bluuebunny/crossref_metadata_2025 huggingface dataset:
N6-Methyladenosine RNA Modification in the Tumor Immune Microenvironment: Novel Implications for Immunotherapy
Authors: Guo Liting , Yang Hui , Zhou Chenfei , Shi Yan , Huang Lei , Zhang Jun
Published: December 2021

N6-methyladenosine (m6A) methylation is one of the most common modifications of RNA in eukaryotic cells, and is mainly regulated by m6A methyltransferases (writers), m6A demethylases (erasers), and m6A binding proteins (readers). Recently, accumulating evidence has shown that m6A methylation plays crucial roles in the regulation of the tumor immune microenvironment, greatly impacting the initiation, progression, and metastasis processes of various cancers. In this review we first briefly summarizes the m6A-related concepts and detection methods, and then describes in detail the associations of m6A methylation modification with various tumor immune components especially immune cells (e.g., regulatory T cells, dendritic cells, macrophages, and myeloid-derived suppressor cells) in a variety of cancers. We discuss the relationship between m6A methylation and cancer occurrence and development with the involvement of tumor immunity highlighted, suggesting novel markers and potential targets for molecular pathological diagnosis and immunotherapy of various cancers.
The Prebiotic Effects of Oats on Blood Lipids, Gut Microbiota, and Short-Chain Fatty Acids in Mildly Hypercholesterolemic Subjects Compared With Rice: A Randomized, Controlled Trial
Authors: Xu Dengfeng , Feng Meiyuan , Chu YiFang , Wang Shaokang , Shete Varsha , Tuohy Kieran M. , Liu Feng , Zhou Xirui , Kamil Alison , Pan Da , Liu Hechun , Yang Xian , Yang Chao , Zhu Baoli , Lv Na , Xiong Qian , Wang Xin , Sun Jianqin , Sun Guiju , Yang Yuexin
Published: December 2021

Phytochemicals derived from oats are reported to possess a beneficial effect on modulating dyslipidemia, specifically on lowering total and LDL cholesterol. However, deeper insights into its mechanism remain unclear. In this randomized controlled study, we assigned 210 mildly hypercholesterolemic subjects from three study centers across China (Beijing, Nanjing, and Shanghai) to consume 80 g of oats or rice daily for 45 days. Plasma lipid profiles, short chain fatty acids (SCFAs), and fecal microbiota were measured. The results showed that total cholesterol (TC) and non-high-density lipoprotein cholesterol (non-HDL-C) decreased significantly with both oats and rice intake after 30 and 45 days. The reduction in TC and non-HDL-C was greater in the participants consuming oats compared with rice at day 45 (p = 0.011 and 0.049, respectively). Oat consumption significantly increased the abundance of Akkermansia muciniphila and Roseburia, and the relative abundance of Dialister, Butyrivibrio, and Paraprevotella, and decreased unclassified f-Sutterellaceae. In the oat group, Bifidobacterium abundance was negatively correlated with LDL-C (p = 0.01, r = −0.31) and, TC and LDL-C were negatively correlated to Faecalibacterium prausnitzii (p = 0.02, r = −0.29; p = 0.03, r = −0.27, respectively). Enterobacteriaceae, Roseburia, and Faecalibacterium prausnitzii were positively correlated with plasma butyric acid and valeric acid concentrations and negatively correlated to isobutyric acid. HDL-C was negatively correlated with valeric acid (p = 0.02, r = −0.25) and total triglyceride (TG) was positively correlated to isovaleric acid (p = 0.03, r = 0.23). Taken together, oats consumption significantly reduced TC and LDL-C, and also mediated a prebiotic effect on gut microbiome. Akkermansia muciniphila, Roseburia, Bifidobacterium, and Faecalibacterium prausnitzii, and plasma SCFA correlated with oat-induced changes in plasma lipids, suggesting prebiotic activity of oats to modulate gut microbiome could contribute towards its cholesterol-lowering effect.
Immune Thrombocytopenia Induced by Immune Checkpoint Inhibitrs in Lung Cancer: Case Report and Literature Review
Authors: Xie Wang , Hu NaNa , Cao LeJie
Published: December 2021

Immune checkpoint inhibitors (ICIs), including antibodies targeting programmed cell death protein-1 (PD-1) and programmed cell death ligand-1 (PD-L1), are being extensively used on advanced human malignancies therapy. The treatment with ICIs have acquired durable tumor inhibition and changed the treatment landscape in lung cancer. Immune-related adverse events including pneumonitis and thyroiditis have been well described, but less frequent events, such as ICIs-induced thrombocytopenia, are now emerging and may sometimes be severe or fatal. Since early detection and prompt intervention are crucial to prevent fatal consequences, it is of outmost importance that medical staff is aware of these potential toxicities and learn to recognize and treat them adequately. This review focuses on the epidemiology, clinical presentation, mechanisms, and clinical management of ICIs-induced thrombocytopenia in patients with lung cancer. We also present a patient with advanced lung adenocarcinoma who received the PD-L1 inhibitor atezolizumab and eventually developed severe thrombocytopenia. The case indirectly suggests that cytokine changes might contribute to immune dysregulation in ICIs-induced thrombocytopenia.
Bacterial Nanotubes as Intercellular Linkages in Marine Assemblages
Authors: Patel Nirav , Yamada Yosuke , Azam Farooq
Published: December 2021

