bluuebunny/crossref_metadata_2025 huggingface dataset:
Subtidal secondary circulation induced by eddy viscosity-velocity shear covariance in a predominantly well-mixed tidal inlet
Authors: Chen Wei , Jacob Benjamin , Valle-Levinson Arnoldo , Stanev Emil , Staneva Joanna , Badewien Thomas H.
Published: April 2023

The secondary circulation in a predominantly well-mixed estuarine tidal inlet is examined with three-dimensional numerical simulations of the currents and density field in the German Bight. Simulations analyze two complete neap and spring tidal cycles, inspired by cross-section measurements in the tidal inlet, with a focus on subtidal time scales. The study scrutinizes the lateral momentum balance and quantifies the individual forces that drive the residual flow on the cross-section. Forces (per unit mass) from the covariance between eddy viscosity and tidal vertical shear (ESCO) play a role in the lateral momentum budget. During neap tide, the ESCO-driven flow is weak. Accelerations driven by advection dominate the subtidal secondary circulation, which shows an anti-clockwise rotation. During spring tide, the ESCO acceleration, together with the baroclinicity and centrifugal acceleration, drives a clockwise circulation (looking seaward). This structure counteracts the advection-induced flow, leading to the reversal of the secondary circulation. The decomposition of the lateral ESCO term contributors reveals that the difference in ESCO between neap and spring tides is attributed to the change in the vertical structure of lateral tidal currents, which are maximum near the bottom in spring tide. The findings highlight the role of the tidally varying vertical shears in the ESCO mechanism.
Longitudinal and lateral circulation and tidal impacts in salt-plug estuaries
Authors: Hosseini Seyed Taleb , Stanev Emil , Pein Johannes , Valle-Levinson Arnoldo , Schrum Corinna
Published: April 2023

This study presents a comparison of forcings between density gradient and tides in idealized funnel-shaped salt-plug estuaries. Three-dimensional numerical model results also examine longitudinal and lateral circulations. In salt-plug estuaries, a positive longitudinal estuarine circulation is observed landward of a salinity maximum zone or salt plug. Seaward of the salt plug, the estuary shows an inverse circulation cell. The longitudinal flows show a fortnightly variability inside the salt plug. Also, the salt plug is saltier in spring tides than in neap tidal cycles mainly owing to higher landward salt transport by tidal advection during the spring tides. The lateral circulation and divergence dv/dy have the influence of Coriolis acceleration. In the absence of Earth’s rotation, the tidally averaged lateral circulations have nearly the same directions within the positive and inverse cells. Directions of lateral flow reverse in the salt-plug area. Inside this area, the lateral circulation also shows clear neap–spring variability, including downwelling cells during spring tides and upwelling in neap tides. The salinity maximum zone exhibits a vertically homogeneous condition particularly in meso-tidal salt-plug estuaries. Finally, this study introduces the threshold of “log(tidal Froude number)=3” (tidal forcing 3 orders of magnitude ≥ density gradients) for salt-plug estuaries as the condition under which the tidal forcing can overcome the density gradient, and consequently salinity inside the salt plug zone is reinforced by tides with a landward movement. This robust salinity maximum zone is also identified by a high Ekman number (log(Ekman number)>0.25).
Synoptic-to-intraseasonal atmospheric modulation of phytoplankton biomass in the inner sea of Chiloé, Northwest Patagonia (42.5°-43.5°S, 72.5°-74°W), Chile
Authors: Jacques-Coper Martín , Segura Christian , de la Torre María Belén , Valdebenito Muñoz Pedro , Vásquez Sebastián I. , Narváez Diego A.
Published: April 2023

The Inner Sea of Chiloé (ISC) in northwestern Patagonia has experienced large harmful algal blooms in the past decade, impacting human health and affecting the large aquaculture industry of the region. Thus, the investigation of factors favouring regional phytoplankton growth are of particular interest. Analysing the synoptic-to-intraseasonal variability, we explore changes in phytoplankton biomass in southern ISC (S-ISC, 42.5°-43.5°S, 72.5°-74°W) and their concurrent mesoscale and large-scale meteorological and oceanographic conditions. We use high-resolution satellite normalized fluorescence line height (nFLH) and chlorophyll-a (CHL-A) from the MODIS-Aqua sensor as proxies for phytoplankton biomass, besides oceanic and atmospheric variables derived from various remote-sensing sources and atmospheric fields from the ERA5 reanalysis. Specifically, we focus on high phytoplankton biomass events HBEs, which are defined as those cases when intraseasonal nFLH anomaly (nFLH’) exceeds the 95th percentile threshold. Each event was characterised by its first date of occurrence (called day 0). We detected 16 HBE between 2003 and 2019 in S-ISC. HBEs tend to occur under the influence of a mid-latitude migratory anticyclone that induce persistent cloudless conditions preceding day 0, leading to enhanced photosynthetically active radiation (PAR) starting around day -8, and positive sea surface temperature (SST) anomalies between days -4 and +4. We hypothesise that HBEs are mainly modulated by i) mixing and advection that could contribute to a greater availability of nutrients in the upper sea layers before the onset of the anticyclonic anomalies; and ii) increased thermal stratification related to positive PAR and SST anomalies that would promote phytoplankton growth during the anticyclonic regime. Furthermore, we show that the Madden-Julian Oscillation modulates the frequency of nFLH’ and thus of HBEs, a result that suggests an enhanced predictability of these cases.
Single cell analysis of the localization of the hematopoietic stem cells within the bone marrow architecture identifies niche-specific proliferation dynamics
Authors: Mazzarini Maria , Arciprete Francesca , Picconi Orietta , Valeri Mauro , Verachi Paola , Martelli Fabrizio , Migliaccio Anna Rita , Falchi Mario , Zingariello Maria
Published: April 2023

