bluuebunny/crossref_metadata_2025 huggingface dataset:
Germline Mutation Analysis in Sporadic Breast Cancer Cases With Clinical Correlations
Authors: Ajaz Sadia , Zaidi Sani-e-Zehra , Ali Saleema , Siddiqa Aisha , Memon Muhammad Ali
Published: March 2022

Demographics for breast cancers vary widely among nations. The frequency of germline mutations in breast cancers, which reflects the hereditary cases, has not been investigated adequately and accurately in highly-consanguineous Pakistani population. In the present discovery case series, germ-line mutations in twenty-seven breast cancer candidate genes were investigated in eighty-four sporadic breast cancer patients along with the clinical correlations. The germ-line variants were also assessed in two healthy gender-matched controls. The clinico-pathological features were evaluated by descriptive analysis and Pearson χ2 test (with significant p-value <0.05). The most frequent parameters associated with hereditary cancer cases are age and ethnicity. Therefore, the analyses were stratified on the basis of age (≤40 years vs. >40 years) and ethnicity. The breast cancer gene panel assay was carried out by BROCA, which is a genomic capture, massively parallel next generation sequencing assay on Illumina Hiseq2000 with 100bp read lengths. Copy number variations were determined by partially-mapped read algorithm. Once the mutation was identified, it was validated by Sanger sequencing. The ethnic analysis stratified on the basis of age showed that the frequency of breast cancer at young age (≤40 years) was higher in Sindhis (n = 12/19; 64%) in contrast to patients in other ethnic groups. Majority of the patients had stage III (38.1%), grade III (50%), tumor size 2–5 cm (54.8%), and invasive ductal carcinoma (81%). Overall, the analysis revealed germ-line mutations in 11.9% of the patients, which was not significantly associated with younger age or any particular ethnicity. The mutational spectrum was restricted to three genes: BRCA1, BRCA2, and TP53. The identified mutations consist of seven novel germ-line mutations, while three mutations have been reported previously. All the mutations are predicted to result in protein truncation. No mutations were identified in the remaining twenty-four candidate breast cancer genes. The present study provides the framework for the development of hereditary-based preventive and treatment strategies against breast cancers in Pakistani population.
Contribution of FBLN5 to Unstable Plaques in Carotid Atherosclerosis via mir128 and mir532–3p Based on Bioinformatics Prediction and Validation
Authors: Zheng Lin , Yue Xinyang , Li Minhui , Hu Jie , Zhang Bojin , Zhang Ruijing , Zheng Guoping , Chen Ruihan , Dong Honglin
Published: March 2022

FBLN5, a member of the short fibulins in the fibulin family of extracellular matrix/matricellular proteins, is involved in interactions with components of the basement membrane and extracellular matrix proteins. It plays key roles in endothelial tissues in many vascular diseases. In this study, the relationship between FBLN5 and carotid atherosclerotic plaque stability as well as the regulatory roles of miRNAs were evaluated. Differential gene expression analyses and weighted gene co-expression network analysis (WGCNA) based on the GSE163154 dataset (including 16 samples without intraplaque hemorrhage and 27 samples with intraplaque hemorrhage) in GEO revealed that FBLN5 is related to plaque stability and is the most significantly differentially expressed gene. LASSO regression was used to evaluate genes obtained from the intersection of differentially expressed genes and clinically significant modules identified by WGCNA. A prediction model based on eight genes, including FBLN5, was constructed and showed an accuracy of 0.951 based on an ROC analysis. Low FBLN5 expression in plaque tissues was confirmed by immunohistochemistry and western blotting. GO (Gene Ontology) and KEGG (Kyoto Encyclopedia of Genes and Genomes) enrichment analyses showed that FBLN5 acted mainly by the maintenance of the cellular matrix and reactive oxygen species production. miRNAs upstream of these eight predictive genes, including FBLN5, were identified and used to construct a network diagram. These results revealed that hsa-mir-128 and hsa-mir-532–3p were upstream regulatory factors of FBLN5, as verified by PCR assays of human plaque tissues demonstrating that both miRNAs were significantly up-regulated. Therefore, FBLN5 may play an important role in carotid atherosclerosis via hsa-mir-128 and hsa-mir-532–3p as well as become an essential target for treatment.
Response of Human Liver Tissue to Innate Immune Stimuli
Authors: Wu Xia , Roberto Jessica B. , Knupp Allison , Greninger Alexander L. , Truong Camtu D. , Hollingshead Nicole , Kenerson Heidi L. , Tuefferd Marianne , Chen Antony , Koelle David M. , Horton Helen , Jerome Keith R. , Polyak Stephen J. , Yeung Raymond S. , Crispe Ian N.
Published: March 2022

Precision-cut human liver slice cultures (PCLS) have become an important alternative immunological platform in preclinical testing. To further evaluate the capacity of PCLS, we investigated the innate immune response to TLR3 agonist (poly-I:C) and TLR4 agonist (LPS) using normal and diseased liver tissue. Pathological liver tissue was obtained from patients with active chronic HCV infection, and patients with former chronic HCV infection cured by recent Direct-Acting Antiviral (DAA) drug therapy. We found that hepatic innate immunity in response to TLR3 and TLR4 agonists was not suppressed but enhanced in the HCV-infected tissue, compared with the healthy controls. Furthermore, despite recent HCV elimination, DAA-cured liver tissue manifested ongoing abnormalities in liver immunity: sustained abnormal immune gene expression in DAA-cured samples was identified in direct ex vivo measurements and in TLR3 and TLR4 stimulation assays. Genes that were up-regulated in chronic HCV-infected liver tissue were mostly characteristic of the non-parenchymal cell compartment. These results demonstrated the utility of PCLS in studying both liver pathology and innate immunity.
Activation of NLRP3 Inflammasome by Virus-Like Particles of Human Polyomaviruses in Macrophages
Authors: Lučiūnaitė Asta , Dalgėdienė Indrė , Žilionis Rapolas , Mašalaitė Kristina , Norkienė Milda , Šinkūnas Andrius , Gedvilaitė Alma , Kučinskaitė-Kodzė Indrė , Žvirblienė Aurelija
Published: March 2022