Several types of bacterial appendages, e.g., pili and fimbriae, are known for their role in promoting interactions and aggregation with particles and bacteria in the ocean. First discovered in Bacillus subtilis and Escherichia coli, but novel to marine bacteria, bacterial nanotubes are hollow tubular structures connecting cell pairs that allow for the internal transport of cytoplasmic metabolites across the connecting structure. While the significance of nanotubes in exchange of cytoplasmic content has been established in non-marine bacteria, their occurrence and potential ecological significance in marine bacteria has not been reported. Using multiple high-resolution microscopy methods (atomic force microscopy, scanning, and transmission electron microscopy), we have determined that marine bacteria isolates and natural assemblages from nearshore upper ocean waters can express bacterial nanotubes. In marine isolates Pseudoalteromonas sp. TW7 and Alteromonas sp. ALTSIO, individual bacterial nanotubes measured 50–160 nm in width and extended 100–600 nm between connected cells. The spatial coupling of different cells via nanotubes can last for at least 90 min, extending the duration of interaction events between marine bacteria within natural assemblages. The nanomechanical properties of bacterial nanotubes vary in adhesion and dissipation properties, which has implication for structural and functional variability of these structures in their ability to stick to surfaces and respond to mechanical forces. Nanotube frequency is low among cells in enriched natural assemblages, where nanotubes form short, intimate connections, <200 nm, between certain neighboring cells. Bacterial nanotubes can form the structural basis for a bacterial ensemble and function as a conduit for cytoplasmic exchange (not explicitly studied here) between members for multicellular coordination and expression. The structural measurements and nanomechanical analyses in this study also extends knowledge about the physical properties of bacterial nanotubes and their consequences for marine microenvironments. The discovery of nanotube expression in marine bacteria has significant potential implications regarding intimate bacterial interactions in spatially correlated marine microbial communities.
Soluble Iodine Speciation in Marine Aerosols Across the Indian and Pacific Ocean Basins
Authors: Droste Elise S. , Baker Alex R. , Yodle Chan , Smith Andrew , Ganzeveld Laurens
Published: December 2021

Iodine affects the radiative budget and the oxidative capacity of the atmosphere and is consequently involved in important climate feedbacks. A fraction of the iodine emitted by oceans ends up in aerosols, where complex halogen chemistry regulates the recycling of iodine to the gas-phase where it effectively destroys ozone. The iodine speciation and major ion composition of aerosol samples collected during four cruises in the East and West Pacific and Indian Oceans was studied to understand the influences on iodine’s gas-aerosol phase recycling. A significant inverse relationship exists between iodide (I–) and iodate (IO3–) proportions in both fine and coarse mode aerosols, with a relatively constant soluble organic iodine (SOI) fraction of 19.8% (median) for fine and coarse mode samples of all cruises combined. Consistent with previous work on the Atlantic Ocean, this work further provides observational support that IO3– reduction is attributed to aerosol acidity, which is associated to smaller aerosol particles and air masses that have been influenced by anthropogenic emissions. Significant correlations are found between SOI and I–, which supports hypotheses that SOI may be a source for I–. This data contributes to a growing observational dataset on aerosol iodine speciation and provides evidence for relatively constant proportions of iodine species in unpolluted marine aerosols. Future development in our understanding of iodine speciation depends on aerosol pH measurements and unravelling the complex composition of SOI in aerosols.
Gold Nanoclusters Exert Bactericidal Activity and Enhance Phagocytosis of Macrophage Mediated Killing of Fusobacterium nucleatum
Authors: Chen Rixin , Qiao Dan , Wang Peng , Li Lingjun , Zhang Yangheng , Yan Fuhua
Published: December 2021

Fusobacterium nucleatum is a typical periodontal opportunistic pathogen that contributes to inflammatory diseases at oral or extra-oral sites. The emergence of antibiotics resistance calls for a substitute therapeutic strategy to control bacterial infections effectively. In addition, macrophage is an essential part of host defense against microorganism invasion in vivo. Herein, we synthesized gold nanoclusters (AuNCs) as potent antibacterial material to kill F. nucleatum through bactericidal behavior and pro-phagocytic activity. Firstly, we evaluated the bactericidal effect of AuNCs on F. nucleatum by the means of plate counting, growth curve measurement, bacterial viability analysis, and live/dead fluorescent imaging. Morphological changes and the intracellular reactive oxygen species levels of bacteria were further analyzed to explore the possible mechanisms. Additionally, the impact of AuNCs on the ability of macrophages to uptake bacteria under normal and inflammatory circumstance was also evaluated by fluorescent imaging. We found that AuNCs exhibited superior antibacterial performance on F. nucleatum in vitro by a combination of membrane disruption and oxidative stress. Furthermore, in the presence of AuNCs, macrophages displayed enhanced phagocytosis against F. nucleatum without inducing any significant cytotoxicity. Therefore, AuNCs are providing a new platform for the prevention and treatment of F. nucleatum-associated diseases.
Change of Retinal Vessel Density After Lowering Intraocular Pressure in Ocular Hypertension
Authors: Chen Xuhao , Hong Ying , Di Haohao , Wu Qianru , Zhang Di , Zhang Chun
Published: December 2021

Purpose: To investigate the relationship between retinal microvasculature changes and intraocular pressure (IOP) for ocular hypertension (OHT) patients and further assess the factors associated with retinal microcirculation changes.

Methods: This was a single-center prospective study designed for OHT patients, which consisted of two visits. After collecting baseline data of those who met the eligibility criteria, these patients were treated with latanoprost 0.005% ophthalmic solution for 4 weeks. Peripapillary vessel density (VD) of radial peripapillary capillaries (RPC) layer, macular VD in both superficial and deep layers, and foveal avascular zone (FAZ) area were measured by optical coherence tomography angiography (OCTA) before and after the treatment. We compared the changes in IOP and VD among the two visits by paired-sample t-test. Bonferroni correction was applied. Factors associated with VD changes were analyzed by linear regression analysis.