Introduction

Hematopoietic stem cells (HSC) reside in the bone marrow (BM) in specialized niches which provide support for their self-replication and differentiation into the blood cells. Recently, numerous studies using sophisticated molecular and microscopic technology have provided snap-shots information on the identity of the BM niches in mice. In adults, HSC are localized around arterioles and sinusoids/venules whereas in juvenile mice they are in close to the osteoblasts. However, although it is well recognized that in mice the nature of the hematopoietic niche change with age or after exposure to inflammatory insults, much work remains to be done to identify changes occurring under these conditions. The dynamic changes occurring in niche/HSC interactions as HSC enter into cycle are also poorly defined.

Methods

We exploit mice harboring the hCD34tTA/Tet-O-H2BGFP transgene to establish the feasibility to assess interactions of the HSC with their niche as they cycle. In this model, H2BGFP expression is driven by the TET trans-activator under the control of the human CD34 promoter which in mice is active only in the HSC. Since Doxycycline inhibits TET, HSC exposed to this drug no longer express H2BGFP and loose half of their label every division allowing establishing the dynamics of their first 1-3 divisions. To this aim, we first validated user-friendly confocal microscopy methods to determine HSC divisions by hemi-decrement changes in levels of GFP expression. We then tracked the interaction occurring in old mice between the HSC and their niche during the first HSC divisions.

Results

We determined that in old mice, most of the HSC are located around vessels, both arterioles which sustain quiescence and self-replication, and venules/sinusoids, which sustain differentiation. After just 1 week of exposure to Doxycycline, great numbers of the HSC around the venules lost most of their GFP label, indicating that they had cycled. By contrast, the few HSC surrounding the arterioles retained maximal levels of GFP expression, indicating that they are either dormant or cycle at very low rates.

Conclusion

These results reveal that in old mice, HSC cycle very dynamically and are biased toward interactions with the niche that instructs them to differentiate.
Novel diagnostic techniques in interstitial lung disease
Authors: Glenn Laura M. , Troy Lauren K. , Corte Tamera J.
Published: April 2023

Research into novel diagnostic techniques and targeted therapeutics in interstitial lung disease (ILD) is moving the field toward increased precision and improved patient outcomes. An array of molecular techniques, machine learning approaches and other innovative methods including electronic nose technology and endobronchial optical coherence tomography are promising tools with potential to increase diagnostic accuracy. This review provides a comprehensive overview of the current evidence regarding evolving diagnostic methods in ILD and to consider their future role in routine clinical care.
The IFN-stimulated gene IFI27 counteracts innate immune responses after viral infections by interfering with RIG-I signaling
Authors: Villamayor Laura , López-García Darío , Rivero Vanessa , Martínez-Sobrido Luis , Nogales Aitor , DeDiego Marta L.
Published: April 2023

The recognition of viral nucleic acids by host pattern recognition receptors (PRRs) is critical for initiating innate immune responses against viral infections. These innate immune responses are mediated by the induction of interferons (IFNs), IFN-stimulated genes (ISGs) and pro-inflammatory cytokines. However, regulatory mechanisms are critical to avoid excessive or long-lasting innate immune responses that may cause detrimental hyperinflammation. Here, we identified a novel regulatory function of the ISG, IFN alpha inducible protein 27 (IFI27) in counteracting the innate immune responses triggered by cytoplasmic RNA recognition and binding. Our model systems included three unrelated viral infections caused by Influenza A virus (IAV), Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), and Sendai virus (SeV), and transfection with an analog of double-stranded (ds) RNA. Furthermore, we found that IFI27 has a positive effect on IAV and SARS-CoV-2 replication, most likely due to its ability to counteract host-induced antiviral responses, including in vivo. We also show that IFI27 interacts with nucleic acids and PRR retinoic acid-inducible gene I (RIG-I), being the interaction of IFI27 with RIG-I most likely mediated through RNA binding. Interestingly, our results indicate that interaction of IFI27 with RIG-I impairs RIG-I activation, providing a molecular mechanism for the effect of IFI27 on modulating innate immune responses. Our study identifies a molecular mechanism that may explain the effect of IFI27 in counterbalancing innate immune responses to RNA viral infections and preventing excessive innate immune responses. Therefore, this study will have important implications in drug design to control viral infections and viral-induced pathology.
Acyl-coenzyme A binding protein MoAcb1 regulates conidiation and pathogenicity in Magnaporthe oryzae
Authors: Cao Na , Zhu Xue-Ming , Bao Jian-Dong , Zhu Li-Hong , Liu Hao , Lin Fu-Cheng , Li Lin
Published: April 2023