Viral antigens can activate phagocytes, inducing inflammation, but the mechanisms are barely explored. The aim of this study is to investigate how viral oligomeric proteins of different structures induce inflammatory response in macrophages. Human THP-1 cell line was used to prepare macrophages that were treated with filamentous nucleocapsid-like particles (NLPs) of paramyxoviruses and spherical virus-like particles (VLPs) of human polyomaviruses. The effects of viral proteins on cell viability, pro-inflammatory cytokines’ production, and NLRP3 inflammasome activation were investigated. Filamentous NLPs did not induce inflammation while spherical VLPs mediated inflammatory response followed by NLRP3 inflammasome activation. Inhibitors of cathepsins and K+efflux decreased IL-1β release and cell death, indicating a complex inflammasome activation process. A similar activation pattern was observed in primary human macrophages. Single-cell RNAseq analysis of THP-1 cells revealed several cell activation states different in inflammation-related genes. This study provides new insights into the interaction of viral proteins with immune cells and suggests that structural properties of oligomeric proteins may define cell activation pathways.
Novel Synthetic Lipopeptides as Potential Mucosal Adjuvants Enhanced SARS-CoV-2 rRBD-Induced Immune Response
Authors: Mao Ling , Liu Chang , Liu Jing-Yi , Jin Zi-Li , Jin Zhe , Xue Ruo-Yi , Feng Rang , Li Guo-Cheng , Deng Yan , Cheng Hao , Zou Quan-Ming , Li Hai-Bo
Published: March 2022

As TLR2 agonists, several lipopeptides had been proved to be candidate vaccine adjuvants. In our previous study, lipopeptides mimicking N-terminal structures of the bacterial lipoproteins were also able to promote antigen-specific immune response. However, the structure-activity relationship of lipopeptides as TLR2 agonists is still unclear. Here, 23 synthetic lipopeptides with the same lipid moiety but different peptide sequences were synthesized, and their TLR2 activities in vitro and mucosal adjuvant effects to OVA were evaluated. LP1-14, LP1-30, LP1-34 and LP2-2 exhibited significantly lower cytotoxicity and stronger TLR2 activity compared with Pam2CSK4, the latter being one of the most potent TLR2 agonists. LP1-34 and LP2-2 assisted OVA to induce more profound specific IgG in sera or sIgA in BALF than Pam2CSK4. Furthermore, the possibility of LP1-34, LP2-2 and Pam2CSK4 as the mucosal adjuvant for the SARS-CoV-2 recombinant RBD (rRBD) was investigated. Intranasally immunized with rRBD plus either the novel lipopeptide or Pam2CSK4 significantly increased the levels of specific serum and respiratory mucosal IgG and IgA, while rRBD alone failed to induce specific immune response due to its low immunogenicity. The novel lipopeptides, especially LP2-2, significantly increased levels of rRBD-induced SARS-CoV-2 neutralizing antibody in sera, BALF and nasal wash. Finally, Support vector machine (SVM) results suggested that charged residues in lipopeptides might be beneficial to the agonist activity, while lipophilic residues might adversely affect the agonistic activity. Figuring out the relationship between peptide sequence in the lipopeptide and its TLR2 activity may lay the foundation for the rational design of novel lipopeptide adjuvant for COVID-19 vaccine.
Who Gets the Catch? How Conventional Catch Attribution Frameworks Undermine Equity in Transboundary Fisheries
Authors: Davis Ruth A. , Hanich Quentin , Haas Bianca , Cisneros-Montemayor Andrés M. , Azmi Kamal , Seto Katherine L. , Swartz Wilf , González-Espinosa Pedro C. , Colléter Mathieu , Adams Timothy J. H.
Published: March 2022

The focus on flag States for the purpose of attributing fisheries catch is inconsistent with the assignment of sovereign rights to coastal States under international law and undermines equity in contemporary quota allocation negotiations. We propose modernizing reporting frameworks to include zone-based reporting of fish catches to more equitably present data, ensure consistency with the Law of the Sea, and better support the realization by developing coastal States of their development aspirations consistent with SDG 14, Life Below Water. States are already required to collect the data necessary to support this change, and many regional fisheries management authorities already do so. Reforms to data collection and reporting mechanisms should support zone-based catch attribution as a central feature of negotiations around access to future fishing opportunities on shared resources. Doing so will ensure that the sovereign rights of developing coastal States are properly accounted for and implemented.
Comparison of Neoadjuvant Chemotherapy Efficiency in Advanced Ovarian Cancer Patients Treated With Paclitaxel Plus Carboplatin and Intraperitoneal Bevacizumab vs. Paclitaxel With Carboplatin
Authors: Tao Yin , Tang Xue-Ting , Li Xing , Wu An-Shan , Zhou Hou-Shen , Zhou Cheng-fang
Published: March 2022

Objective

This study evaluated the role of neoadjuvant chemotherapy (NACT) with bevacizumab intraperitoneal perfusion in advanced ovarian cancer (AOC).