Results: Thirty-four eyes of thirty-four patients were included. The mean IOP decreased by 6.5 ± 2.2 mmHg (p < 0.001). The peripapillary RPC VD increased significantly from 51.8 ± 2.5 to 53.0 ± 3.1% (Adjusted-p = 0.012). We found no significant difference in detailed sectors of the peripapillary region after correction. In the macular area, both the superficial and deep layers in foveal (superficial: 0.2 ± 1.9%, p = 0.523; deep: 0.0 ± 2.3%, p = 0.969) and parafoveal (superficial: 0.3 ± 3.0%, p = 0.565; deep: 0.5 ± 3.1%, p = 0.423) VD remained unchanged. The decrease of the mean FAZ area was insignificant (p = 0.295). The percentage of IOP reduction (β = 0.330, p = 0.031) and the baseline RNFL thickness (β = 0.450, p = 0.004) significantly correlated with the percentage of peripapillary RPC VD improvement in the multivariate linear regression analysis.

Conclusion: The peripapillary VD in OHT patients increased after the reduction of IOP. The mild change of IOP did not alter the microcirculation in the macula. In addition, the percentage of IOP change and the baseline RNFL thickness were independent factors for the peripapillary RPC VD improvement.
Multimodal Imaging of Torpedo Maculopathy With Fluorescence Adaptive Optics Imaging of Individual Retinal Pigmented Epithelial Cells
Authors: Vienola Kari V. , Dansingani Kunal K. , Eller Andrew W. , Martel Joseph N. , Snyder Valerie C. , Rossi Ethan A.
Published: December 2021

Torpedo maculopathy (TM) is a rare congenital defect of the retinal pigment epithelium (RPE). The RPE is often evaluated clinically using fundus autofluorescence (AF), a technique that visualizes RPE structure at the tissue level from the intrinsic AF of RPE fluorophores. TM lesions typically emit little or no AF, but this macroscopic assessment is unable to resolve the RPE cells, leaving the organization of the RPE cell mosaic in TM unknown. We used fluorescence adaptive optics scanning laser ophthalmoscopy (AOSLO) to show here for the first time the microscopic cellular-level structural alterations to the RPE cell mosaic in TM that underlie the tissue-level changes seen in conventional clinical imaging. We evaluated two patients with TM using conventional clinical imaging techniques and adaptive optics (AO) infrared autofluorescence (IRAF) in AOSLO. Confocal AOSLO revealed relatively normal cones outside the TM lesion but altered cone appearance within it and along its margins in both patients. We quantified cone topography and RPE cell morphometry from the fovea to the margin of the lesion in case 1 and found cone density to be within the normal range across the locations imaged. However, RPE morphometric analysis revealed disrupted RPE cells outside the margin of the lesion; the mean RPE cell area was greater than two standard deviations above the normative range up to approximately 1.5 mm from the lesion margin. Similar morphometric changes were seen to individual RPE cells in case 2. Multi-modal imaging with AOSLO reveals that RPE cells are abnormal in TM well beyond the margins of the characteristic TM lesion boundary defined with conventional clinical imaging. Since the TM fovea appears to be fully formed, with normal cone packing, it is possible that the congenital RPE defect in TM occurs relatively late in retinal development. This work demonstrates how cellular level imaging of the RPE can provide new insight into RPE pathologies, particularly for rare conditions such as TM.
Whole-Genome Sequencing-Based Antimicrobial Resistance Characterization and Phylogenomic Investigation of 19 Multidrug-Resistant and Extended-Spectrum Beta-Lactamase-Positive Escherichia coli Strains Collected From Hospital Patients in Benin in 2019
Authors: Yehouenou Carine Laurence , Bogaerts Bert , De Keersmaecker Sigrid C. J. , Roosens Nancy H. C. , Marchal Kathleen , Tchiakpe Edmond , Affolabi Dissou , Simon Anne , Dossou Francis Moise , Vanneste Kevin , Dalleur Olivia
Published: December 2021

The increasing worldwide prevalence of extended-spectrum beta-lactamase (ESBL) producing Escherichia coli constitutes a serious threat to global public health. Surgical site infections are associated with high morbidity and mortality rates in developing countries, fueled by the limited availability of effective antibiotics. We used whole-genome sequencing (WGS) to evaluate antimicrobial resistance and the phylogenomic relationships of 19 ESBL-positive E. coli isolates collected from surgical site infections in patients across public hospitals in Benin in 2019. Isolates were identified by MALDI-TOF mass spectrometry and phenotypically tested for susceptibility to 16 antibiotics. Core-genome multi-locus sequence typing and single-nucleotide polymorphism-based phylogenomic methods were used to investigate the relatedness between samples. The broader phylogenetic context was characterized through the inclusion of publicly available genome data. Among the 19 isolates, 13 different sequence types (STs) were observed, including ST131 (n = 2), ST38 (n = 2), ST410 (n = 2), ST405 (n = 2), ST617 (n = 2), and ST1193 (n = 2). The blaCTX-M-15 gene encoding ESBL resistance was found in 15 isolates (78.9%), as well as other genes associated with ESBL, such as blaOXA-1 (n = 14) and blaTEM-1 (n = 9). Additionally, we frequently observed genes encoding resistance against aminoglycosides [aac-(6')-Ib-cr, n = 14], quinolones (qnrS1, n = 4), tetracyclines [tet(B), n = 14], sulfonamides (sul2, n = 14), and trimethoprim (dfrA17, n = 13). Nonsynonymous chromosomal mutations in the housekeeping genes parC and gyrA associated with resistance to fluoroquinolones were also detected in multiple isolates. Although the phylogenomic investigation did not reveal evidence of hospital-acquired transmissions, we observed two very similar strains collected from patients in different hospitals. By characterizing a set of multidrug-resistant isolates collected from a largely unexplored environment, this study highlights the added value for WGS as an effective early warning system for emerging pathogens and antimicrobial resistance.
Freeze-Thaw Pretreatment Can Improve Efficiency of Bacterial DNA Extraction From Meconium
Authors: Xin Yuntian , Xie Jingxian , Nan Bingru , Tang Chen , Xiao Yunshan , Wu Quanfeng , Lin Yi , Zhang Xueqin , Shen Heqing
Published: December 2021