Magnaporthe oryzae is a filamentous fungus that causes rice blast. Rice blast seriously threatens the safety of food production. The normal synthesis and metabolism of fatty acids are extremely important for eukaryotes, and acyl-CoA is involved in fatty acid metabolism. Acyl-CoA binding (ACB) proteins specifically bind both medium-chain and long-chain acyl-CoA esters. However, the role of the Acb protein in plant-pathogenic fungi has not yet been investigated. Here, we identified MoAcb1, a homolog of the Acb protein in Saccharomyces cerevisiae. Disruption of MoACB1 causes delayed hyphal growth, significant reduction in conidial production and delayed appressorium development, glycogen availability, and reduced pathogenicity. Using immunoblotting and chemical drug sensitivity analysis, MoAcb1 was found to be involved in endoplasmic reticulum autophagy (ER-phagy). In conclusion, our results suggested that MoAcb1 is involved in conidia germination, appressorium development, pathogenicity and autophagy processes in M. oryzae.
Achieving robust and highly efficient nitrogen removal in a mainstream anammox reactor by introducing low concentrations of readily biodegradable organics
Authors: Yang Yandong , Long Yanan , Xu Jiarui , Liu Shichong , Liu Lei , Liu Changqing , Tian Yong
Published: April 2023

In this study, an anammox reactor was operated to treat low-strength (NH4+ + NO2−, 25–35  mg/L) wastewater without (phase I) or with (phase II) readily biodegradable chemical oxygen demand (rbCOD). In phase I, although efficient nitrogen removal was achieved at the beginning, nitrate accumulated in the effluent after long-term operation (75  days), resulting in a decrease in the nitrogen removal efficiency to 30%. Microbial analysis revealed that the abundance of anammox bacteria decreased from 2.15 to 1.78%, whereas that of nitrite-oxidizing bacteria (NOB) increased from 0.14 to 0.56%. In phase II, rbCOD, in terms of acetate, was introduced into the reactor with a carbon/nitrogen ratio of 0.9. The nitrate concentration in the effluent decreased within 2 days. Advanced nitrogen removal was achieved in the following operation, with an average effluent total nitrogen of 3.4 mg/L. Despite the introduction of rbCOD, anammox pathway still dominated to the nitrogen loss. High-throughput sequencing indicated that high anammox abundance (2.48%) further supports its dominant position. The improvement in nitrogen removal was attributed to the enhanced suppression of NOB activity, simultaneous nitrate polishing through partial denitrification and anammox, and promotion of sludge granulation. Overall, the introduction of low concentrations of rbCOD is a feasible strategy for achieving robust and efficient nitrogen removal in mainstream anammox reactors.
Identification and validation of biomarkers based on cellular senescence in mild cognitive impairment
Authors: Ma Songmei , Xia Tong , Wang Xinyi , Wang Haiyun
Published: April 2023

Background

Mild cognitive impairment (MCI), a syndrome defined as decline of cognitive function greater than expected for an individual’s age and education level, occurs in up to 22.7% of elderly patients in United States, causing the heavy psychological and economic burdens to families and society. Cellular senescence (CS) is a stress response that accompanies permanent cell-cycle arrest, which has been reported to be a fundamental pathological mechanism of many age-related diseases. This study aims to explore biomarkers and potential therapeutic targets in MCI based on CS.

Methods

The mRNA expression profiles of peripheral blood samples from patients in MCI and non-MCI group were download from gene expression omnibus (GEO) database (GSE63060 for training and GSE18309 for external validation), CS-related genes were obtained from CellAge database. Weighted gene co-expression network analysis (WGCNA) was conducted to discover the key relationships behind the co-expression modules. The differentially expressed CS-related genes would be obtained through overlapping among the above datasets. Then, pathway and GO enrichment analyses were performed to further elucidate the mechanism of MCI. The protein–protein interaction network was used to extract hub genes and the logistic regression was performed to distinguish the MCI patients from controls. The hub gene-drug network, hub gene-miRNA network as well as transcription factor-gene regulatory network were used to analyze potential therapeutic targets for MCI.

Results

Eight CS-related genes were identified as key gene signatures in MCI group, which were mainly enriched in the regulation of response to DNA damage stimulus, Sin3 complex and transcription corepressor activity. The receiver operating characteristic curves of logistic regression diagnostic model were constructed and presented great diagnostic value in both training and validation set.

Conclusion

Eight CS-related hub genes – SMARCA4, GAPDH, SMARCB1, RUNX1, SRC, TRIM28, TXN, and PRPF19 – serve as candidate biomarkers for MCI and display the excellent diagnostic value. Furthermore, we also provide a theoretical basis for targeted therapy against MCI through the above hub genes.
The comorbidity of depression and neurocognitive disorder in persons with HIV infection: call for investigation and treatment
Authors: Goodkin Karl , Evering Teresa H. , Anderson Albert M. , Ragin Ann , Monaco Cynthia L. , Gavegnano Christina , Avery Ryan J. , Rourke Sean B. , Cysique Lucette A. , Brew Bruce J.
Published: April 2023