Methods

In this study, 80 patients with advanced epithelial ovarian cancer (stage IIIc or IV) who received NACT at the Central Hospital of Zhuzhou between February 2019 and October 2020 were enrolled. Patients were randomized to receive paclitaxel plus carboplatin (TC) or TC plus intraperitoneal perfusion of bevacizumab (TCB). The effect of chemotherapy was assessed following two cycles of chemotherapy. Cancer antigen 125 (CA125), tumor size, ascites volume, bleeding volume, duration of operation, surgical satisfaction rate, complication rate, and residual tumor were assessed to monitor response to chemotherapy.

Results

Treatment with TCB regimen significantly reduced serum levels of CA125 and ascites volume (p < 0.001). Meanwhile, the TCB group had significantly lower intraoperative blood loss and shorter operation time (p < 0.001). Most importantly, patients treated with TCB regimen had a higher surgical satisfaction rate (p < 0.01). Moreover, the incidence of postoperative wound infection, hypoproteinemia, abdominal distension, and fever was lower in the TCB group compared with the TC group. Assessment of adverse reactions during chemotherapy showed no severe complications between the two groups.

Conclusions

The results demonstrated that the TCB regimen is superior to the TC regimen alone in the treatment of AOC. These findings could help improve the surgical satisfaction rate, provide more effective treatment strategies to prolong progression-free survival and reduce postoperative complications, and promote surgical recovery in AOC.
Prevalence and Risk Factors for Human T-Cell Lymphotropic Virus (HTLV) in Blood Donors in Brazil—A 10-Year Study (2007–2016)
Authors: Miranda Carolina , Utsch-Gonçalves Denise , Piassi Fabiana Chagas Camargos , Loureiro Paula , Gomes Isabel , Ribeiro Maísa Aparecida , de Almeida-Neto César , Blatyta Paula , Amorim Luiz , Garcia Mateos Sheila Oliveira , Murphy Edward L. , Custer Brian , Carneiro-Proietti Anna Barbara F. , Sabino Ester C.
Published: March 2022

It is unknown whether HTLV-1/2 prevalence has been stable or changing with time in Brazil. We present a 10-year (2007–2016) analysis of HTLV-1/2 infection in first-time blood donors from four blood banks in Brazil. The Brazilian blood centers participating in this multicenter Recipient Epidemiology and Donor Evaluation Study (REDS) are located in Recife in the Northeast and in São Paulo, Rio de Janeiro and Belo Horizonte located in the Southeast of the country. A previous REDS study using the same database from 2007 to 2009 showed that the prevalence per 100,000 donors was 222 in Recife, 83 in Belo Horizonte and 101 in São Paulo. From 2007 to 2016, HTLV-1/2 prevalence was calculated by year, blood center and birth cohort. Covariates included age, gender, schooling, self-reported skin color and type of donation. From 1,092,174 first-blood donations, in the general analysis, HTLV-1/2 infection predominated in females, donors over 50 years of age, black skin color and less educated. The average prevalence was 228 per 100,000 donors in Recife, 222 in Rio de Janeiro, 104 in Belo Horizonte and 103 in São Paulo. In the 10-year analysis, HTLV-1/2 prevalence was stable, but a trend was observed toward an increase in HTLV-1/2 infection among younger people (p < 0.001), males (p = 0.049), those with white skin color (p < 0.001), and higher education (p = 0.014). Therefore, this 10-year surveillance of the infection showed stable HTLV-1/2 prevalence overall but a trend toward increased prevalence among the younger and more educated donors despite Brazilian policies to control sexually transmitted infections being in place for more than 10 years.
Comparative Analysis of the Gut Microbiota of Mongolian Gazelle (Procapra gutturosa) Under Fragmented Habitats
Authors: Shi Lupeng , Yang Xiufeng , Dou Huashan , Lyu Tianshu , Wang Lidong , Zhou Shengyang , Shang Yongquan , Dong Yuehuan , Zhang Honghai
Published: March 2022

The existence of man-made facilities such as pasture fences makes the grassland ecosystem fragmented and endangers the survival of local wild animals. The Mongolian gazelle is highly sensitive to hunting and habitat destruction, and is one of the most threatened artiodactyls in Eurasia. It provides a critical model to studying gut microbiota under fragmented habitats. Therefore, we applied metagenomics sequencing to analyze the gut microbiota communities and functions of Mongolian gazelle under fragmented habitats. The results demonstrated that there were no significant differences in gut microbial communities between the different groups at both the phylum and genus level. The functional analyses showed that the Mongolian gazelle in fragmented habitat had a stronger ability to degrade naphthalene, but their ability to absorb carbohydrates was weaker. This study provided fundamental information about the gut microbiota of Mongolian gazelle, and we recommend reducing habitat fragmentation to better protect the Mongolian gazelle.
Prolonged Outbreak of Carbapenem and Colistin-Resistant Klebsiella pneumoniae at a Large Tertiary Hospital in Brazil
Authors: Rocha Verônica França Diniz , Barbosa Matheus Sales , Leal Helena Ferreira , Silva Giulyana Evelyn Oliveira , Sales Nabila Monalisa Mendes Dantas , Monteiro Adriano de Souza Santos , Azevedo Jailton , Malheiros Allan Roberto Xavier , Ataide Ledilce Almeida , Moreira Beatriz Meurer , Reis Mitermayer Galvão , Bahia Fabianna Márcia Maranhão , Reis Joice Neves
Published: March 2022