Although the presence of live microbes in utero remains under debate, newborn gastrointestinal bacteria are undoubtedly important to infant health. Measuring bacteria in meconium is an ideal strategy to understand this issue; however, the low efficiency of bacterial DNA extraction from meconium has limited its utilization. This study aims to improve the efficiency of bacterial DNA extraction from meconium, which generally has low levels of microflora but high levels of PCR inhibitors in the viscous matrix. The research was approved by the ethical committee of the Xiamen Maternity and Child Health Care Hospital, Xiamen, China. All the mothers delivered naturally, and their newborns were healthy. Meconium samples passed by the newborns within 24 h were collected. Each sample was scraped off of a sterile diaper, transferred to a 5-ml sterile tube, and stored at −80°C. For the assay, a freeze-thawing sample preparation protocol was designed, in which a meconium-InhibitEX buffer mixture was intentionally frozen 1–3 times at −20°C, −80°C, and (or) in liquid nitrogen. Then, DNA was extracted using a commercial kit and sequenced by 16S rDNA to verify the enhanced bacterial DNA extraction efficiency. Ultimately, we observed the following: (1) About 30 mg lyophilized meconium was the optimal amount for DNA extraction. (2) Freezing treatment for 6 h improved DNA extraction at −20°C. (3) DNA extraction efficiency was significantly higher with the immediate thaw strategy than with gradient thawing at −20°C, −80°C, and in liquid nitrogen. (4) Among the conditions of −20°C, −80°C, and liquid nitrogen, −20°C was the best freezing condition for both improving DNA extraction efficiency and preserving microbial species diversity in meconium, while liquid nitrogen was the worst condition. (5) Three freeze-thaw cycles could markedly enhance DNA extraction efficiency and preserve the species diversity of meconium microflora. We developed a feasible freeze-thaw pretreatment protocol to improve the extraction of microbial DNA from meconium, which may be beneficial for newborn bacterial colonization studies.
First Comparative Analysis of Clostridium septicum Genomes Provides Insights Into the Taxonomy, Species Genetic Diversity, and Virulence Related to Gas Gangrene
Authors: Thomas Prasad , Abdel-Glil Mostafa Y. , Subbaiyan Anbazhagan , Busch Anne , Eichhorn Inga , Wieler Lothar H. , Neubauer Heinrich , Pletz Mathias , Seyboldt Christian
Published: December 2021

Clostridium septicum is a Gram-positive, toxin-producing, and spore-forming bacterium that is recognized, together with C. perfringens, as the most important etiologic agent of progressive gas gangrene. Clostridium septicum infections are almost always fatal in humans and animals. Despite its clinical and agricultural relevance, there is currently limited knowledge of the diversity and genome structure of C. septicum. This study presents the complete genome sequence of C. septicum DSM 7534T type strain as well as the first comparative analysis of five C. septicum genomes. The taxonomy of C. septicum, as revealed by 16S rRNA analysis as well as by genomic wide indices such as protein-based phylogeny, average nucleotide identity, and digital DNA–DNA hybridization indicates a stable clade. The composition and presence of prophages, CRISPR elements and accessory genetic material was variable in the investigated genomes. This is in contrast to the limited genetic variability described for the phylogenetically and phenotypically related species Clostridium chauvoei. The restriction-modification (RM) systems between two C. septicum genomes were heterogeneous for the RM types they encoded. C. septicum has an open pangenome with 2,311 genes representing the core genes and 1,429 accessory genes. The core genome SNP divergence between genome pairs varied up to 4,886 pairwise SNPs. A vast arsenal of potential virulence genes was detected in the genomes studied. Sequence analysis of these genes revealed that sialidase, hemolysin, and collagenase genes are conserved compared to the α-toxin and hyaluronidase genes. In addition, a conserved gene found in all C. septicum genomes was predicted to encode a leucocidin homolog (beta-channel forming cytolysin) similar (71.10% protein identity) to Clostridium chauvoei toxin A (CctA), which is a potent toxin. In conclusion, our results provide first, valuable insights into strain relatedness and genomic plasticity of C. septicum and contribute to our understanding of the virulence mechanisms of this important human and animal pathogen.
Hepatocyte Growth Factor-Preconditioned Neural Progenitor Cells Attenuate Astrocyte Reactivity and Promote Neurite Outgrowth
Authors: Hong James , Dragas Rachel , Khazaei Mohammad , Ahuja Christopher S. , Fehlings Michael G.
Published: December 2021