Depression and neurocognitive disorder continue to be the major neuropsychiatric disorders affecting persons with HIV (PWH). The prevalence of major depressive disorder is two to fourfold higher among PWH than the general population (∼6.7%). Prevalence estimates of neurocognitive disorder among PWH range from 25 to over 47% – depending upon the definition used (which is currently evolving), the size of the test battery employed, and the demographic and HIV disease characteristics of the participants included, such as age range and sex distribution. Both major depressive disorder and neurocognitive disorder also result in substantial morbidity and premature mortality. However, though anticipated to be relatively common, the comorbidity of these two disorders in PWH has not been formally studied. This is partly due to the clinical overlap of the neurocognitive symptoms of these two disorders. Both also share neurobehavioral aspects — particularly apathy — as well as an increased risk for non-adherence to antiretroviral therapy. Shared pathophysiological mechanisms potentially explain these intersecting phenotypes, including neuroinflammatory, vascular, and microbiomic, as well as neuroendocrine/neurotransmitter dynamic mechanisms. Treatment of either disorder affects the other with respect to symptom reduction as well as medication toxicity. We present a unified model for the comorbidity based upon deficits in dopaminergic transmission that occur in both major depressive disorder and HIV-associated neurocognitive disorder. Specific treatments for the comorbidity that decrease neuroinflammation and/or restore associated deficits in dopaminergic transmission may be indicated and merit study.
A neural tract tracing study on synaptic connections for cortical glutamatergic terminals and cervical spinal calretinin neurons in rats
Authors: Huang Ziyun , Sun Liping , Zheng Xuefeng , Zhang Ye , Zhu Yaxi , Chen Tao , Chen Zhi , Ja Linju , OuYang Lisi , Zhu Yaofeng , Chen Si , Lei Wanlong
Published: April 2023

The cerebral cortex innervates motor neurons in the anterior horn of the spinal cord by regulating of interneurons. At present, nerve tracing, immunohistochemistry, and immunoelectron microscopy are used to explore and confirm the characteristics of synaptic connections between the corticospinal tract (CST) and cervical spinal calretinin (Cr) interneurons. Our morphological results revealed that (1) biotinylated dextran amine labeled (BDA+) fibers from the cerebral cortex primarily presented a contralateral spinal distribution, with a denser distribution in the ventral horn (VH) than in the dorsal horn (DH). An electron microscope (EM) showed that BDA+ terminals formed asymmetric synapses with spinal neurons, and their mean labeling rate was not different between the DH and VH. (2) Cr-immunoreactive (Cr+) neurons were unevenly distributed throughout the spinal gray matter, and were denser and larger in the VH than in the DH. At the single labeling electron microscope (EM) level, the labeling rate of Cr+ dendrites was higher in the VH than in the DH, in which Cr+ dendrites mainly received asymmetric synaptic inputs, and between the VH and DH. (3) Immunofluorescence triple labeling showed obvious apposition points among BDA+ terminals, synaptophysin and Cr+ dendrites, with a higher density in the VH than in the DH. (4) Double labeling in EM, BDA+ terminals and Cr+ dendrites presented the same pattern, BDA+ terminals formed asymmetric synapses either with Cr+ dendrites or Cr negative (Cr-) dendrites, and Cr+ dendrites received either BDA+ terminals or BDA- synaptic inputs. The average percentage of BDA+ terminals targeting Cr+ dendrites was higher in the VH than in the DH, but the percentage of BDA+ terminals targeting Cr- dendrites was prominently higher than that targeting Cr+ dendrites. There was no difference in BDA+ terminal size. The percentage rate for Cr+ dendrites receiving BDA+ terminal inputs was lower than that receiving BDA- terminal inputs, and the BDA+ terminal size was larger than the BDA- terminal size received by Cr+ dendrites. The present morphological results suggested that spinal Cr+ interneurons are involved in the regulatory process of the cortico-spinal pathway.
Effects of strength training in fibromyalgia on balance, neuromuscular performance, and symptomatic analysis: a 12-week study protocol
Authors: Albuquerque Maria Luiza L. , Monteiro Diogo , Alvarez Marcos C. , Vilarino Guilherme Torres , Andrade Alexandro , Neiva Henrique P.
Published: April 2023

Fibromyalgia affects skeletal muscles presenting with muscle stiffness, pain, and fatigue. The exercise practice is wellstabilized and suggested for the reduction of symptoms. However, there are some gaps in the literature related to balance and neuromuscular performance in a strength training protocol. The aim of this study is to structure a protocol to verify the effects of strength training applied over a short period, on balance, neuromuscular performance, and fibromyalgia symptoms. Additionally, we intend to analyze the effects of a short period of cessation of training. Participants will be recruited through flyers, internet advertisements, clinical referrals, health professionals, and email outreach. Volunteers will be randomly assigned to the control group or experimental group. Before the training period, symptoms (Fibromyalgia Impact Questionnaire, Visual Analog Scale), balance (force plate), and neuromuscular performance (medicine ball throw and vertical jump) will be assessed. Participants in the experimental group will perform strength training twice a week (50 min each), on alternate days, for 8 weeks (16 sessions). Then, 4 weeks of detraining will be completed. This training program will be carried out online, using real-time videos, and the participants will be divided into two groups with different schedules. The Borg scale will be used to monitor perceived effort in each session. There is a gap in the literature about exercise prescriptions for fibromyalgia. The supervised online intervention enables a wide range of participation. The strength exercises used (without the use of external materials and/or machines) and load (few repetitions per set) represent a novelty to training programming. Moreover, this training program respects the limitations and individuality of the volunteers, providing exercise adaptations. With positive results, the present protocol could be an easy-to-apply guideline with clear instructions on the details related to exercise prescription. Also, ensure the effectiveness of a low-cost and feasible treatment, especially for fibromyalgia patients.