Multidrug-resistant gram-negative bacteria, such as carbapenem and colistin-resistant Klebsiella pneumoniae (ColR-CRKP), represent a major problem for health systems worldwide and have high lethality. This study investigated the genetic relationship, antimicrobial susceptibility profile, and resistance mechanisms to ColR-CRKP isolates from patients infected/colonized in a tertiary hospital in Salvador, Bahia/Brazil. From September 2016 to January 2018, 46 patients (56 ColR-CRKP positive cultures) were enrolled in the investigation but clinical and demographic data were obtained from 31 patients. Most of them were men (67.7%) and elderly (median age of 62 years old), and the median Charlson score was 3. The main comorbidities were systemic arterial hypertension (38.7%), diabetes (32.2%), and cerebrovascular disease (25.8%). The average hospitalization stay until ColR-CRKP identification in days were 35.12. A total of 90.6% used mechanical ventilation and 93.7% used a central venous catheter. Of the 31 patients who had the data evaluated, 12 had ColR-CRKP infection, and seven died (58.4%). Previous use of polymyxins was identified in 32.2% of the cases, and carbapenems were identified in 70.9%. The minimum inhibitory concentration (MIC) for colistin was > 16 μg/mL, with more than half of the isolates (55%) having a MIC of 256 μg/mL. The blaKPC gene was detected in 94.7% of the isolates, blaNDM in 16.0%, and blaGES in 1.7%. The blaOXA–48, blaVIM, and blaIMP genes were not detected. The mcr-1 test was negative in all 56 isolates. Alteration of the mgrB gene was detected in 87.5% (n = 49/56) of the isolates, and of these, 49.0% (24/49) had alteration in size probably due to IS903B, 22.4% (11/49) did not have the mgrB gene detected, 20.4% (10/49) presented the IS903B, 6.1% (3/49) had a premature stop codon (Q30*), and 2.1% (1/49) presented a thymine deletion at position 104 – 104delT (F35fs). The PFGE profile showed a monoclonal profile in 84.7% of the isolates in different hospital sectors, with ST11 (CC-258) being the most frequent sequence type. This study presents a prolonged outbreak of ColR-CRKP in which 83.9% of the isolates belonged to the same cluster, and 67.6% of the patients evaluated had not used polymyxin, suggesting the possibility of cross-transmission of ColR-CRKP isolates.
Microbial Hydrocarbon Degradation in Guaymas Basin—Exploring the Roles and Potential Interactions of Fungi and Sulfate-Reducing Bacteria
Authors: Edgcomb Virginia P. , Teske Andreas P. , Mara Paraskevi
Published: March 2022

Hydrocarbons are degraded by specialized types of bacteria, archaea, and fungi. Their occurrence in marine hydrocarbon seeps and sediments prompted a study of their role and their potential interactions, using the hydrocarbon-rich hydrothermal sediments of Guaymas Basin in the Gulf of California as a model system. This sedimented vent site is characterized by localized hydrothermal circulation that introduces seawater sulfate into methane- and hydrocarbon-rich sediments, and thus selects for diverse hydrocarbon-degrading communities of which methane, alkane- and aromatics-oxidizing sulfate-reducing bacteria and archaea have been especially well-studied. Current molecular and cultivation surveys are detecting diverse fungi in Guaymas Basin hydrothermal sediments, and draw attention to possible fungal-bacterial interactions. In this Hypothesis and Theory article, we report on background, recent results and outcomes, and underlying hypotheses that guide current experiments on this topic in the Edgcomb and Teske labs in 2021, and that we will revisit during our ongoing investigations of bacterial, archaeal, and fungal communities in the deep sedimentary subsurface of Guaymas Basin.
Human Mitochondrial DNA Polymerase Metal Dependent UV Lesion Bypassing Ability
Authors: Park Joon , Baruch-Torres Noe , Iwai Shigenori , Herrmann Geoffrey K. , Brieba Luis G. , Yin Y. Whitney
Published: March 2022

Human mitochondrial DNA contains more UV-induced lesions than the nuclear DNA due to lack of mechanism to remove bulky photoproducts. Human DNA polymerase gamma (Pol γ) is the sole DNA replicase in mitochondria, which contains a polymerase (pol) and an exonuclease (exo) active site. Previous studies showed that Pol γ only displays UV lesion bypassing when its exonuclease activity is obliterated. To investigate the reaction environment on Pol γ translesion activity, we tested Pol γ DNA activity in the presence of different metal ions. While Pol γ is unable to replicate through UV lesions on DNA templates in the presence of Mg2+, it exhibits robust translesion DNA synthesis (TLS) on cyclobutane pyrimidine dimer (CPD)-containing template when Mg2+ was mixed with or completely replaced by Mn2+. Under these conditions, the efficiency of Pol γ′s TLS opposite CPD is near to that on a non-damaged template and is 800-fold higher than that of exonuclease-deficient Pol γ. Interestingly, Pol γ exhibits higher exonuclease activity in the presence of Mn2+ than with Mg2+, suggesting Mn2+-stimulated Pol γ TLS is not via suppressing its exonuclease activity. We suggest that Mn2+ ion expands Pol γ′s pol active site relative to Mg2+ so that a UV lesion can be accommodated and blocks the communication between pol and exo active sites to execute translesion DNA synthesis.
A Preclinical Rodent Model for Repetitive Subconcussive Head Impact Exposure in Contact Sport Athletes
Authors: Stemper Brian D. , Shah Alok , Chiariello Rachel , McCarthy Cassandra , Jessen Kristin , Sarka Bailey , Seifert Jack , Budde Matthew D. , Wang Kevin , Olsen Christopher M. , McCrea Michael
Published: March 2022