The astroglial scar is a defining hallmark of secondary pathology following central nervous system (CNS) injury that, despite its role in limiting tissue damage, presents a significant barrier to neuroregeneration. Neural progenitor cell (NPC) therapies for tissue repair and regeneration have demonstrated favorable outcomes, the effects of which are ascribed not only to direct cell replacement but trophic support. Cytokines and growth factors secreted by NPCs aid in modifying the inhibitory and cytotoxic post-injury microenvironment. In an effort to harness and enhance the reparative potential of NPC secretome, we utilized the multifunctional and pro-regenerative cytokine, hepatocyte growth factor (HGF), as a cellular preconditioning agent. We first demonstrated the capacity of HGF to promote NPC survival in the presence of oxidative stress. We then assessed the capacity of this modified conditioned media (CM) to attenuate astrocyte reactivity and promote neurite outgrowth in vitro. HGF pre-conditioned NPCs demonstrated significantly increased levels of tissue inhibitor of metalloproteinases-1 and reduced vascular endothelial growth factor compared to untreated NPCs. In reactive astrocytes, HGF-enhanced NPC-CM effectively reduced glial fibrillary acidic protein (GFAP) expression and chondroitin sulfate proteoglycan deposition to a greater extent than either treatment alone, and enhanced neurite outgrowth of co-cultured neurons. in vivo, this combinatorial treatment strategy might enable tactical modification of the post-injury inhibitory astroglial environment to one that is more conducive to regeneration and functional recovery. These findings have important translational implications for the optimization of current cell-based therapies for CNS injury.
Ghrelin and Cannabinoid Functional Interactions Mediated by Ghrelin/CB1 Receptor Heteromers That Are Upregulated in the Striatum From Offspring of Mice Under a High-Fat Diet
Authors: Lillo Alejandro , Lillo Jaume , Raïch Iu , Miralpeix Cristina , Dosrius Francesc , Franco Rafael , Navarro Gemma
Published: December 2021

There is evidence of ghrelinergic-cannabinoidergic interactions in the central nervous system (CNS) that may impact on the plasticity of reward circuits. The aim of this article was to look for molecular and/or functional interactions between cannabinoid CB1 and ghrelin GHS-R1a receptors. In a heterologous system and using the bioluminescence resonance energy transfer technique we show that human versions of cannabinoid CB1 and ghrelin GHS-R1a receptors may form macromolecular complexes. Such receptor heteromers have particular properties in terms of CB1/Gi-mediated signaling and in terms of GHS-R1a-Gq-mediated signaling. On the one hand, just co-expression of CB1R and GHS-R1a led to impairment of cannabinoid signaling. On the other hand, cannabinoids led to an increase in ghrelin-derived calcium mobilization that was stronger at low concentrations of the CB1 receptor agonist, arachidonyl-2’-chloroethylamide (ACEA). The expression of CB1-GHS-R1a receptor complexes in striatal neurons was confirmed by in situ proximity ligation imaging assays. Upregulation of CB1-GHS-R1a- receptor complexes was found in striatal neurons from siblings of pregnant female mice on a high-fat diet. Surprisingly, the expression was upregulated after treatment of neurons with ghrelin (200 nM) or with ACEA (100 nM). These results help to better understand the complexities underlying the functional interactions of neuromodulators in the reward areas of the brain.
Resective, Ablative and Radiosurgical Interventions for Drug Resistant Mesial Temporal Lobe Epilepsy: A Systematic Review and Meta-Analysis of Outcomes
Authors: Marathe Kajol , Alim-Marvasti Ali , Dahele Karan , Xiao Fenglai , Buck Sarah , O'Keeffe Aidan G. , Duncan John S. , Vakharia Vejay N.
Published: December 2021

Objectives: One-third of individuals with focal epilepsy do not achieve seizure freedom despite best medical therapy. Mesial temporal lobe epilepsy (MTLE) is the most common form of drug resistant focal epilepsy. Surgery may lead to long-term seizure remission if the epileptogenic zone can be defined and safely removed or disconnected. We compare published outcomes following open surgical techniques, radiosurgery (SRS), laser interstitial thermal therapy (LITT) and radiofrequency ablation (RF-TC).

Methods: PRISMA systematic review was performed through structured searches of PubMed, Embase and Cochrane databases. Inclusion criteria encompassed studies of MTLE reporting seizure-free outcomes in ≥10 patients with ≥12 months follow-up. Due to variability in open surgical approaches, only comparative studies were included to minimize the risk of bias. Random effects meta-analysis was performed to calculate effects sizes and a pooled estimate of the probability of seizure freedom per person-year. A mixed effects linear regression model was performed to compare effect sizes between interventions.

Results: From 1,801 screened articles, 41 articles were included in the quantitative analysis. Open surgery included anterior temporal lobe resection as well as transcortical and trans-sylvian selective amygdalohippocampectomy. The pooled seizure-free rate per person-year was 0.72 (95% CI 0.66–0.79) with trans-sylvian selective amygdalohippocampectomy, 0.59 (95% CI 0.53–0.65) with LITT, 0.70 (95% CI 0.64–0.77) with anterior temporal lobe resection, 0.60 (95% CI 0.49–0.73) with transcortical selective amygdalohippocampectomy, 0.38 (95% CI 0.14–1.00) with RF-TC and 0.50 (95% CI 0.34–0.73) with SRS. Follow up duration and study sizes were limited with LITT and RF-TC. A mixed-effects linear regression model suggests significant differences between interventions, with LITT, ATLR and SAH demonstrating the largest effects estimates and RF-TC the lowest.