Clinical trial registration

https://clinicaltrials.gov/, identifier: NCT05646641.
Low-dose vs. standard-dose intravenous alteplase for acute ischemic stroke with unknown time of onset
Authors: Wang Zekun , Ji Kangxiang , Fang Qi
Published: April 2023

Background

Standard-dose intravenous alteplase for acute ischemic stroke (AIS) in the unknown or extended time window beyond 4.5 h after symptom onset is both effective and safe for certain patients who were selected based on multimodal neuroimaging. However, uncertainty exists regarding the potential benefit of using low-dose alteplase among the Asian population outside the 4.5-h time window.

Methods

Consecutive AIS patients who received intravenous alteplase between 4.5 and 9 h after symptom onset or with an unknown time of onset guided by multimodal computed tomography (CT) imaging were identified from our prospectively maintained database. The primary outcome was excellent functional recovery, defined as having a modified Rankin scale (mRS) score of 0–1 at 90 days. Secondary outcomes included functional independence (an mRS score of 0–2 at 90 days), early major neurologic improvement (ENI), early neurologic deterioration (END), any intracranial hemorrhage (ICH), symptomatic ICH (sICH), and 90-day mortality. Propensity score matching (PSM) and multivariable logistic regression models were used to adjust for confounding factors and compare the clinical outcomes between the low- and standard-dose groups.

Results

From June 2019 to June 2022, a total of 206 patients were included in the final analysis, of which 143 were treated with low-dose alteplase and 63 were treated with standard-dose alteplase. After accounting for confounding factors, we observed that there were no statistically significant differences between the standard- and low-dose groups with respect to excellent functional recovery [adjusted odds ratio = 1.22 (aOR), 95% confidence interval (CI): 0.62–2.39; adjusted rate difference (aRD) = 4.6%, and 95% CI: −11.2 to 20.3%]. Patients of both groups had similar rates of functional independence, ENI, END, any ICH, sICH, and 90-day mortality. In the subgroup analysis, patients aged ≥70 years were more likely to achieve excellent functional recovery when receiving standard-dose rather than low-dose alteplase.

Conclusion

The effectiveness of low-dose alteplase might be comparable to that of standard-dose alteplase in AIS patients aged <70 years with favorable perfusion-imaging profiles in the unknown or extended time window but not in those aged ≥70 years. Furthermore, low-dose alteplase did not significantly reduce the risk of sICH compared to standard-dose alteplase.
Translocator protein PET imaging in temporal lobe epilepsy: A reliable test-retest study using asymmetry index
Authors: Mahmud Mohammad , Wade Charles , Jawad Sarah , Hadi Zaeem , Otoul Christian , Kaminski Rafal M. , Muglia Pierandrea , Kadiu Irena , Rabiner Eugenii , Maguire Paul , Owen David R. , Johnson Michael R.
Published: April 2023

Objective

Translocator protein (TSPO) targeting positron emission tomography (PET) imaging radioligands have potential utility in epilepsy to assess the efficacy of novel therapeutics for targeting neuroinflammation. However, previous studies in healthy volunteers have indicated limited test-retest reliability of TSPO ligands. Here, we examine test-retest measures using TSPO PET imaging in subjects with epilepsy and healthy controls, to explore whether this biomarker can be used as an endpoint in clinical trials for epilepsy.

Methods

Five subjects with epilepsy and confirmed mesial temporal lobe sclerosis (mean age 36 years, 3 men) were scanned twice—on average 8 weeks apart—using a second generation TSPO targeting radioligand, [11C]PBR28. We evaluated the test-retest reliability of the volume of distribution and derived hemispheric asymmetry index of [11C]PBR28 binding in these subjects and compared the results with 8 (mean age 45, 6 men) previously studied healthy volunteers.

Results

The mean (± SD) of the volume of distribution (VT), of all subjects, in patients living with epilepsy for both test and retest scans on all regions of interest (ROI) is 4.49 ± 1.54 vs. 5.89 ± 1.23 in healthy volunteers. The bias between test and retest in an asymmetry index as a percentage was small (−1.5%), and reliability is demonstrated here with Bland-Altman Plots (test mean 1.062, retest mean 2.56). In subjects with epilepsy, VT of [11C]PBR28 is higher in the (ipsilateral) hippocampal region where sclerosis is present than in the contralateral region.

Conclusion

When using TSPO PET in patients with epilepsy with hippocampal sclerosis (HS), an inter-hemispheric asymmetry index in the hippocampus is a measure with good test-retest reliability. We provide estimates of test-retest variability that may be useful for estimating power where group change in VT represents the clinical outcome.
Expression changes of ER, PR, HER2, and Ki-67 in primary and metastatic breast cancer and its clinical significance
Authors: Hu Xueyang , Chen Wenjun , Li Fanfan , Ren Pengfei , Wu Hongyang , Zhang Congjun , Gu Kangsheng
Published: April 2023

Objective

To explore the altered expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and cell proliferation index (Ki-67) in primary and metastatic breast cancer lesions and the correlation between the primary tumor size, lymph node metastasis, Tumor Node Metastasis (TNM) stage, molecular typing, and disease-free survival (DFS) and their clinical significance.

Methods

A retrospective analysis was conducted on the clinical data of 130 patients with metastatic breast cancer biopsy admitted to the Cancer Center of the Second Affiliated Hospital of Anhui Medical University in Hefei, China, from 2014–2019. The altered expression of ER, PR, HER2, and Ki-67 in primary and metastatic lesions of breast cancer was analyzed with respect to the site of metastasis, size of the primary tumor, lymph node metastasis, disease progression, and prognosis.

