bluuebunny/crossref_metadata_2025 huggingface dataset:
Bidirectional Association Between Psoriasis and Nonalcoholic Fatty Liver Disease: Real-World Evidence From Two Longitudinal Cohort Studies
Authors: Gau Shuo-Yan , Huang Kuang-Hua , Lee Chiu Hsiang , Kuan Yu-Hsiang , Tsai Tung-Han , Lee Chien-Ying
Published: February 2022

Background

Association between nonalcoholic fatty liver disease (NAFLD) and future psoriasis has not yet been confirmed, although the two diseases partially share a common pathogenesis pathway. Studies have revealed an association between psoriasis and subsequent NAFLD; however, these studies were limited to small sample sizes and a cross-sectional study design. Hence, the main objective of this population-based longitudinal cohort study was to evaluate the bidirectional association between psoriasis and NAFLD.

Methods

Data were retrieved from Taiwan’s National Health Insurance Research Database. Patients with new-onset NAFLD and psoriasis were respectively enrolled in two cohorts. For each comparison cohort, propensity-score-matched controls with no record of NAFLD or psoriasis were selected. An adjusted hazard ratio (aHR) was applied to evaluate subsequent risks.

Results

The risk of patients with new-onset NAFLD developing psoriasis was statistically significant, with an HR of 1.07 (95% CI, 1.01–1.14). For younger patients with NAFLD, the risk of developing psoriasis was 1.3-fold higher. The risk of patients with new-onset psoriasis developing NAFLD in the future was 1.28-fold higher than that of patients without psoriasis (95% CI, 1.21–1.35), and patients in younger psoriasis subgroups below the age of 40 years were at a higher risk than those in older subgroups, with an aHR of 1.55 (95% CI, 1.40–1.71).

Conclusion

Evidence supports a bidirectional association between NAFLD and psoriasis, especially in patients below the age of 40 years. The correlation between the two diseases and the subsequent risk of disease development should be considered when caring for patients.
A Critical Function for the Transcription Factors GLI1 and GLI2 in the Proliferation and Survival of Human Mast Cells
Authors: Falduto Guido Hernan , Pfeiffer Annika , Zhang Qunshu , Yin Yuzhi , Metcalfe Dean Darrel , Olivera Ana
Published: February 2022

Mast cell hyperactivity and accumulation in tissues are associated with allergy and other mast cell-related disorders. However, the molecular pathways regulating mast cell survival in homeostasis and disease are not completely understood. As glioma-associated oncogene (GLI) proteins are involved in both tissue homeostasis and in the hematopoietic system by regulating cell fate decisions, we sought to investigate the role for GLI proteins in the control of proliferation and survival of human mast cells. GLI1 transcripts were present in primary human mast cells and mast cell lines harboring or not activating mutations in the tyrosine kinase receptor KIT (HMC-1.1 and HMC-1.2, and LAD2 cells, respectively), while GLI2 transcripts were only present in HMC-1.1 and HMC-1.2 cells, suggesting a role for oncogenic KIT signaling in the regulation of GLI2. Reduction in GLI activity by small molecule inhibitors, or by shRNA-mediated knockdown of GLI1 or GLI2, led to increases in apoptotic cell death in both cultured human and murine mast cells, and reduced the number of peritoneal mast cells in mice. Although GLI proteins are typically activated via the hedgehog pathway, steady-state activation of GLI in mast cells occurred primarily via non-canonical pathways. Apoptosis induced by GLI silencing was associated with a downregulation in the expression of KIT and of genes that influence p53 stability and function including USP48, which promotes p53 degradation; and iASPP, which inhibits p53-induced transcription, thus leading to the induction of p53-regulated apoptotic genes. Furthermore, we found that GLI silencing inhibited the proliferation of neoplastic mast cell lines, an effect that was more pronounced in rapidly growing cells. Our findings support the conclusion that GLI1/2 transcription factors are critical regulators of mast cell survival and that their inhibition leads to a significant reduction in the number of mast cells in vitro and in vivo, even in cells with constitutively active KIT variants. This knowledge can potentially be applicable to reducing mast cell burden in mast cell-related diseases.
Vertical Distribution of Particulate Matter in the Clarion Clipperton Zone (German Sector)—Potential Impacts From Deep-Sea Mining Discharge in the Water Column
Authors: Gillard Benjamin , Harbour Rob P. , Nowald Nicolas , Thomsen Laurenz , Iversen Morten H.
Published: February 2022

Most studies on the potential impacts of deep-sea mining in the Clarion Clipperton Zone (CCZ) have largely focused on benthic ecosystems but ignore the pelagic environment. To model full-scale impacts, it is important to understand how sediment discharge might affect the pelagic zone as well. This study combines in situ optics, hydrography, and remote sensing to describe particle abundance and size distribution through the entire water column in the CCZ (German sector). CCZ surface waters were characterized as productive over the year. During the winter, we observed the formation of a sharp transition zone in Chla concentration, identifying the area as a productive transitional zone toward a more depleted ocean gyre. In the German sector, median particle size was small (± 77 μm), and large particles (>300 μm) were rare. By assessing particle flux attenuation, we could show that the presence of a thick oxygen minimum zone (OMZ) plays an essential role in export and transformation of settling aggregates, with strong diel variations. We suggest that the combination of small aggregate size, bottom currents and slow seafloor consolidation may explain the extremely low sedimentation rate in the CCZ. We conclude that sediment incorporations and ballasting effect on settling particulate matter represent the most significant hazard on midwater and benthic ecosystems.
Human Genetic Host Factors and Its Role in the Pathogenesis of Chikungunya Virus Infection
Authors: Rueda Juan C. , Arcos-Burgos Mauricio , Santos Ana M. , Martin-Arsanios Daniel , Villota-Erazo Catalina , Reyes Viviana , Bernal-Macías Santiago , Peláez-Ballestas Ingris , Cardiel Mario H. , Londono John
Published: February 2022