Repetitive subconcussive head impact exposure has been associated with clinical and MRI changes in some non-concussed contact sport athletes over the course of a season. However, analysis of human tolerance for repeated head impacts is complicated by concussion and head impact exposure history, genetics, and other personal factors. Therefore, the objective of the current study was to develop a rodent model for repetitive subconcussive head impact exposure that can be used to understand injury mechanisms and tolerance in the human. This study incorporated the Medical College of Wisconsin Rotational Injury Model to expose rats to multiple low-level head accelerations per day over a 4-week period. The peak magnitude of head accelerations were scaled from our prior human studies of contact sport athletes and the number of exposures per day were based on the median (moderate exposure) and 95th percentile (high exposure) number of exposures per day across the human sample. Following the exposure protocol, rats were assessed for cognitive deficits, emotional changes, blood serum levels of axonal injury biomarkers, and histopathological evidence of injury. High exposure rats demonstrated cognitive deficits and evidence of anxiety-like behaviors relative to shams. Moderate exposure rats did not demonstrate either of those behaviors. Similarly, high exposure rats had histopathological evidence of gliosis [i.e., elevated Iba1 intensity and glial fibrillary acidic protein (GFAP) volume relative to shams] in the basolateral amygdala and other areas. Blood serum levels of neurofilament light (NFL) demonstrated a dose response relationship with increasing numbers of low-level head acceleration exposures with a higher week-to-week rate of NFL increase for the high exposure group compared to the moderate exposure group. These findings demonstrate a cumulative effect of repeated low-level head accelerations and provide a model that can be used in future studies to better understand mechanisms and tolerance for brain injury resulting from repeated low-level head accelerations, with scalable biomechanics between the rat and human.
Case Report: A Novel Missense Mutation c.517G>C in the UMPS Gene Associated With Mild Orotic Aciduria
Authors: Ma Rui , Ye Jing , Han Jiaqi , Gao Lehong , Wang Chaodong , Wang Yuping
Published: March 2022

Background

Hereditary orotic aciduria (HOA) is a rare genetic disorder of pyrimidine metabolism caused by variations in the uridine monophosphate synthetase (UMPS) gene and inheritance are autosomal recessive. Heterozygous UMPS mutations can also lead to orotic aciduria without clinical consequence.

Methods

We conducted molecular genetic analyses on proband using whole-exome sequencing (WES) and on 12 family members using Sanger sequencing for UMPS mutation. We analyzed the urine metabolites of family members carrying UMPS heterozygous variants with standard gas chromatography-mass spectrometry (GC-MS).

Results

We identified a novel UMPS mutation (c.517G>C) in a Chinese-origin of orotic aciduria pedigree. The proband presented with epilepsy and intellectual disability (ID). Other mutation carriers in our pedigree presented with mild orotic aciduria without relevant medical complaints except for the proband.

Conclusion

Our study further expanded the genotype of orotic aciduria and highlighted the probability of misdiagnosis in clinical practice.
Balance Impairment in Fahr’s Disease: Mixed Signs of Parkinsonism and Cerebellar Disorder. A Case Study
Authors: Scarano Stefano , Rota Viviana , Tesio Luigi , Perucca Laura , Robecchi Majnardi Antonio , Caronni Antonio
Published: March 2022

Fahr’s disease is a rare idiopathic degenerative disease characterized by calcifications in the brain, and has also been associated with balance impairment. However, a detailed analysis of balance in these patients has not been performed. A 69-year-old woman with Fahr’s disease presented with a long-lasting subjective imbalance. Balance was analyzed using both clinical (EquiScale, Timed Up and Go test, and Dizziness Handicap Inventory-short form) and instrumented tests (the sway of the body center of mass during quiet, perturbed, and self-perturbed stance, and the peak curvature of the center of mass during single stance while walking on a force-treadmill). The patient’s balance was normal during clinical tests and walking. However, during standing, a striking impairment in vestibular control of balance emerged. The balance behavior displayed mixed parkinsonian (e.g., slowness and reduced amplitude of movement) and cerebellar (e.g., increased sway during standing in all conditions and decomposition of movement) features, with a discrepancy between the high severity of the static and the low severity of the dynamic balance impairment. The balance impairment characteristics outlined in this study could help neurologists and physiatrists detect, stage, and treat this rare condition.
Panama: An Open-Source Educational App for Ion Channel Biophysics Simulation
Authors: Rajbanshi Binita , Guruacharya Anuj
Published: March 2022

This article describes an open-source educational software, called Panama, developed using R, that simulates the biophysics of voltage-gated ion channels. It is made publicly available as an R package called Panama and as a web app at http://www.neuronsimulator.com. A need for such a tool was observed after surveying available software packages. Available packages are either not robust enough to simulate multiple ion channels, too complicated, usable only as desktop software, not optimized for mobile devices, not interactive, lack intuitive graphical controls, or not appropriate for educational purposes. This app simulates the physiology of voltage-gated sodium, potassium, and chlorine channels; A channel; M channel; AHP channel; calcium-activated potassium channel; transient-calcium channel; and leak-calcium channel, under current-clamp or voltage-clamp conditions. As the input values on the app are changed, the output can be instantaneously visualized on the web browser and downloaded as a data table to be further analyzed in a spreadsheet program. This app is a first-of-its-kind, mobile-friendly, and touchscreen-friendly online tool that can be used as an installable R package. It has intuitive touch-optimized controls, instantaneous graphical output, and yet is pedagogically robust for educational purposes.
Learning New Vocabulary Implicitly During Sleep Transfers With Cross-Modal Generalization Into Wakefulness
Authors: Koroma Matthieu , Elbaz Maxime , Léger Damien , Kouider Sid
Published: March 2022