Conclusions: Overall, novel “minimally invasive” approaches are still comparatively less efficacious than open surgery. LITT shows promising seizure effectiveness, however follow-up durations are shorter for minimally invasive approaches so the durability of the outcomes cannot yet be assessed. Secondary outcome measures such as Neurological complications, neuropsychological outcome and interventional morbidity are poorly reported but are important considerations when deciding on first-line treatments.
Spatio-Semantic Graphs From Picture Description: Applications to Detection of Cognitive Impairment
Authors: Ambadi Pranav S. , Basche Kristin , Koscik Rebecca L. , Berisha Visar , Liss Julie M. , Mueller Kimberly D.
Published: December 2021

Clinical assessments often use complex picture description tasks to elicit natural speech patterns and magnify changes occurring in brain regions implicated in Alzheimer's disease and dementia. As The Cookie Theft picture description task is used in the largest Alzheimer's disease and dementia cohort studies available, we aimed to create algorithms that could characterize the visual narrative path a participant takes in describing what is happening in this image. We proposed spatio-semantic graphs, models based on graph theory that transform the participants' narratives into graphs that retain semantic order and encode the visuospatial information between content units in the image. The resulting graphs differ between Cognitively Impaired and Unimpaired participants in several important ways. Cognitively Impaired participants consistently scored higher on features that are heavily associated with symptoms of cognitive decline, including repetition, evidence of short-term memory lapses, and generally disorganized narrative descriptions, while Cognitively Unimpaired participants produced more efficient narrative paths. These results provide evidence that spatio-semantic graph analysis of these tasks can generate important insights into a participant's cognitive performance that cannot be generated from semantic analysis alone.
Congenital Hypothyroidism and Brain Development: Association With Other Psychiatric Disorders
Authors: Uchida Katsuya , Suzuki Mao
Published: December 2021

Thyroid hormones play an important role in brain development, and thyroid hormone insufficiency during the perinatal period results in severe developmental delays. Perinatal thyroid hormone deficiency is clinically known as congenital hypothyroidism, which is caused by dysgenesis of the thyroid gland or low iodine intake. If the disorder is not diagnosed or not treated early, the neuronal architecture is perturbed by thyroid hormone insufficiency, and neuropathological findings, such as abnormal synapse formation, defects in neuronal migration, and impairment of myelination, are observed in the brains of such patients. Furthermore, the expression of psychiatric disorder-related molecules, especially parvalbumin, is significantly decreased by thyroid hormone insufficiency during the perinatal period. Animal experiments using hypothyroidism models display decreased parvalbumin expression and abnormal brain architecture, and these experimental results show reproducibility and stability. These basic studies reinforce the results of epidemiological studies, suggesting the relevance of thyroid dysfunction in psychiatric disorders. In this review, we discuss the disruption of brain function associated with congenital hypothyroidism from the perspective of basic and clinical research.
Rutaecarpine Inhibits U87 Glioblastoma Cell Migration by Activating the Aryl Hydrocarbon Receptor Signaling Pathway
Authors: Liu Yiyun , Chen Yangsheng , Zhu Ruihong , Xu Li , Xie Heidi Qunhui , Zhao Bin
Published: December 2021

Glioblastoma is the most frequent and aggressive primary astrocytoma in adults. The high migration ability of the tumor cells is an important reason for the high recurrence rate and poor prognosis of glioblastoma. Recently, emerging evidence has shown that the migration ability of glioblastoma cells was inhibited upon the activation of aryl hydrocarbon receptor (AhR), suggesting potential anti-tumor effects of AhR agonists. Rutaecarpine is a natural compound with potential tumor therapeutic effects which can possibly bind to AhR. However, its effect on the migration of glioblastoma is unclear. Therefore, we aim to explore the effects of rutaecarpine on the migration of human glioblastoma cells U87 and the involvement of the AhR signaling pathway. The results showed that: (i) compared with other structural related alkaloids, like evodiamine and dehydroevodiamine, rutaecarpine was a more potent AhR activator, and has a stronger inhibitory effect on the glioblastoma cell migration; (ii) rutaecarpine decreased the migration ability of U87 cells in an AhR-dependent manner; (iii) AhR mediated the expression of a tumor suppressor interleukin 24 (IL24) induced by rutaecarpine, and AhR-IL24 axis was involved in the anti-migratory effects of rutaecarpine on the glioblastoma. Besides IL24, other candidates AhR downstream genes both associated with cancer and migration were proposed to participate in the migration regulation of rutaecarpine by RNA-Seq and bioinformatic analysis. These data indicate that rutaecarpine is a naturally-derived AhR agonist that could inhibit the migration of U87 human glioblastoma cells mostly via the AhR-IL24 axis.
Quality Characteristics and Inhibitory Xanthine Oxidase Potential of 21 Sour Cherry (Prunus Cerasus L.) Varieties Cultivated in China
Authors: Wang Rui , Zhang Fang , Zan Shengyue , Gao Chang , Tian Changping , Meng Xianghong
Published: December 2021