Chikungunya virus (CHIKV) is an alphavirus from the Togaviridae family that causes acute arthropathy in humans. It is an arthropod-borne virus transmitted initially by the Aedes (Ae) aegypti and after 2006's epidemic in La Reunion by Ae albopictus due to an adaptive mutation of alanine for valine in the position 226 of the E1 glycoprotein genome (A226V). The first isolated cases of CHIKV were reported in Tanzania, however since its arrival to the Western Hemisphere in 2013, the infection became a pandemic. After a mosquito bite from an infected viremic patient the virus replicates eliciting viremia, fever, rash, myalgia, arthralgia, and arthritis. After the acute phase, CHIKV infection can progress to a chronic stage where rheumatic symptoms can last for several months to years. Although there is a great number of studies on the pathogenesis of CHIKV infection not only in humans but also in animal models, there still gaps in the proper understanding of the disease. To this date, it is unknown why a percentage of patients do not develop clinical symptoms despite having been exposed to the virus and developing an adaptive immune response. Also, controversy stills exist on the pathogenesis of chronic joint symptoms. It is known that host immune response to an infectious disease is reflected on patient's symptoms. At the same time, it is now well-established that host genetic variation is an important component of the varied onset, severity, and outcome of infectious disease. It is essential to understand the interaction between the aetiological agent and the host to know the chronic sequelae of the disease. The present review summarizes the current findings on human host genetics and its relationship with immune response in CHIKV infection.
Pre-Clinical Study of the [18F]AlF-Labeled HER2 Affibody for Non-Invasive HER2 Detection in Gastric Cancer
Authors: Han Jingya , Chen Yang , Zhao Yan , Zhao Xinming , Zhang Jingmian , Wang Jianfang , Zhang Zhaoqi
Published: February 2022

Human epidermal growth factor receptor 2 (HER2) is an important biomarker in gastric cancer (GC) and directly influences the therapeutic effect. Fluorine is firmly bound to Al3+ forming [18F]AlF-1,4,7-triazacyclononanetriacetic acid (NOTA)-HER2 affibody is a promising radiolabeled tracer that can monitor the changes of HER2 expression combining the advantages of simple preparation and the properties of 18F. The aim of this study was to develop a quick method for the synthesis of [18F]AlF-NOTA-HER2 affibody and evaluate its utility for HER2+ GC imaging in mouse models. Moreover, 68Ga-NOTA-HER2 affibody imaging was also performed to highlight the superiority of [18F]AlF-NOTA-HER2 affibody imaging in resolution. The HER2 affibody was conjugated with NOTA and labeled using 18F based on the complexation of [18F]AlF by NOTA. Its quality control and stability were performed by high-pressure liquid chromatography (HPLC). The molecular specificity and binding affinity of the novel radiotracer were evaluated in the GC cell line with HER2 overexpression (NCI-N87) and negative expression (MKN74). Distribution studies and PET/CT imaging were performed in mouse models. 68Ga-NOTA-HER2 affibody PET/CT imaging was also performed. [18F]AlF-NOTA-HER2 affibody was efficiently prepared within 30 min with a non-decay-corrected maximum yield of 32.69% and a radiochemical purity of more than 98%. [18F]AlF-NOTA-HER2 affibody was highly stable in incubation medium for 4 h in vitro and in the blood of nude mice at 30 min post-injection (p.i.). In vitro studies revealed specific binding and high binding affinity of the probe in NCI-N87 cells, while no binding was seen in MKN74 cells. PET imaging showed that NCI-N87 xenografts were differentiated from MKN74 xenografts with excellent contrast and low abdominal background, which was confirmed by the distribution results. High-level accumulation of the [18F]AlF-NOTA-HER2 affibody in HER2+ tumors was blocked by excess unlabeled NOTA-HER2 affibody. [18F]AlF-NOTA-HER2 affibody has a higher image resolution than that of 68Ga-NOTA-HER2 affibody. [18F]AlF-NOTA-HER2 affibody could be produced facilely with high radiochemical yield and may serve as a novel molecular probe with tremendous clinical potential for the non-invasive whole-body detection of the HER2 status in GC with good image contrast and resolution. This method could provide an in vivo understanding of GC biology that will ultimately guide the accurate diagnosis and treatment of GC.
Prevalence and Risk Factors of Functional Constipation According to the Rome Criteria in China: A Systematic Review and Meta-Analysis
Authors: Chen Zhe , Peng Yingying , Shi Qingyang , Chen Yongjie , Cao Lujia , Jia Jiannan , Liu Chunxiang , Zhang Junhua
Published: February 2022

Background

Functional constipation (FC) is a common bowel disorder that prevails worldwide. In China, although a heterogeneous prevalence of constipation is expected, it is currently not demonstrated. In this study, we aimed to evaluate the prevalence and related risk factors of FC in the Chinese population, according to the Rome criteria.