New information can be learned during sleep but the extent to which we can access this knowledge after awakening is far less understood. Using a novel Associative Transfer Learning paradigm, we show that, after hearing unknown Japanese words with sounds referring to their meaning during sleep, participants could identify the images depicting the meaning of newly acquired Japanese words after awakening (N = 22). Moreover, we demonstrate that this cross-modal generalization is implicit, meaning that participants remain unaware of this knowledge. Using electroencephalography, we further show that frontal slow-wave responses to auditory stimuli during sleep predicted memory performance after awakening. This neural signature of memory formation gradually emerged over the course of the sleep phase, highlighting the dynamics of associative learning during sleep. This study provides novel evidence that the formation of new associative memories can be traced back to the dynamics of slow-wave responses to stimuli during sleep and that their implicit transfer into wakefulness can be generalized across sensory modalities.
Residual Block Based Nested U-Type Architecture for Multi-Modal Brain Tumor Image Segmentation
Authors: Chen Sirui , Zhao Shengjie , Lan Quan
Published: March 2022

Multi-modal magnetic resonance imaging (MRI) segmentation of brain tumors is a hot topic in brain tumor processing research in recent years, which can make full use of the feature information of different modalities in MRI images, so that tumors can be segmented more effectively. In this article, convolutional neural networks (CNN) is used as a tool to improve the efficiency and effectiveness of segmentation. Based on this, Dense-ResUNet, a multi-modal MRI image segmentation model for brain tumors is created. The Dense-ResUNet consists of a series of nested dense convolutional blocks and a U-Net shaped model with residual connections. The nested dense convolutional blocks can bridge the semantic disparity between the feature maps of the encoder and decoder before fusion and make full use of different levels of features. The residual blocks and skip connection can extract pixel information from the image and skip the link to solve the traditional deep traditional CNN network problem. The experiment results show that our Dense-ResUNet can effectively help to extract the brain tumor and has great clinical research and application value.
Dietary Pattern Extraction Using Natural Language Processing Techniques
Authors: Choi Insu , Kim Jihye , Kim Woo Chang
Published: March 2022

In this study, we observed the changes in dietary patterns among Korean adults in the previous decade. We evaluated dietary intake using 24-h recall data from the fourth (2007–2009) and seventh (2016–2018) Korea National Health and Nutrition Examination Survey. Machine learning-based methodologies were used to extract these dietary patterns. Particularly, we observed three dietary patterns from each survey similar to the traditional and Western dietary patterns in 2007–2009 and 2016–2018, respectively. Our results reveal a considerable increase in the number of Western dietary patterns compared with the previous decade. Thus, our study contributes to the use of novel methods using natural language processing (NLP) techniques for dietary pattern extraction to obtain more useful dietary information, unlike the traditional methodology.
Exercise Interventions Combined With Dietary Supplements in Type 2 Diabetes Mellitus Patients—A Systematic Review of Relevant Health Outcomes
Authors: Meuffels Frederike Maria , Isenmann Eduard , Strube Malte , Lesch Alessio , Oberste Max , Brinkmann Christian
Published: March 2022

Introduction

Physical training can improve several health variables in patients with type 2 diabetes mellitus (T2DM). A growing body of studies also finds a positive influence of dietary supplement (DS) intake. The aim of this review is to shed light on the possible effects of training interventions combined with DS intake in T2DM patients.

Methods

A systematic search was performed following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines in the PubMed and BISp Surf databases. Inclusion criteria were defined using the Patient-Intervention-Comparison-Outcome (PICO) scheme. The Physiotherapy Evidence Database (PEDro) scale was used for quality assessment and risk of bias analysis.

Results

Ten controlled interventional studies with a total number of 643 subjects met the inclusion criteria. These studies investigated the effects of (a) vitamin D (VD), (b) VD + whey protein, (c) polyphenol containing antioxidant capsules, (d) creatine, (e) L-arginine, (f) leucine-rich amino acids, and (g) broccoli sprouts powder. Eight studies investigated effects on one or more of the following health outcomes: body mass index, fat mass, insulin resistance, glycemic control, lipid profile, oxidative stress/antioxidative capacity and/or inflammatory markers/molecules. Five of the studies show clear superior effects of physical training combined with DS intake (supplements a, b, c, e) on some of these variables compared with training only. However, one study indicates that VD intake might attenuate the training effects on triglyceride levels. Another study found that training + VD + whey protein intake increased tumor necrosis factor-α levels in T2DM patients. The effects of training combined with DS intake on renal function (supplement d) or incretin metabolism (supplement a) were investigated in two further studies. These studies do not show any additional effects of DS intake. The quality of the majority of the studies was high.

Conclusion

DS intake can potentially increase the benefits of physical training for specific health outcomes in T2DM patients. However, negative effects can also be observed. Possible cellular and molecular mechanisms behind potential synergistic or divergent effects of exercise training and DS use in T2DM should be explored in detail in future studies for the development of safe recommendations.
Management of Motion and Anatomical Variations in Charged Particle Therapy: Past, Present, and Into the Future
Authors: Pakela Julia M. , Knopf Antje , Dong Lei , Rucinski Antoni , Zou Wei
Published: March 2022