Results

The inconsistent expression rates of ER, PR, HER2, and Ki-67 in primary and metastatic lesions were 47.69%, 51.54%, 28.10%, and 29.23%, respectively. The size of the primary lesion was not, but that accompanied by lymph node metastasis was related to the altered receptor expression. Patients with positive ER and PR expression in both primary and metastatic lesions had the longest DFS, while those with negative expression had the shortest DFS. Also, changes in HER2 expression in primary and metastatic lesions were not associated with DFS. Patients with low expression of Ki-67 in both primary and metastatic lesions had the longest DFS, while patients with high expression had the shortest DFS.

Conclusion

Heterogeneity was detected in the expression levels of ER, PR, HER2, and Ki-67 in the primary and metastatic breast cancer lesions, which has a guiding significance for the treatment and prognosis of patients.
Comprehensive clinical evaluation of deep learning-based auto-segmentation for radiotherapy in patients with cervical cancer
Authors: Chung Seung Yeun , Chang Jee Suk , Kim Yong Bae
Published: April 2023

Background and purpose

Deep learning-based models have been actively investigated for various aspects of radiotherapy. However, for cervical cancer, only a few studies dealing with the auto-segmentation of organs-at-risk (OARs) and clinical target volumes (CTVs) exist. This study aimed to train a deep learning-based auto-segmentation model for OAR/CTVs for patients with cervical cancer undergoing radiotherapy and to evaluate the model’s feasibility and efficacy with not only geometric indices but also comprehensive clinical evaluation.

Materials and methods

A total of 180 abdominopelvic computed tomography images were included (training set, 165; validation set, 15). Geometric indices such as the Dice similarity coefficient (DSC) and the 95% Hausdorff distance (HD) were analyzed. A Turing test was performed and physicians from other institutions were asked to delineate contours with and without using auto-segmented contours to assess inter-physician heterogeneity and contouring time.

Results

The correlation between the manual and auto-segmented contours was acceptable for the anorectum, bladder, spinal cord, cauda equina, right and left femoral heads, bowel bag, uterocervix, liver, and left and right kidneys (DSC greater than 0.80). The stomach and duodenum showed DSCs of 0.67 and 0.73, respectively. CTVs showed DSCs between 0.75 and 0.80. Turing test results were favorable for most OARs and CTVs. No auto-segmented contours had large, obvious errors. The median overall satisfaction score of the participating physicians was 7 out of 10. Auto-segmentation reduced heterogeneity and shortened contouring time by 30 min among radiation oncologists from different institutions. Most participants favored the auto-contouring system.

Conclusion

The proposed deep learning-based auto-segmentation model may be an efficient tool for patients with cervical cancer undergoing radiotherapy. Although the current model may not completely replace humans, it can serve as a useful and efficient tool in real-world clinics.
Differential regional importance mapping for thyroid nodule malignancy prediction with potential to improve needle aspiration biopsy sampling reliability
Authors: Wang Liping , Wang Yuan , Lu Wenliang , Xu Dong , Yao Jincao , Wang Lijing , Xu Lei
Published: April 2023

Objective

Existing guidelines for ultrasound-guided fine-needle aspiration biopsy lack specifications on sampling sites, but the number of biopsies improves diagnostic reliability. We propose the use of class activation maps (CAMs) and our modified malignancy-specific heat maps that locate important deep representations of thyroid nodules for class predictions.

Methods

We applied adversarial noise perturbations to the segmented concentric “hot” nodular regions of equal sizes to differentiate regional importance for the malignancy diagnostic performances of an accurate ultrasound-based artificial intelligence computer-aided diagnosis (AI-CADx) system using 2,602 retrospectively collected thyroid nodules with known histopathological diagnosis.

Results

The AI system demonstrated high diagnostic performance with an area under the curve (AUC) value of 0.9302 and good nodule identification capability with a median dice coefficient >0.9 when compared to radiologists’ segmentations. Experiments confirmed that the CAM-based heat maps reflect the differentiable importance of different nodular regions for an AI-CADx system to make its predictions. No less importantly, the hot regions in malignancy heat maps of ultrasound images in comparison with the inactivated regions of the same 100 malignant nodules randomly selected from the dataset had higher summed frequency-weighted feature scores of 6.04 versus 4.96 rated by radiologists with more than 15 years of ultrasound examination experience according to widely used ultrasound-based risk stratification American College of Radiology (ACR) Thyroid Imaging Reporting and Data System (TI-RADS) in terms of nodule composition, echogenicity, and echogenic foci, excluding shape and margin attributes, which could only be evaluated on the whole rather than on the sub-nodular component levels. In addition, we show examples demonstrating good spatial correspondence of highlighted regions of malignancy heat map to malignant tumor cell-rich regions in hematoxylin and eosin-stained histopathological images.

Conclusion

Our proposed CAM-based ultrasonographic malignancy heat map provides quantitative visualization of malignancy heterogeneity within a tumor, and it is of clinical interest to investigate in the future its usefulness to improve fine-needle aspiration biopsy (FNAB) sampling reliability by targeting potentially more suspicious sub-nodular regions.
The efficacy of dermoscopy in defining the surgical margins of cutaneous squamous cell carcinoma: a retrospective study
Authors: Liu Zhenru , Huang Shudai , Li Fang , Wang Xiaoqing , Liu Mengxi , Wong Hoi Shiwn , Jiang Jiayi , Zhou Yuan , Wang Daguang
Published: April 2023

Objective

To investigate the diagnostic value of dermoscopy in defining the tumor margin of cutaneous squamous cell carcinoma (cSCC) for the appropriate surgical margin.