Methods

We searched the PubMed, the Embase, the Cochrane Library, the Web of Science, the China National Knowledge Infrastructure (CNKI), the Wanfang data knowledge service platform, the VIP information resource integration service platform, and the Chinese Biomedical Literature Service System (SinoMed) databases from the inception of database to July 2021. Population-based cross-section studies that enrolled adults with FC, diagnosed by the Rome criteria, were deemed eligible. We summarized the overall prevalence and detected the subgroup effect per the Rome I, Rome II, Rome III, and Rome IV criteria. We used the generalized linear mixed model (GLMM) with a random-effect intercept to pool the prevalence and performed pairwise meta-analyses for prevalence comparisons by risk factors.

Results

We identified 3,213 records through our database search, and 39 studies from China, comprising 1,240,79 participants, met the eligibility criteria for our study. The pooled overall prevalence of FC using the Rome criteria was 8.5% in China. Heterogeneous prevalence was detected within the Rome criteria (Rome II: 10.6%, 95% CI: 7.2–15.4; Rome III: 6.5%, 95% CI: 3.4–12.0; Rome IV: 8.1%, 95% CI: 5.6–11.8). The prevalence increased between 1991 and 2020 (from 5.5% with 95% CI: 3.6–8.2 between 1991 and 2000 to 10.9% with 95% CI: 5.5–20.4 between 2011 and 2020). Higher prevalence was found in women [odds ratio (OR) = 1.53, 95% CI: 1.31–1.78] and the elderly (≥70 years vs. ≤ 29 years: OR = 3.38, 95% CI: 2.16–5.30) than in men and the younger population. A high-fiber diet was associated with lower prevalence (OR = 0.33, 95% CI: 0.15–0.75), whereas irregular bowel habit and inactivity were associated with higher prevalence (OR = 3.64, 95% CI: 2.64–5.03; OR = 1.97, 95% CI: 1.14–3.43). Unhealthy mental states, such as anxiety and depression, and poor sleep quality led to high prevalence (OR = 3.16, 95%C I: 1.96–5.11; OR = 2.74, 95% CI: 1.76–4.26; OR = 2.14, 95% CI: 1.69–2.72, respectively).

Conclusion

Various types of FC prevail in China based on the different Rome criteria, personal characteristics, and habits. The prevalence also increased over the past three decades. The FC should be included under the primary care setting with uniform diagnosis criteria in China.

Systematic Review Registration

http://www.crd.york.ac.uk/PROSPERO, CRD42021277172.
Platelet Transfusion in Patients With Sepsis and Thrombocytopenia: A Propensity Score-Matched Analysis Using a Large ICU Database
Authors: He Shuangjun , Fan Chenyu , Ma Jun , Tang Chao , Chen Yi
Published: February 2022

Purpose

Sepsis with thrombocytopenia is highly prevalent in critically ill intensive care unit (ICU) patients and is associated with adverse outcomes. Platelet transfusion is the primary treatment of choice. However, evidence for the beneficial effects of platelet transfusion in patients with sepsis and thrombocytopenia is scarce and low in quality. This study aimed to evaluate the association between platelet transfusion and mortality among ICU patients with sepsis and thrombocytopenia.

Patients and Methods

Using the Medical Information Mart for Intensive Care III database (v. 1.4), the outcomes of sepsis patients with platelet counts of ≤ 150,000/μL were compared between those who did and did not receive platelet transfusion. The primary outcomes were 28- and 90-day all-cause mortalities. The secondary outcomes were red blood cell (RBC) transfusion, ICU-free days, and hospital-free days. Propensity score matching was employed to assemble a cohort of patients with similar baseline characteristics.

Results

Among 7,765 eligible patients, 677 received platelet transfusion and were matched with 677 patients who did not receive platelet transfusion according to propensity scores. Platelet transfusion, as compared with no platelet transfusion, was associated with an increased risk of 28-day all-cause mortality [36.9 vs. 30.4%, odds ratio (OR), 1.21; 95% confidence interval (CI), 1.01–1.46; p = 0.039], increased risk of 90-day all-cause mortality (50.8 vs. 44.6%, OR, 1.13; 95% CI, 1.00–1.31; p = 0.048), fewer mean (standard deviation) 28-day ICU-free days (15.88 ± 8.97 vs. 18.64 ± 8.33 days, p < 0.001), and fewer hospital-free days (10.29 ± 8.49 vs. 11.43 ± 8.85 days, p = 0.017). The rate of RBC transfusion was not significantly different between the platelet transfusion and non-transfusion groups (p = 0.149). The results were maintained across several subgroup and sensitivity analyses.

Conclusion

In this study, platelet transfusion was associated with higher 28- and 90-day all-cause mortalities. These results suggest the potential hazards of platelet transfusion in ICU patients with sepsis and thrombocytopenia.
Response of Coastal Shewanella and Duganella Bacteria to Planktonic and Terrestrial Food Substrates
Authors: Zhao Li , Brugel Sonia , Ramasamy Kesava Priyan , Andersson Agneta
Published: February 2022