The major aim of radiation therapy is to provide curative or palliative treatment to cancerous malignancies while minimizing damage to healthy tissues. Charged particle radiotherapy utilizing carbon ions or protons is uniquely suited for this task due to its ability to achieve highly conformal dose distributions around the tumor volume. For these treatment modalities, uncertainties in the localization of patient anatomy due to inter- and intra-fractional motion present a heightened risk of undesired dose delivery. A diverse range of mitigation strategies have been developed and clinically implemented in various disease sites to monitor and correct for patient motion, but much work remains. This review provides an overview of current clinical practices for inter and intra-fractional motion management in charged particle therapy, including motion control, current imaging and motion tracking modalities, as well as treatment planning and delivery techniques. We also cover progress to date on emerging technologies including particle-based radiography imaging, novel treatment delivery methods such as tumor tracking and FLASH, and artificial intelligence and discuss their potential impact towards improving or increasing the challenge of motion mitigation in charged particle therapy.
The Effect of Metabolic Syndrome on the Outcome of Hepatitis B-Associated Hepatocellular Carcinoma Patients After Hepatectomy: A Multicenter Study
Authors: Dai Junlong , Zhu Xinrui , Shen Junyi , Zhang Yu , Xie Fei , Yu Yu , Jiang Kangyi , Wen Tianfu , Li Chuan
Published: March 2022

Background and Aims

With changes in dietary patterns and modern lifestyles, the prevalence of metabolic syndrome (MetS) in hepatitis B virus (HBV)-associated hepatocellular carcinoma (HCC) patients is increasing. The purpose of our study is to explore the impact of MetS on the prognosis of HBV-associated HCC patients following radical hepatectomy.

Methods

Data on consecutive HCC patients who underwent radical hepatectomy were prospectively obtained and retrospectively analyzed from seven medical centers in west areas of China. Propensity score matching (PSM) analysis was conducted to balance the heterogeneity between MetS-HBV-HCC group and HBV-HCC group. Surgical outcomes have been contrasted between the two groups.

Results

In 984 patients, 179 (18.19%) were diagnosed with MetS. Patients in the MetS-HBV-HCC group had higher CCI score (8.7 [0.0, 12.2] vs. 0.0 [0.0, 8.7], p = 0.048) and a higher rate of severe complications (Clavien–Dindo ≥3, 7.82% vs. 4.10%, p = 0.035), to be more precise: postoperative liver failure, hydrothorax, and hyperglycemia. Patients in the MetS-HBV-HCC group tended to have worse 5-year overall survival (OS) rate (61.45% vs. 69.94%, p = 0.027) and recurrence-free survival (RFS) rate (62.57% vs. 53.66%, p = 0.030), consistent with the results of the competing risk models. Last, MetS was identified to be an independent unfavorable prognostic factor in the multivariate analysis.

Conclusion

The involvement of MetS increased the risk of postoperative complications and worsens the overall survival and recurrence-free survival time, reminding us to be more prudent to face metabolic disorder among tumor patients.
DNA Methylation Associates With Clinical Courses of Atypical Meningiomas: A Matched Case–Control Study
Authors: Millesi Matthias , Ryba Alice Senta , Hainfellner Johannes A. , Roetzer Thomas , Berghoff Anna Sophie , Preusser Matthias , Heller Gerwin , Tomasich Erwin , Sahm Felix , Roessler Karl , Wolfsberger Stefan
Published: March 2022

Background

Accounting for 15–20% of all meningiomas, WHO grade II meningiomas represent an intermediate group regarding risk of tumor recurrence. However, even within this subgroup varying clinical courses are observed with potential occurrence of multiple recurrences. Recently, DNA methylation profiles showed their value for distinguishing biological behaviors in meningiomas. Therefore, aim of this study was to investigate DNA methylation profiles in WHO grade II meningiomas.

Methods

All patients that underwent resection of WHO grade II meningiomas between 1993 and 2015 were screened for a dismal course clinical course with ≥2 recurrences. These were matched to control cases with benign clinical courses without tumor recurrence. DNA methylation was assessed using the Infinium Methylation EPIC BeadChip microarray. Unsupervised hierarchical clustering was performed for identification of DNA methylation profiles associated with such a dismal clinical course.

Results

Overall, 11 patients with WHO grade II meningiomas with ≥2 recurrences (Group dismal) and matched 11 patients without tumor recurrence (Group benign) were identified. DNA methylation profiles revealed 3 clusters—one comprising only patients of group dismal, a second cluster comprising mainly patients from group benign and a third cluster comprising one group dismal and one group benign patient. Based on differential methylation pattern associations with the Wnt and the related cadherin signaling pathway was observed.

Conclusion

DNA methylation clustering showed remarkable differences between two matched subgroups of WHO grade II meningiomas. Thus, DNA methylation profiles may have the potential to support prognostic considerations regarding meningioma recurrence and radiotherapeutic treatment allocation after surgical resection.
UGT1A1 Allele Test Not Only Minimizes the Toxicity But Also Maximizes the Therapeutic Effect of Irinotecan in the Treatment of Colorectal Cancer: A Narrative Review
Authors: Li Yaoyuan , Zheng Honggang , Zhang Xiwen , Xi Yupeng , Cheng Mengqi , Zhao Yuwei , Wang Liya , Hua Baojin
Published: March 2022

Background

Irinotecan is a first-line agent in the systematic treatment of colorectal cancer (CRC). Adjusting the dose of irinotecan according to the uridine diphosphate glucuronosyltransferase (UGT) 1A1 genotype reflects the principle of individualized and precision medicine, and may improve the chemotherapy response and survival of CRC.

Methods

To summarize the feasibility, efficacy and safety of high dose irinotecan in CRC patients with UGT1A1 wild-type or heterozygous alleles, PubMed, EMBASE, MEDLINE and the Cochrane Central Register of Controlled Trials online databases were searched from the date of creation to October 22, 2021.

Results

A total of 1,186 related literatures were searched, and 14 studies were included for review according to the inclusion criteria. The results indicated that the maximum tolerated dose of irinotecan in CRC patients with UGT1A1 wild-type or heterozygous variant was significantly higher than the conventional recommended dose. Chemotherapy based on high dose irinotecan improved the clinical efficacy in mCRC patients with UGT1A1*28 wild-type and heterozygous variant, and the toxicity was tolerated, as reflected in most studies.