This study aims to analyze the physicochemical characteristics and activities of 21 sour cherry cultivars in China. The evaluated accessions differ in several quality traits including weight, moisture, color, total soluble solids, and total acids. Glucose and malic acid were the predominant individual sugar and organic acid in all accessions. The potassium (K) and iron (Fe) were of the highest contents in Érid jubileum (453.887 mg/100 g FW) and Meili (2.988 mg/100 g FW), respectively. The contents of total phenolics (TP) were from 9.309 to 24.118 mg GAE/g DW, and total flavonoids (TF) were 8.935–27.198 mg RE/g DW, which were highly positively correlated (r = 0.892, p < 0.001). M-15, Érdi fubileum, and Érid jubileum showed the highest inhibitory effects on xanthine oxidase, and the IC50 inhibitory were 2.619, 3.117, and 3.940 mg/ml, respectively. This work evaluated the quality and nutritional characteristics of 21 sour cherry cultivars grown in China and explored their potential as an innovative food ingredient for hyperuricemia by evaluating the inhibitory effects of xanthine oxidase. And these results provide valuable data and new ideas for the future sour cherry breeding program as well as a processing guide.
Fractal-Based Radiomic Approach to Tailor the Chemotherapy Treatment in Rectal Cancer: A Generating Hypothesis Study
Authors: Di Dio Carmela , Chiloiro Giuditta , Cusumano Davide , Catucci Francesco , Boldrini Luca , Romano Angela , Meldolesi Elisa , Marazzi Fabio , Corvari Barbara , Barbaro Brunella , Manfredi Riccardo , Valentini Vincenzo , Gambacorta Maria Antonietta
Published: December 2021

Introduction

The aim of this study was to create a radiomic model able to calculate the probability of 5-year disease-free survival (5yDFS) when oxaliplatin (OXA) is or not administered in patients with locally advanced rectal cancer (LARC) and treated with neoadjuvant chemoradiotherapy (nCRT), allowing physicians to choose the best chemotherapy (CT) regimen.

Methods

LARC patients with cT3–4 cN0 or cT1–4 cN1–2 were treated according to an nCRT protocol that included concomitant CT schedules with or without OXA and radiotherapy dose of 55 Gy in 25 fractions. Radiomic analysis was performed on the T2-weighted (T2-w) MR images acquired during the initial tumor staging. Statistical analysis was performed separately for the cohort of patients treated with and without OXA. The ability of every single radiomic feature in predicting 5yDFS as a univariate analysis was assessed using the Wilcoxon–Mann–Whitney (WMW) test or t-test. Two logistic models (one for each cohort) were calculated, and their performance was assessed using the area under the receiver operating characteristic (ROC) curve (AUC).

Results

A total of 176 image features belonging to four families (morphological, statistical, textural, and fractal) were calculated for each patient. At the univariate analysis, the only feature showing significance in predicting 5yDFS was the maximum fractal dimension of the subpopulation identified considering 30% and 50% as threshold levels (maxFD30–50). Once the models were developed using this feature, an AUC of 0.67 (0.57–0.77) and 0.75 (0.56–0.95) was obtained for patients treated with and without OXA, respectively. A maxFD30–50 >1.6 was correlated to a higher 5yDFS probability in patients treated with OXA.

Conclusion

This study suggests that radiomic analysis of MR T2-w images can be used to define the optimal concomitant CT regimen for stage III LARC cancer patients. In particular, by providing an indication of the gross tumor volume (GTV) spatial heterogeneity at initial staging, maxFD30–50 seems to be able to predict the probability of 5yDFS. New studies including a larger cohort of patients and external validation sets are recommended to verify the results of this hypothesis-generating study.
Future Developments in Charged Particle Therapy: Improving Beam Delivery for Efficiency and Efficacy
Authors: Yap Jacinta , De Franco Andrea , Sheehy Suzie
Published: December 2021

The physical and clinical benefits of charged particle therapy (CPT) are well recognized. However, the availability of CPT and complete exploitation of dosimetric advantages are still limited by high facility costs and technological challenges. There are extensive ongoing efforts to improve upon these, which will lead to greater accessibility, superior delivery, and therefore better treatment outcomes. Yet, the issue of cost remains a primary hurdle as utility of CPT is largely driven by the affordability, complexity and performance of current technology. Modern delivery techniques are necessary but limited by extended treatment times. Several of these aspects can be addressed by developments in the beam delivery system (BDS) which determines the overall shaping and timing capabilities enabling high quality treatments. The energy layer switching time (ELST) is a limiting constraint of the BDS and a determinant of the beam delivery time (BDT), along with the accelerator and other factors. This review evaluates the delivery process in detail, presenting the limitations and developments for the BDS and related accelerator technology, toward decreasing the BDT. As extended BDT impacts motion and has dosimetric implications for treatment, we discuss avenues to minimize the ELST and overview the clinical benefits and feasibility of a large energy acceptance BDS. These developments support the possibility of advanced modalities and faster delivery for a greater range of treatment indications which could also further reduce costs. Further work to realize methodologies such as volumetric rescanning, FLASH, arc, multi-ion and online image guided therapies are discussed. In this review we examine how increased treatment efficiency and efficacy could be achieved with improvements in beam delivery and how this could lead to faster and higher quality treatments for the future of CPT.
Maternal Transmission of SARS-CoV-2: Safety of Breastfeeding in Infants Born to Infected Mothers
Authors: Al-kuraishy Hayder M. , Al-Gareeb Ali I. , Atanu Francis O. , EL-Zamkan Mona A. , Diab Hassan M. , Ahmed Ahmed S. , Al-Maiahy Thabat J. , Obaidullah Ahmad J. , Alshehri Sultan , Ghoniem Mohammed M. , Batiha Gaber E.
Published: December 2021