Global warming scenarios indicate that in subarctic regions, the precipitation will increase in the future. Coastal bacteria will thus receive increasing organic carbon sources from land runoff. How such changes will affect the function and taxonomic composition of coastal bacteria is poorly known. We performed a 10-day experiment with two isolated bacteria: Shewanella baltica from a seaside location and Duganella sp. from a river mouth, and provided them with a plankton and a river extract as food substrate. The bacterial growth and carbon consumption were monitored over the experimental period. Shewanella and Duganella consumed 40% and 30% of the plankton extract, respectively, while the consumption of the river extract was low for both bacteria, ∼1%. Shewanella showed the highest bacterial growth efficiency (BGE) (12%) when grown on plankton extract, while when grown on river extract, the BGE was only 1%. Duganella showed low BGE when grown on plankton extract (< 1%) and slightly higher BGE when grown on river extract (2%). The cell growth yield of Duganella was higher than that of Shewanella when grown on river extract. These results indicate that Duganella is more adapted to terrestrial organic substrates with low nutritional availability, while Shewanella is adapted to eutrophied conditions. The different growth performance of the bacteria could be traced to genomic variations. A closely related genome of Shewanella was shown to harbor genes for the sequestration of autochthonously produced carbon substrates, while Duganella contained genes for the degradation of relatively refractive terrestrial organic matter. The results may reflect the influence of environmental drivers on bacterial community composition in natural aquatic environments. Elevated inflows of terrestrial organic matter to coastal areas in subarctic regions would lead to increased occurrence of bacteria adapted to the degradation of complex terrestrial compounds with a low bioavailability.
Enhanced Antiviral Ability by a Combination of Zidovudine and Short Hairpin RNA Targeting Avian Leukosis Virus
Authors: Wang Qun , Su Qi , Liu Bowen , Li Yan , Sun Wanli , Liu Yanxue , Xue Ruyu , Chang Shuang , Wang Yixin , Zhao Peng
Published: February 2022

Avian leukosis virus (ALV) causes tumor diseases in poultry and is circulating all over the world, leading to significant economic losses. In addition, mixed infection of ALV with other viruses is very common and is often reported to contaminate live vaccines. At present, there is no effective method to suppress the replication of ALV in vitro, so it is very difficult to remove it in mixed infection. As a retrovirus, the replication of ALV can be limited by reverse transcriptase (RT) inhibitors like zidovudine (AZT), but it also causes nontargeted cytotoxicity. To find the optimal solution in cytotoxicity and inhibition efficiency in vitro culture system, we firstly designed a combination therapy of AZT and short hairpin RNA (shRNA) targeting ALV and then verified its efficiency by multiple biological methods. Results showed that shRNA can effectively inhibit the expression of RT and then limit the replication of ALV. The combination of AZT and shRNA can significantly improve the antiviral efficiency in viral replication, shedding, and provirus assembly under the condition of low cytotoxicity. Overall, in this study, the combination therapy of AZT and shRNA targeting ALV showed excellent antiviral performance against ALV in vitro culture system. This method can be applied to multiple scenarios, such as the removal of ALV in mixed infection or the purification of contaminated vaccine strains.
A Case Report and Review of the Literature: Reactive Arthritis Caused by Clostridioides difficile ribotype 027
Authors: Zimmermann Ortrud , Köchel Heinrich , Bohne Wolfgang , Pollok-Kopp Beatrix , Passenberg Peter , Groß Uwe
Published: February 2022

With an annual incidence of 250-300 per 100,000 inhabitants, reactive arthritis is not uncommon. However, the fact that Clostridioides difficile infection (CDI) can also lead to this complication is largely unknown. We report on a 69-years-old man who developed reactive arthritis of his right knee joint one week after antibiotic-associated diarrhea with evidence of C. difficile of the hypervirulent ribotype 027. His female partner also became infected with C. difficile ribotype 027, but did not develop reactive arthritis. The further investigation showed that the patient - in contrast to his partner - was HLA-B27 positive and had strong antibody levels against C. difficile. The case history together with the review of 45 other cases described so far shows that C. difficile can also lead to reactive arthritis. C. difficile-associated reactive arthritis (CDARA) is characterized by the fact that patients suffer from diarrhea or colitis after taking antibiotics, toxigenic C. difficile or only the toxins are detectable in the stool and there are no other explanations for the arthritis and diarrhea.
Gut Microbiome and the Role of Metabolites in the Study of Graves’ Disease
Authors: Liu Haihua , Liu Huiying , Liu Chang , Shang Mengxue , Wei Tianfu , Yin Peiyuan
Published: February 2022

Graves’ disease (GD) is an autoimmune thyroid disease (AITD), which is one of the most common organ-specific autoimmune disorders with an increasing prevalence worldwide. But the etiology of GD is still unclear. A growing number of studies show correlations between gut microbiota and GD. The dysbiosis of gut microbiota may be the reason for the development of GD by modulating the immune system. Metabolites act as mediators or modulators between gut microbiota and thyroid. The purpose of this review is to summarize the correlations between gut microbiota, microbial metabolites and GD. Challenges in the future study are also discussed. The combination of microbiome and metabolome may provide new insight for the study and put forward the diagnosis, treatment, prevention of GD in the future.
A Synergistic Combination of DHA, Luteolin, and Urolithin A Against Alzheimer’s Disease
Authors: Jayatunga Dona P. W. , Hone Eugene , Fernando W. M. A. D. Binosha , Garg Manohar L. , Verdile Giuseppe , Martins Ralph N.
Published: February 2022