Conclusions

We are optimistic about the application of high dose irinotecan for mCRC patients with UGT1A1*28 wild-type or heterozygous variant, which will provide a relatively clear direction for future research and certain norms for clinical practice.
Melanoma and Nanotechnology-Based Treatment
Authors: Zeng Hong , Li Jia , Hou Kai , Wu Yiping , Chen Hongbo , Ning Zeng
Published: March 2022

Melanoma is a malignant tumor arising in melanocytes from the basal layer of the epidermis and is the fifth most commonly diagnosed cancer in the United States. Melanoma is aggressive and easily metastasizes, and the survival rate is low. Nanotechnology-based diagnosis and treatment of melanoma have attracted increasing attention. Importantly, nano drug delivery systems have the advantages of increasing drug solubility, enhancing drug stability, prolonging half-life, optimizing bioavailability, targeting tumors, and minimizing side effects; thus, these systems can facilitate tumor cytotoxicity to achieve effective treatment of melanoma. In this review, we discuss current nanosystems used in the diagnosis and treatment of melanoma, including lipid systems, inorganic nanoparticles, polymeric systems, and natural nanosystems. The excellent characteristics of novel and effective drug delivery systems provide a basis for the broad applications of these systems in the diagnosis and treatment of melanoma, particularly metastatic melanoma.
Application of Allogeneic Human Acellular Dermal Matrix Reduces the Incidence of Fistula in Hypospadias Repair
Authors: Wu Shijian , Ye Chenglong , Yang Huai , Chen Bote , Nie Haibo , Li Shaowei
Published: March 2022

Background

Urethrocutaneous fistula is one of the most common complications arising from hypospadias surgery. The purpose of our study was to investigate the effectiveness and safety of allogeneic human acellular dermal matrix (HADM) application as a means of preventing the occurrence of urethrocutaneous fistula following hypospadias surgery.

Methods

This is a non-randomized study of 219 cases (out of 270 patients with hypospadias) which satisfied inclusion and exclusion criteria. These patients were divided into two groups: 101 HADM patients, and 118 control patients (who did not receive HADM). In the control group, 77 boys were treated by single-stage urethroplasty (TIP) and 41 underwent staged urethroplasty (Thiersch-Duplay). In the HADM group, 59 boys underwent the TIP and 42 underwent the Thiersch-Duplay. In the postoperative period, we recorded the incidence of infection, urethrocutaneous fistula, and urethral stricture complications in these two groups of patients. The effectiveness and safety of HADM in preventing urethrocutaneous fistula following hypospadias surgery were evaluated according to these indicators.

Results

In the control group, following the operation there were 16 cases of infection, 38 cases of urethrocutaneous fistula after extubating, and 5 cases of urethral stricture. In the HADM group, there were 19 cases of postoperative infection, 12 cases of urethrocutaneous fistula after extubating, and 5 children with urethral stricture. In comparing the two groups, it was found that the postoperative infection rate (13.6 vs. 18.8%) and the incidence of urethral stricture (4.2 vs. 5.0%) were not statistically significant (P > 0.05), while the postoperative urethrocutaneous fistula rate (32.2 vs. 11.9%) was statistically significant (P < 0.001).

Conclusion

It is found that HADM application can significantly reduce the incidence of urethrocutaneous fistula complications, without increasing the risk of infection and urethral stricture.
Simulation-Based Training in High-Quality Cardiopulmonary Resuscitation Among Neonatal Intensive Care Unit Providers
Authors: Parikh Pratik , Samraj Ravi , Ogbeifun Henry , Sumbel Lydia , Brimager Kelli , Alhendy Mohammed , McElroy James , Whitt Dottie , Henderson Cody , Bhalala Utpal
Published: March 2022

Introduction

American Heart Association guidelines recommend the use of feedback devices for CPR provider resuscitation training. There is paucity of published literature regarding the utility of these devices especially in neonates and infants. We sought to evaluate if simulation-based education and debriefing using a CPR feedback device would improve CPR performance on an infant manikin in a cohort of NICU nurses as evaluated by CPR feedback device.

Methods

We conducted a prospective, observational simulation study to assess the quality of chest compressions by NICU nurses before and after debriefing using CPR quality data captured by an accelerometer-based device. Chest compression (CC) depth, rate, recoil, CC fraction and nursing confidence level related to performing a high-quality CPR were compared before and after debriefing using paired t-test and Wilcoxon rank sum test.

Results

A total of 62 NICU nurses participated in the study and all of them were Neonatal Resuscitation Program (NRP) certified. There was a significant improvement in CC depth and CC fraction [mean + SD values = 0.79 in + 0.17 (pre-debrief), 0.86 in + 0.21 (post-debrief) (p = 0.034) and 56.8% + 17.7 (pre-debrief), 70.8% + 18.4 (post-debrief) (0.0014), respectively]. There was no difference in CC rate (p = 0.36) and recoil (p = 0.25) between pre and post structured debriefing. The confidence level of nurses in all CPR dynamics (appropriate CC rate, CC depth, team communication, minimizing interruption in CC and coordinating CC with ventilation) was significantly higher after simulation and structured debriefing. All the nurses used 3:1 compression: ventilation ratio of NRP despite the patient being a 4 month old premature baby in the NICU.

Conclusions

Simulation training and debriefing of NICU nurses using CPR feedback device improved their chest compression quality on an infant mannequin and their confidence level for performing high-quality CPR. NICU providers tend to use NRP protocol of 3:1 compression: ventilation ratio during CPR in the NICU irrespective of age of the infant.