Methods

A total of 90 cSCC patients were enrolled in the study. All patients were recruited into two groups: those who preserved intact macroscopic features of neoplasms without or after incisional biopsy and those with uncertain residual tumors after excisional biopsy. A dermoscopy-defined surgical margin of 8mm outward was used according to the tumor boundaries observed with the naked eye and dermoscopy. All excised tumor specimens were divided into serial sections according to the four “3, 6, 9, 12” directions at every 4-mm interval from the dermoscopy-detected tumor margin. Pathological examination was performed at 0 mm, 4 mm, and 8 mm margins to confirm tumor remnants.

Results

Retrospective analysis of dermatoscopic results showed inconsistent clinical and dermatoscopic borders in 43 of 90 cases (47.8%). The ability of dermoscopy to detect tumor borders showed no statistical difference between the two groups (p > 0.05). In the unbiopsy or incisional biopsy group, 66.6% of the tumors were resected with a 4-mm margin and 98.3% with an 8-mm margin, with significant differences (p = 0.047). For patients with inconspicuous clinical evidence of residual tumor after excisional biopsy, the tumor clearance rate was 53.3% at 0 mm, 93.3% at 4 mm, and 100.0% at 8 mm. Statistically significant differences were noted between 0 mm and 4 mm (p = 0.017), as well as between 0 mm and 8 mm (p = 0.043) but did not differ between 4 mm and 8 mm (p > 0.05).

Conclusions

Dermoscopy defined the tumor margin of cSCC better than visual inspection alone. Direct dermoscopic-guided surgery with at least 8-mm expansion was recommended for high-risk cSCC. Dermoscopy also assisted in identifying surgical margins at the healing biopsy site, making 8 mm still the recommended expansion range.
Recent advances of three-dimensional bioprinting technology in hepato-pancreato-biliary cancer models
Authors: Zhuang Xiaomei , Deng Gang , Wu Xiaoying , Xie Juping , Li Dong , Peng Songlin , Tang Di , Zhou Guoying
Published: April 2023

Hepato-pancreato-biliary (HPB) cancer is a serious category of cancer including tumors originating in the liver, pancreas, gallbladder and biliary ducts. It is limited by two-dimensional (2D) cell culture models for studying its complicated tumor microenvironment including diverse contents and dynamic nature. Recently developed three-dimensional (3D) bioprinting is a state-of-the-art technology for fabrication of biological constructs through layer-by-layer deposition of bioinks in a spatially defined manner, which is computer-aided and designed to generate viable 3D constructs. 3D bioprinting has the potential to more closely recapitulate the tumor microenvironment, dynamic and complex cell-cell and cell-matrix interactions compared to the current methods, which benefits from its precise definition of positioning of various cell types and perfusing network in a high-throughput manner. In this review, we introduce and compare multiple types of 3D bioprinting methodologies for HPB cancer and other digestive tumors. We discuss the progress and application of 3D bioprinting in HPB and gastrointestinal cancers, focusing on tumor model manufacturing. We also highlight the current challenges regarding clinical translation of 3D bioprinting and bioinks in the field of digestive tumor research. Finally, we suggest valuable perspectives for this advanced technology, including combination of 3D bioprinting with microfluidics and application of 3D bioprinting in the field of tumor immunology.
Postoperative circulating tumor DNA testing based on tumor naïve strategy after liver metastasis surgery in colorectal cancer patients
Authors: Jiang Huiqin , Huang Fei , Yang Yihui , Chen Xinning , Shen Minna , Zhang Chunyan , Pan Baishen , Wang Beili , Guo Wei
Published: April 2023

Objective

There is still a lack of highly sensitive methods for monitoring recurrence of colorectal cancer patients after liver metastasis surgery. The aim of this study was to evaluate the prognostic value of tumor-naive ctDNA detection after resection of colorectal liver metastases (CRLM).

Methods

Patients with resectable CRLM were prospectively enrolled. Based on the tumor-naive strategy, NGS panels containing 15 colorectal cancer hotspot mutated genes were used to detect ctDNA 3-6 weeks after surgery.

Results

A total of 67 patients were included in the study, and the positive rate of postoperative ctDNA was 77.6% (52/67). Patients with positive ctDNA had a significantly higher risk of recurrence after surgery (HR 3.596, 95% CI 1.479 to 8.744, P = 0.005), and a higher proportion relapsed within 3 months after surgery (46.7% vs 3.8%). The C-index of postoperative ctDNA in predicting recurrence was higher than that of CRS and postoperative CEA. The nomogram combining CRS and postoperative ctDNA can improve the accuracy of recurrence prediction.