Alzheimer’s disease (AD) is a devastating neurodegenerative disorder and the most common form of dementia worldwide. The classical AD brain is characterized by extracellular deposition of amyloid-β (Aβ) protein aggregates as senile plaques and intracellular neurofibrillary tangles (NFTs), composed of hyper-phosphorylated forms of the microtubule-associated protein Tau. There has been limited success in clinical trials for some proposed therapies for AD, so attention has been drawn toward using alternative approaches, including prevention strategies. As a result, nutraceuticals have become attractive compounds for their potential neuroprotective capabilities. The objective of the present study was to derive a synergistic nutraceutical combinationin vitrothat may act as a potential preventative therapy for AD. The compounds of interest were docosahexaenoic acid (DHA), luteolin (LUT), and urolithin A (UA). The cell viability and cytotoxicity assays MTS and LDH were used to evaluate the compounds individually and in two-compound combinations, for their ability to inhibit Aβ1–42-induced toxicity in human neuroblastoma BE(2)-M17 cells. The LDH-derived% protection values were used in the program CompuSyn v.1.0 to calculate the combination index (CI) of the two-compound combinations. The software-predicted potentially synergistic (CI < 1) two-compound combinations were validated using CellTiter Glo assay. Finally, a three-compound combination was predicted (D5L5U5) and shown to be the most effective at inhibiting Aβ1–42-induced toxicity. The synergistic combination, D5L5U5warrants further research for its mechanism of action; however, it can serve as a basis to develop an advanced functional food for the prevention or co-treatment of AD.
Extracellular Vesicles Derived From Plasma of Patients With Neurodegenerative Disease Have Common Transcriptomic Profiling
Authors: Sproviero Daisy , Gagliardi Stella , Zucca Susanna , Arigoni Maddalena , Giannini Marta , Garofalo Maria , Fantini Valentina , Pansarasa Orietta , Avenali Micol , Ramusino Matteo Cotta , Diamanti Luca , Minafra Brigida , Perini Giulia , Zangaglia Roberta , Costa Alfredo , Ceroni Mauro , Calogero Raffaele A. , Cereda Cristina
Published: February 2022

Objectives

There is a lack of effective biomarkers for neurodegenerative diseases (NDs) such as Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS), and frontotemporal dementia. Extracellular vesicle (EV) RNA cargo can have an interesting potential as a non-invasive biomarker for NDs. However, the knowledge about the abundance of EV-mRNAs and their contribution to neurodegeneration is not clear.

Methods

Large and small EVs (LEVs and SEVs) were isolated from plasma of patients and healthy volunteers (control, CTR) by differential centrifugation and filtration, and RNA was extracted. Whole transcriptome was carried out using next generation sequencing (NGS).

Results

Coding RNA (i.e., mRNA) but not long non-coding RNAs (lncRNAs) in SEVs and LEVs of patients with ALS could be distinguished from healthy CTRs and from other NDs using the principal component analysis (PCA). Some mRNAs were found in commonly deregulated between SEVs of patients with ALS and frontotemporal dementia (FTD), and they were classified in mRNA processing and splicing pathways. In LEVs, instead, one mRNA and one antisense RNA (i.e., MAP3K7CL and AP003068.3) were found to be in common among ALS, FTD, and PD. No deregulated mRNAs were found in EVs of patients with AD.

Conclusion

Different RNA regulation occurs in LEVs and SEVs of NDs. mRNAs and lncRNAs are present in plasma-derived EVs of NDs, and there are common and specific transcripts that characterize LEVs and SEVs from the NDs considered in this study.
Multidimensional Clinical Assessment in Frontotemporal Dementia and Its Spectrum in Latin America and the Caribbean: A Narrative Review and a Glance at Future Challenges
Authors: Henríquez Fernando , Cabello Victoria , Baez Sandra , Souza Leonardo Cruz de , Lillo Patricia , Martínez-Pernía David , Olavarría Loreto , Torralva Teresa , Slachevsky Andrea
Published: February 2022

Frontotemporal dementia (FTD) is the third most common form of dementia across all age groups and is a leading cause of early-onset dementia. The Frontotemporal dementia (FTD) includes a spectrum of diseases that are classified according to their clinical presentation and patterns of neurodegeneration. There are two main types of FTD: behavioral FTD variant (bvFTD), characterized by a deterioration in social function, behavior, and personality; and primary progressive aphasias (PPA), characterized by a deficit in language skills. There are other types of FTD-related disorders that present motor impairment and/or parkinsonism, including FTD with motor neuron disease (FTD-MND), progressive supranuclear palsy (PSP), and corticobasal syndrome (CBS). The FTD and its associated disorders present great clinical heterogeneity. The diagnosis of FTD is based on the identification through clinical assessments of a specific clinical phenotype of impairments in different domains, complemented by an evaluation through instruments, i.e., tests and questionnaires, validated for the population under study, thus, achieving timely detection and treatment. While the prevalence of dementia in Latin America and the Caribbean (LAC) is increasing rapidly, there is still a lack of standardized instruments and consensus for FTD diagnosis. In this context, it is important to review the published tests and questionnaires adapted and/or validated in LAC for the assessment of cognition, behavior, functionality, and gait in FTD and its spectrum. Therefore, our paper has three main goals. First, to present a narrative review of the main tests and questionnaires published in LAC for the assessment of FTD and its spectrum in six dimensions: (i) Cognitive screening; (ii) Neuropsychological assessment divided by cognitive domain; (iii) Gait assessment; (iv) Behavioral and neuropsychiatric symptoms; (v) Functional assessment; and (vi) Global Rating Scale. Second, to propose a multidimensional clinical assessment of FTD in LAC identifying the main gaps. Lastly, it is proposed to create a LAC consortium that will discuss strategies to address the current challenges in the field.
Effects of Repetitive Peripheral Sensory Stimulation in the Subacute and Chronic Phases After Stroke: Study Protocol for a Pilot Randomized Trial
Authors: Kroth Jéssica Borges , Handfas Benjamim , Rodrigues Glaucia , Zepeda Francisco , Oliveira Marco Aurélio , Wang Danny J. J. , Azevedo Neto Raymundo Machado de , Silva Gisele Sampaio , Amaro Edson , Sorinola Isaac Olubunmi , Conforto Adriana Bastos
Published: February 2022

Background

Repetitive peripheral nerve sensory stimulation (RPSS) is a potential add-on intervention to motor training for rehabilitation of upper limb paresis after stroke. Benefits of RPSS were reported in subjects in the chronic phase after stroke, but there is limited information about the effects of this intervention within the 1st weeks or months. The primary goal of this study is to compare, in a head-to-head proof-of-principle study, the impact of a single session of suprasensory vs. subsensory RPSS on the upper limb motor performance and learning in subjects at different phases after stroke subacute and chronic phases and mild upper limb motor impairments after stroke. In addition, we examine the effects of RPSS on brain perfusion, functional imaging activation, and γ-aminobutyric acid (GABA) levels. Subjects with mild upper limb motor impairments will be tested with MRI and clinical assessment either at an early (7 days to 3 months post-stroke) or at a chronic (>6 months) stage after stroke.

