (HR 3.53, p < 0.001) showed a relatively higher hazard ratio than T4a (HR 2.27, p < 0.001).

Conclusions

T4a showed more favorable OS and CSS than T4b, especially in stage II. Our findings support the current AJCC guidelines, in which T4b is presented as a more advanced stage than T4a.
Current Progress in Breast Implant-Associated Anaplastic Large Cell Lymphoma
Authors: Wang Yichen , Zhang Qi , Tan Yufang , Lv Wenchang , Zhao Chongru , Xiong Mingchen , Hou Kai , Wu Min , Ren Yuping , Zeng Ning , Wu Yiping
Published: January 2022

Breast implant-associated anaplastic large-cell lymphoma (BIA-ALCL) is an uncommon type of T-cell lymphoma. Although with a low incidence, the epidemiological data raised the biosafety and health concerns of breast reconstruction and breast augmentation for BIA-ALCL. Emerging evidence confirms that genetic features, bacterial contamination, chronic inflammation, and textured breast implant are the relevant factors leading to the development of BIA-ALCL. Almost all reported cases with a medical history involve breast implants with a textured surface, which reflects the role of implant surface characteristics in BIA-ALCL. With this review, we expect to highlight the most significant features on etiology, pathogenesis, diagnosis, and therapy of BIA-ALCL, as well as we review the physical characteristics of breast implants and their potential pathogenic effect and hopefully provide a foundation for optimal choice of type of implant with minimal morbidity.
Current Prophylaxis and Treatment Approaches for Acute Graft-Versus-Host Disease in Haematopoietic Stem Cell Transplantation for Children With Acute Lymphoblastic Leukaemia
Authors: Wölfl Matthias , Qayed Muna , Benitez Carabante Maria Isabel , Sykora Tomas , Bonig Halvard , Lawitschka Anita , Diaz-de-Heredia Cristina
Published: January 2022

Acute graft-versus-host disease (aGvHD) continues to be a leading cause of morbidity and mortality following allogeneic haematopoietic stem cell transplantation (HSCT). However, higher event-free survival (EFS) was observed in patients with acute lymphoblastic leukaemia (ALL) and grade II aGvHD vs. patients with no or grade I GvHD in the randomised, controlled, open-label, international, multicentre Phase III For Omitting Radiation Under Majority age (FORUM) trial. This finding suggests that moderate-severity aGvHD is associated with a graft-versus-leukaemia effect which protects against leukaemia recurrence. In order to optimise the benefits of HSCT for leukaemia patients, reduction of non-relapse mortality—which is predominantly caused by severe GvHD—is of utmost importance. Herein, we review contemporary prophylaxis and treatment options for aGvHD in children with ALL and the key challenges of aGvHD management, focusing on maintaining the graft-versus-leukaemia effect without increasing the severity of GvHD.
Acute Gravitational Stress Selectively Impairs Dynamic Cerebrovascular Reactivity in the Anterior Circulation Independent of Changes to the Central Respiratory Chemoreflex
Authors: Watanabe Hironori , Saito Shotaro , Washio Takuro , Bailey Damian Miles , Ogoh Shigehiko
Published: January 2022

Cerebrovascular reactivity (CVR) to changes in the partial pressure of arterial carbon dioxide (PaCO2) is an important mechanism that maintains CO2 or pH homeostasis in the brain. To what extent this is influenced by gravitational stress and corresponding implications for the regulation of cerebral blood flow (CBF) remain unclear. The present study examined the onset responses of pulmonary ventilation (V̇E) and anterior middle (MCA) and posterior (PCA) cerebral artery mean blood velocity (Vmean) responses to acute hypercapnia (5% CO2) to infer dynamic changes in the central respiratory chemoreflex and cerebrovascular reactivity (CVR), in supine and 50° head-up tilt (HUT) positions. Each onset response was evaluated using a single-exponential regression model consisting of the response time latency [CO2-response delay (t0)] and time constant (τ). Onset response of V̇E and PCA Vmean to changes in CO2 was unchanged during 50° HUT compared with supine (τ: V̇E, p = 0.707; PCA Vmean, p = 0.071 vs. supine) but the MCA Vmean onset response was faster during supine than during 50° HUT (τ: p = 0.003 vs. supine). These data indicate that gravitational stress selectively impaired dynamic CVR in the anterior cerebral circulation, whereas the posterior circulation was preserved, independent of any changes to the central respiratory chemoreflex. Collectively, our findings highlight the regional heterogeneity underlying CBF regulation that may have translational implications for the microgravity (and hypercapnia) associated with deep-space flight notwithstanding terrestrial orthostatic diseases that have been linked to accelerated cognitive decline and neurodegeneration.
Principles of Spatial Transcriptomics Analysis: A Practical Walk-Through in Kidney Tissue
Authors: Noel Teia , Wang Qingbo S. , Greka Anna , Marshall Jamie L.
Published: January 2022

Spatial transcriptomic technologies capture genome-wide readouts across biological tissue space. Moreover, recent advances in this technology, including Slide-seqV2, have achieved spatial transcriptomic data collection at a near-single cell resolution. To-date, a repertoire of computational tools has been developed to discern cell type classes given the transcriptomic profiles of tissue coordinates. Upon applying these tools, we can explore the spatial patterns of distinct cell types and characterize how genes are spatially expressed within different cell type contexts. The kidney is one organ whose function relies upon spatially defined structures consisting of distinct cellular makeup. Thus, the application of Slide-seqV2 to kidney tissue has enabled us to elucidate spatially characteristic cellular and genetic profiles at a scale that remains largely unexplored. Here, we review spatial transcriptomic technologies, as well as computational approaches for cell type mapping and spatial cell type and transcriptomic characterizations. We take kidney tissue as an example to demonstrate how the technologies are applied, while considering the nuances of this architecturally complex tissue.