Conclusion

Tumor-naive ctDNA detection can detect molecular residual lesions in patients with colorectal cancer after liver metastasis, and its prognostic value is superior to conventional clinical factors.
Precise diagnosis and targeted therapy of nodal T-follicular helper cell lymphoma (T-FHCL)
Authors: Du Jun , Jin Shikai , Zhang Minghui , Fu Xuehang , Yang Jingwen , Zhang Liwen , Chen Zhenwei , Huang Zoufang , Li Weisong , Hou Jian , Wang Ting
Published: April 2023

Nodal T-follicular helper cell lymphoma (T-FHCL) derived from T-follicular helper (Tfh) cell falls into a heterogeneous category of peripheral T-cell lymphoma (PTCL). Due to the limited number of therapeutic regimens and limited first-line efficacy, T-FHCL has a poor prognosis, and there is an urgent need for effective targeted therapies. With advancements in sequencing technologies, especially single-cell sequencing and next-generation sequencing, more specific genetic aberrations characteristic of T-FHCL can be discovered, allowing for precise molecular diagnosis and specific research on novel agents. Many biomarker-targeting agents, used either alone or in combination, have been tested, and they have generally enhanced the therapeutic outcomes of T-FHCL. Histone deacetylase inhibitors achieve significant clinical benefits in the treatment of T-FHCL, especially in combination therapy. Chimeric antigen receptor T-cell (CAR-T-cell) immunotherapies, hematopoietic stem cell transplantation, and other potential agents merit further study.
The emerging role of neutrophil extracellular traps in cancer: from lab to ward
Authors: Zhong Wentao , Wang Qianyu , Shen Xiaofei , Du Junfeng
Published: April 2023

Neutrophil extracellular traps (NETs) are web-like structures derived from neutrophils, which typically consist of DNA, released from the nucleus or mitochondria, and decorated with histones and granule proteins. They are well known as an important structure in innate immunity to eliminate pathogenic bacteria, similar to neutrophils. Initially, NETs are reported to take part in the progression of inflammatory diseases; now, they have also been implicated in the progression of sterile inflammation such as autoimmune disease, diabetes, and cancer. In this review, we will describe the recent studies which have investigated the role of NETs in the development of cancer, especially metastasis. We also prescribe the strategies for targeting NETs in the multiple cancer types, which suggest that NETs are a promising treatment for cancer patients.
Neonatologist-performed point-of-care abdominal ultrasound: What have we learned so far?
Authors: Priyadarshi Archana , Rogerson Sheryl , Cruzado Rommel , Crow Amanda , Hinder Murray , Popat Himanshu , Soundappan Soundappan S. V. , Badawi Nadia , Tracy Mark
Published: April 2023

This review describes the sonographic appearances of the neonatal bowel in Necrotising enterocolitis. It compares these findings to those seen in midgut-Volvulus, obstructive intestinal conditions such as milk-curd obstruction, and slow gut motility in preterm infants on continuous positive airway pressure (CPAP)-CPAP belly syndrome. Point-of-care bowel ultrasound is also helpful in ruling out severe and active intestinal conditions, reassuring clinicians when the diagnosis is unclear in a non-specific clinical presentation where NEC cannot be excluded. As NEC is a severe disease, it is often over-diagnosed, mainly due to a lack of reliable biomarkers and clinical presentation similar to sepsis in neonates. Thus, the assessment of the bowel in real-time would allow clinicians to determine the timing of re-initiation of feeds and would also be reassuring based on specific typical bowel characteristics visualised on the ultrasound.
The application of exosomes in the early diagnosis and treatment of osteoarthritis
Authors: Chen Anjing , Chen Yangmengfan , Rong Xiao , You Xuanhe , Wu Diwei , Zhou Xinran , Zeng Weinan , Zhou Zongke
Published: April 2023

With the increase in human lifespan and the aggravation of global aging, the incidence of osteoarthritis (OA) is increasing annually. To better manage and control the progression of OA, prompt diagnosis and treatment for early-stage OA are important. However, a sensitive diagnostic modality and therapy for early OA have not been well developed. The exosome is a class of extracellular vesicles containing bioactive substances, that can be delivered directly from original cells to neighboring cells to modulate cellular activities through intercellular communication. In recent years, exosomes have been considered important in the early diagnosis and treatment of OA. Synovial fluid exosome and its encapsulated substances, e.g., microRNA, lncRNA, and proteins, can not only distinguish OA stages but also prevent the progression of OA by directly targeting cartilage or indirectly modulating the immune microenvironment in the joints. In this mini-review, we include recent studies on the diagnostic and therapeutic modalities of exosomes and hope to provide a new direction for the early diagnosis and treatment of OA disease in the future.
The therapeutic value of treatment for multiple sclerosis: analysis of health technology assessments of three European countries
Authors: Gozzo Lucia , Romano Giovanni Luca , Brancati Serena , Longo Laura , Vitale Daniela Cristina , Drago Filippo
Published: April 2023

In accordance with European regulation, medicines containing a new active substance to treat neurodegenerative diseases as well as autoimmune and other immune dysfunctions must be approved by the European Medicines Agency (EMA) through the centralized procedure before they can be marketed. However, after EMA approval, each country is responsible for national market access, following the assessment performed by health technology assessment (HTA) bodies with regard to the therapeutic value. This study aims to provide a comparative analysis of HTA recommendations issued by three EU countries (France, Germany, and Italy) for new drugs for multiple sclerosis (MS) following EMA approval. In the reference period, we identified 11 medicines authorized in Europe for MS, including relapsing forms of MS (RMS; n = 4), relapsing–remitting MS (RRMS; n = 6), secondary progressive MS (SPMS; n = 1), and the primary progressive form (PPMS; n = 1). We found no agreement on the therapeutic value (in particular, the “added value” compared to the standard of care) of the selected drugs. Most evaluations resulted in the lowest score (“additional benefit not proven/no clinical improvement”), underlining the need for new molecules with better efficacy and safety profiles for MS, especially for some forms and clinical settings.