Methods

In this multicenter, randomized, parallel-group, proof-of-principle clinical trial with blinded assessment of outcomes, we compare the effects of one session of suprasensory or subsensory RPSS in patients with ischemic or hemorrhagic stroke and upper limb paresis. Clinical assessment and MRI will be performed only once in each subject (either at an early or at a chronic stage). The primary outcome is the change in performance in the Jebsen–Taylor test. Secondary outcomes: hand strength, cerebral blood flow assessed with arterial spin labeling, changes in the blood oxygenation level-dependent (BOLD) effect in ipsilesional and contralesional primary motor cortex (M1) on the left and the right hemispheres assessed with functional MRI (fMRI) during a finger-tapping task performed with the paretic hand, and changes in GABA levels in ipsilesional and contralesional M1 evaluated with spectroscopy. The changes in outcomes will be compared in four groups: suprasensory, early; subsensory, early; suprasensory, chronic; and subsensory, chronic.

Discussion

The results of this study are relevant to inform future clinical trials to tailor RPSS to patients more likely to benefit from this intervention.

Trial Registration

NCT03956407.
Gut Microbial Characteristics of Adult Patients With Epilepsy
Authors: Dong Lian , Zheng Qian , Cheng Yongran , Zhou Mengyun , Wang Mingwei , Xu Jianwei , Xu Zucai , Wu Guofeng , Yu Yunli , Ye Lan , Feng Zhanhui
Published: February 2022

Objective

To characterize the intestinal flora of patients with epilepsy and its correlation with epilepsy.

Methods

Patients with ages > 18 years were consecutively enrolled from the outpatient department, Affiliated Hospital of Guizhou Medical University from January 2018 to December 2019. A total of 71 subjects were recruited, including epilepsy patients (n = 41) as an observation group and patient family members (n = 30) as a control group. Fresh stool specimens of all the subjects were collected. The 16S ribosomal RNA sequencing was analyzed to determine changes in intestinal flora composition and its correlation with epilepsy. Subgroup analysis was then conducted. All patients with epilepsy were divided into an urban group (n = 21) and a rural group (n = 20) according to the region, and bioinformatics analyses were repeated between subgroups.

Results

LEfSe analysis showed that Fusobacterium, Megasphaera, Alloprevotella, and Sutterella had relatively increased abundance in the epilepsy group at the genus level. Correlation analysis suggested that Fusobacterium sp. (r = 0.584, P < 0.01), Fusobacterium mortiferum (r = 0.560, P < 0.01), Ruminococcus gnavus (r = 0.541, P < 0.01), and Bacteroides fragilis (r = 0.506, P < 0.01) were significantly positively correlated with the occurrence of epilepsy (r ≥ 0.5, P < 0.05). PICRUSt function prediction analysis showed that there were significant differences in 16 pathways between the groups at level 3. Comparing the rural group with the urban group, Proteobacteria increased at the phylum level and Escherichia coli, Fusobacterium varium, Prevotella stercorea, and Prevotellaceae bacterium DJF VR15 increased at the species level in the rural group.

Conclusion

There were significant differences in the composition and functional pathways of gut flora between epilepsy patients and patient family members. The Fusobacterium may become a potential biomarker for the diagnosis of epilepsy.
Quantitative MR-Neurography at 3.0T: Inter-Scanner Reproducibility
Authors: Preisner Fabian , Behnisch Rouven , Schwehr Véronique , Godel Tim , Schwarz Daniel , Foesleitner Olivia , Bäumer Philipp , Heiland Sabine , Bendszus Martin , Kronlage Moritz
Published: February 2022

Background

Quantitative MR-neurography (MRN) is increasingly applied, however, the impact of the MR-scanner on the derived parameters is unknown. Here, we used different 3.0T MR scanners and applied comparable MR-sequences in order to quantify the inter-scanner reproducibility of various MRN parameters of the sciatic nerve.

Methods

Ten healthy volunteers were prospectively examined at three different 3.0T MR scanners and underwent MRN of their sciatic nerve using comparable imaging protocols including diffusion tensor imaging (DTI) and T2 relaxometry. Subsequently, inter-scanner agreement was assessed for seven different parameters by calculating the intraclass correlation coefficients (ICCs) and the standard error of measurement (SEM).

Results

Assessment of inter-scanner reliability revealed good to excellent agreement for T2 (ICC: 0.846) and the quantitative DTI parameters, such as fractional anisotropy (FA) (ICC: 0.876), whereas moderate agreement was observed for proton spin density (PD) (ICC: 0.51). Analysis of variance identified significant inter-scanner differences for several parameters, such as FA (p < 0.001; p = 0.02), T2 (p < 0.01) and PD (p = 0.02; p < 0.01; p = 0.02). Calculated SEM values were mostly within the range of one standard deviation of the absolute mean values, for example 0.033 for FA, 4.12 ms for T2 and 27.8 for PD.