Coronavirus disease 2019 (COVID-19) is a recent epidemic disease caused by severe acute respiratory syndrome virus type 2 (SARS-CoV-2). In pregnancy, SARS-Cov-2 infection creates additional alarm due to concerns regarding the potential for transmission from the mother to the baby during both the antenatal and postpartum times. In general, breastfeeding is seldom disallowed because of infection of the mother. However, there are few exceptions with regards to certain infectious organisms with established transmission evidence from mother to infant and the link of infection of a newborn with significant morbidity and mortality. It is confirmed that pregnant women can become infected with SARS-CoV-2, although the debate on the possible vertical transmission of SARS-CoV-2 infection during pregnancy is still open. In this regard, the literature is still poor. On the contrary, the information on the safety of breastfeeding even during infections seems reassuring when the mother takes the necessary precautions. However, there are still answered questions regarding the precautions to be taken during breastfeeding by COVID-19 patients. This paper reviews the existing answers to these and many other questions. This review therefore presents a summary of the present-day understanding of infection with SARS-CoV-2 and discusses the answers around the maternal transmission of COVID-19 and the potential threat of breastfeeding to babies born to infected pregnant mothers. In conclusion, intrauterine transmission of SARS-CoV-2 infection is less likely to occur during pregnancy. Most studies suggest that COVID-19 is not transmitted through breast milk. Correspondingly, COVID-19-infected neonates might acquire the infection via the respiratory route because of the postnatal contact with the mother rather than during the prenatal period. International organizations encourage breastfeeding regardless of the COVID-19 status of the mother or child as long as proper hygienic and safety measures are adhered to so as to minimize the chance of infant infection by droplets and direct contact with the infected mother. Pasteurized donor human milk or infant formula as supplemental feeding can be quite beneficial in the case of mother–infant separation till breastfeeding is safe.
Case Report: Clinical Analysis of Fulminant Mycoplasma pneumoniae Pneumonia in Children
Authors: Zhang Tongqiang , Han Chunjiao , Guo Wei , Ning Jing , Cai Chunquan , Xu Yongsheng
Published: December 2021

Fulminant Mycoplasma pneumoniae pneumonia (FMPP) accounts for 0.5–2% of all MPP cases, which is considered as MPP combined with severe complications such as hypoxemia, acute respiratory distress syndrome, or acute respiratory failure. It primarily affects young adults with no underlying disease. Although some studies have proved the severity of FMPP, the details about clinical diagnosis and treatment of FMPP in children have been rarely reported. In this case study, we described three cases who suffered from FMPP. These children not only developed acute lung injury and multiple organ involvement within 7 days of treatment, but were also found plastic bronchitis by bronchoscopy. Finally, all the patients were treated successfully with azithromycin, glucocorticoid, and bronchoscopy lavage. We conclude that this case study would contribute to raise awareness with respect to FMPP, which may occur at a younger age with faster disease progression and common extrapulmonary manifestations. It also reinforces the importance of early identification and prompt intervention to save life of children and reduces sequelae. Further studies are needed about mechanism of FMPP.
Generating Evidence From Contextual Clinical Research in Low- to Middle Income Countries: A Roadmap Based on Theory of Change
Authors: Hasan Babar S. , Rasheed Muneera A. , Wahid Asra , Kumar Raman Krishna , Zuhlke Liesl
Published: December 2021

Along with inadequate access to high-quality care, competing health priorities, fragile health systems, and conflicts, there is an associated delay in evidence generation and research from LMICs. Lack of basic epidemiologic understanding of the disease burden in these regions poses a significant knowledge gap as solutions can only be developed and sustained if the scope of the problem is accurately defined. Congenital heart disease (CHD), for example, is the most common birth defect in children. The prevalence of CHD from 1990 to 2017 has progressively increased by 18.7% and more than 90% of children with CHD are born in Low and Middle-Income Countries (LMICs). If diagnosed and managed in a timely manner, as in high-income countries (HICs), most children lead a healthy life and achieve adulthood. However, children with CHD in LMICs have limited care available with subsequent impact on survival. The large disparity in global health research focus on this complex disease makes it a solid paradigm to shape the debate. Despite many challenges, an essential aspect of improving research in LMICs is the realization and ownership of the problem around paucity of local evidence by patients, health care providers, academic centers, and governments in these countries. We have created a theory of change model to address these challenges at a micro- (individual patient or physician or institutions delivering health care) and a macro- (government and health ministries) level, presenting suggested solutions for these complex problems. All stakeholders in the society, from government bodies, health ministries, and systems, to frontline healthcare workers and patients, need to be invested in addressing the local health problems and significantly increase data to define and improve the gaps in care in LMICs. Moreover, interventions can be designed for a more collaborative and effective HIC-LMIC and LMIC-LMIC partnership to increase resources, capacity building, and representation for long-term productivity.
Vascular Endothelial Growth Factor Signaling in Models of Oxygen-Induced Retinopathy: Insights Into Mechanisms of Pathology in Retinopathy of Prematurity
Authors: Ramshekar Aniket , Hartnett M. Elizabeth
Published: December 2021

Retinopathy of prematurity (ROP) is a leading cause of blindness in children worldwide. Blindness can occur from retinal detachment caused by pathologic retinal angiogenesis into the vitreous, termed intravitreal neovascularization (IVNV). Although agents that interfere with the bioactivity of vascular endothelial growth factor (VEGF) are now used to treat IVNV, concerns exist regarding the identification of optimal doses of anti-VEGF for individual infants and the effect of broad VEGF inhibition on physiologic angiogenesis in external organs or in the retina of a preterm infant. Therefore, it is important to understand VEGF signaling in both physiologic and pathologic angiogenesis in the retina. In this manuscript, we review the role of receptors that interact with VEGF in oxygen-induced retinopathy (OIR) models that represent features of ROP pathology. Specifically, we discuss our work regarding the regulation of VEGFR2 signaling in retinal endothelial cells to not only reduce severe ROP but also facilitate physiologic retinal vascular and neuronal development.