Conclusion

This study quantifies the measurement imprecision for peripheral nerve DTI and T2 relaxometry, which is associated with the use of different MR scanners. The here presented values may serve as an orientation of the possible scanner-associated fluctuations of MRN biomarkers, which can occur under similar conditions.
Non-invasive Vagus Nerve Stimulation in Cerebral Stroke: Current Status and Future Perspectives
Authors: Li Lijuan , Wang Dong , Pan Hongxia , Huang Liyi , Sun Xin , He Chengqi , Wei Quan
Published: February 2022

Stroke poses a serious threat to human health and burdens both society and the healthcare system. Standard rehabilitative therapies may not be effective in improving functions after stroke, so alternative strategies are needed. The FDA has approved vagus nerve stimulation (VNS) for the treatment of epilepsy, migraines, and depression. Recent studies have demonstrated that VNS can facilitate the benefits of rehabilitation interventions. VNS coupled with upper limb rehabilitation enhances the recovery of upper limb function in patients with chronic stroke. However, its invasive nature limits its clinical application. Researchers have developed a non-invasive method to stimulate the vagus nerve (non-invasive vagus nerve stimulation, nVNS). It has been suggested that nVNS coupled with rehabilitation could be a promising alternative for improving muscle function in chronic stroke patients. In this article, we review the current researches in preclinical and clinical studies as well as the potential applications of nVNS in stroke. We summarize the parameters, advantages, potential mechanisms, and adverse effects of current nVNS applications, as well as the future challenges and directions for nVNS in cerebral stroke treatment. These studies indicate that nVNS has promising efficacy in reducing stroke volume and attenuating neurological deficits in ischemic stroke models. While more basic and clinical research is required to fully understand its mechanisms of efficacy, especially Phase III trials with a large number of patients, these data suggest that nVNS can be applied easily not only as a possible secondary prophylactic treatment in chronic cerebral stroke, but also as a promising adjunctive treatment in acute cerebral stroke in the near future.
Deep Learning-Based Mapping of Tumor Infiltrating Lymphocytes in Whole Slide Images of 23 Types of Cancer
Authors: Abousamra Shahira , Gupta Rajarsi , Hou Le , Batiste Rebecca , Zhao Tianhao , Shankar Anand , Rao Arvind , Chen Chao , Samaras Dimitris , Kurc Tahsin , Saltz Joel
Published: February 2022

The role of tumor infiltrating lymphocytes (TILs) as a biomarker to predict disease progression and clinical outcomes has generated tremendous interest in translational cancer research. We present an updated and enhanced deep learning workflow to classify 50x50 um tiled image patches (100x100 pixels at 20x magnification) as TIL positive or negative based on the presence of 2 or more TILs in gigapixel whole slide images (WSIs) from the Cancer Genome Atlas (TCGA). This workflow generates TIL maps to study the abundance and spatial distribution of TILs in 23 different types of cancer. We trained three state-of-the-art, popular convolutional neural network (CNN) architectures (namely VGG16, Inception-V4, and ResNet-34) with a large volume of training data, which combined manual annotations from pathologists (strong annotations) and computer-generated labels from our previously reported first-generation TIL model for 13 cancer types (model-generated annotations). Specifically, this training dataset contains TIL positive and negative patches from cancers in additional organ sites and curated data to help improve algorithmic performance by decreasing known false positives and false negatives. Our new TIL workflow also incorporates automated thresholding to convert model predictions into binary classifications to generate TIL maps. The new TIL models all achieve better performance with improvements of up to 13% in accuracy and 15% in F-score. We report these new TIL models and a curated dataset of TIL maps, referred to as TIL-Maps-23, for 7983 WSIs spanning 23 types of cancer with complex and diverse visual appearances, which will be publicly available along with the code to evaluate performance.

Code Available at:https://github.com/ShahiraAbousamra/til_classification.
Radiomic and Dosiomic Features for the Prediction of Radiation Pneumonitis Across Esophageal Cancer and Lung Cancer
Authors: Puttanawarut Chanon , Sirirutbunkajorn Nat , Tawong Narisara , Jiarpinitnun Chuleeporn , Khachonkham Suphalak , Pattaranutaporn Poompis , Wongsawat Yodchanan
Published: February 2022

Purpose

The aim was to investigate the advantages of dosiomic and radiomic features over traditional dose-volume histogram (DVH) features for predicting the development of radiation pneumonitis (RP), to validate the generalizability of dosiomic and radiomic features by using features selected from an esophageal cancer dataset and to use these features with a lung cancer dataset.

Materials and Methods

A dataset containing 101 patients with esophageal cancer and 93 patients with lung cancer was included in this study. DVH and dosiomic features were extracted from 3D dose distributions. Radiomic features were extracted from pretreatment CT images. Feature selection was performed using only the esophageal cancer dataset. Four predictive models for RP (DVH, dosiomic, radiomic and dosiomic + radiomic models) were compared on the esophageal cancer dataset. We further used a lung cancer dataset for the external validation of the selected dosiomic and radiomic features from the esophageal cancer dataset. The performance of the predictive models was evaluated by the area under the curve (AUC) of the receiver operating characteristic curve (ROCAUC) and the AUC of the precision recall curve (PRAUC) metrics.

Result

The ROCAUCs and PRAUCs of the DVH, dosiomic, radiomic and dosiomic + radiomic models on esophageal cancer dataset were 0.67 ± 0.11 and 0.75 ± 0.10, 0.71 ± 0.10 and 0.77 ± 0.09, 0.71 ± 0.11 and 0.79 ± 0.09, and 0.75 ± 0.10 and 0.81 ± 0.09, respectively. The predictive performance of the dosiomic- and radiomic-based models was significantly higher than that of the DVH-based model with respect to esophageal cancer. The ROCAUCs and PRAUCs of the DVH, dosiomic, radiomic and dosiomic + radiomic models on the lung cancer dataset were 0.64 ± 0.18 and 0.37 ± 0.20, 0.67 ± 0.17 and 0.37 ± 0.20, 0.67 ± 0.16 and 0.45 ± 0.23, and 0.68 ± 0.16 and 0.44 ± 0.22, respectively. On the lung cancer dataset, the predictive performance of the radiomic and dosiomic + radiomic models was significantly higher than that of the DVH-based model. However, the PRAUC of the dosiomic-based model showed no significant difference relative to the corresponding RP prediction performance on the lung cancer dataset.

Conclusion

The results suggested that dosiomic and CT radiomic features could improve RP prediction in thoracic radiotherapy. Dosiomic and radiomic feature knowledge might be transferrable from esophageal cancer to lung cancer.
Screening and Identification of Human Endogenous Retrovirus-K mRNAs for Breast Cancer Through Integrative Analysis of Multiple Datasets
Authors: Wei Yongzhong , Wei Huilin , Wei Yinfeng , Tan Aihua , Chen Xiuyong , Liao Xiuquan , Xie Bo , Wei Xihua , Li Lanxiang , Liu Zengjing , Dai Shengkang , Khan Adil , Pang Xianwu , Hassan Nada M. A. , Xiong Kai , Zhang Kai , Leng Jing , Lv Jiannan , Hu Yanling
Published: February 2022

Objective

Human endogenous retroviruses (HERVs) make up 8% of the human genome. HERVs are biologically active elements related to multiple diseases. HERV-K, a subfamily of HERVs, has been associated with certain types of cancer and suggested as an immunologic target in some tumors. The expression levels of HERV-K in breast cancer (BCa) have been studied as biomarkers and immunologic therapeutic targets. However, HERV-K has multiple copies in the human genome, and few studies determined the transcriptional profile of HERV-K copies across the human genome for BCa.

Methods

Ninety-one HERV-K indexes with entire proviral sequences were used as the reference database. Nine raw sequencing datasets with 243 BCa and 137 control samples were mapped to this database by Salmon software. The differential proviral expression across several groups was analyzed by DESeq2 software.

Results

First, the clustering of each dataset demonstrated that these 91 HERV-K proviruses could well cluster the BCa and control samples when the normal controls were normal cells or healthy donor tissues. Second, several common HERV-K proviruses that are closely related with BCa risk were significantly differentially expressed (padj < 0.05 and absolute log2FC > 1.5) in the tissues and cell lines. Additionally, almost all the HERV-K proviruses had higher expression in BCa tissue than in healthy donor tissue. Notably, we first found the expression of 17p13.1 provirus that located with TP53 should regulate TP53 expression in ER+ and HER2+ BCa.

Conclusion

The expression profiling of these 91 HERV-K proviruses can be used as biomarkers to distinguish individuals with BCa and healthy controls. Some proviruses, especially 17p13.1, were strongly associated with BCa risk. The results suggest that HERV-K expression profiles may be appropriate biomarkers and targets for BCa.
Predicting HER2 Status in Breast Cancer on Ultrasound Images Using Deep Learning Method
Authors: Xu Zilong , Yang Qiwei , Li Minghao , Gu Jiabing , Du Changping , Chen Yang , Li Baosheng
Published: February 2022

Purpose

The expression of human epidermal growth factor receptor 2 (HER2) in breast cancer is critical in the treatment with targeted therapy. A 3-block-DenseNet-based deep learning model was developed to predict the expression of HER2 in breast cancer by ultrasound images.

Methods

The data from 144 breast cancer patients with preoperative ultrasound images and clinical information were retrospectively collected from the Shandong Province Tumor Hospital. An end-to-end 3-block-DenseNet deep learning classifier was built to predict the expression of human epidermal growth factor receptor 2 by ultrasound images. The patients were randomly divided into a training (n = 108) and a validation set (n = 36).

Results

Our proposed deep learning model achieved an encouraging predictive performance in the training set (accuracy = 85.79%, AUC = 0.87) and the validation set (accuracy = 80.56%, AUC = 0.84). The effectiveness of our model significantly exceeded the clinical model and the radiomics model. The score of the proposed model showed significant differences between HER2-positive and -negative expression (p < 0.001).

Conclusions

These results demonstrate that ultrasound images are predictive of HER2 expression through a deep learning classifier. Our method provides a non-invasive, simple, and feasible method for the prediction of HER2 expression without the manual delineation of the regions of interest (ROI). The performance of our deep learning model significantly exceeded the traditional texture analysis based on the radiomics model.
Ferroptosis: A New Strategy for Cancer Therapy
Authors: Chen Yu , Fan Zhihua , Hu Shen , Lu Chengchao , Xiang Yi , Liao Shuzhi
Published: February 2022

Ferroptosis is a newly discovered form of iron-dependent cell death, which is different from other death forms. The main characteristics of ferroptosis are: (1) Amino acid metabolism. (2) Iron metabolism; (3) Lipid metabolism and Reactive oxygen species (ROS). Ferroptosis is related to the occurrence and development of a variety of cancers, especially in the drug resistance. This article reviews the research progress of iron death in tumors, and provides a theoretical reference for its further research and clinical application.