bluuebunny/crossref_metadata_2025 huggingface dataset:
DOT1L inhibition does not modify the sensitivity of cutaneous T cell lymphoma to pan-HDAC inhibitors in vitro
Authors: Kwesi-Maliepaard Eliza Mari , Malik Muddassir , van Welsem Tibor , van Doorn Remco , Vermeer Maarten H. , Vlaming Hanneke , Jacobs Heinz , van Leeuwen Fred
Published: November 2022

Cutaneous T-cell lymphomas (CTCLs) are a subset of T-cell malignancies presenting in the skin. The treatment options for CTCL, in particular in advanced stages, are limited. One of the emerging therapies for CTCL is treatment with histone deacetylase (HDAC) inhibitors. We recently discovered an evolutionarily conserved crosstalk between HDAC1, one of the targets of HDAC inhibitors, and the histone methyltransferase DOT1L. HDAC1 negatively regulates DOT1L activity in yeast, mouse thymocytes, and mouse thymic lymphoma. Here we studied the functional relationship between HDAC inhibitors and DOT1L in two human CTCL cell lines, specifically addressing the question whether the crosstalk between DOT1L and HDAC1 observed in mouse T cells plays a role in the therapeutic effect of clinically relevant broad-acting HDAC inhibitors in the treatment of human CTCL. We confirmed that human CTCL cell lines were sensitive to treatment with pan-HDAC inhibitors. In contrast, the cell lines were not sensitive to DOT1L inhibitors. Combining both types of inhibitors did neither enhance nor suppress the inhibitory effect of HDAC inhibitors on CTCL cells. Thus our in vitro studies suggest that the effect of commonly used pan-HDAC inhibitors in CTCL cells relies on downstream effects other than DOT1L misregulation.
Structure and evolution of the squamate major histocompatibility complex as revealed by two Anolis lizard genomes
Authors: Card Daren C. , Van Camp Andrew G. , Santonastaso Trenten , Jensen-Seaman Michael I. , Anthony Nicola M. , Edwards Scott V.
Published: November 2022

The major histocompatibility complex (MHC) is an important genomic region for adaptive immunity and has long been studied in ecological and evolutionary contexts, such as disease resistance and mate and kin selection. The MHC has been investigated extensively in mammals and birds but far less so in squamate reptiles, the third major radiation of amniotes. We localized the core MHC genomic region in two squamate species, the green anole (Anolis carolinensis) and brown anole (A. sagrei), and provide the first detailed characterization of the squamate MHC, including the presence and ordering of known MHC genes in these species and comparative assessments of genomic structure and composition in MHC regions. We find that the Anolis MHC, located on chromosome 2 in both species, contains homologs of many previously-identified mammalian MHC genes in a single core MHC region. The repetitive element composition in anole MHC regions was similar to those observed in mammals but had important distinctions, such as higher proportions of DNA transposons. Moreover, longer introns and intergenic regions result in a much larger squamate MHC region (11.7 Mb and 24.6 Mb in the green and brown anole, respectively). Evolutionary analyses of MHC homologs of anoles and other representative amniotes uncovered generally monophyletic relationships between species-specific homologs and a loss of the peptide-binding domain exon 2 in one of two mhc2β gene homologs of each anole species. Signals of diversifying selection in each anole species was evident across codons of mhc1, many of which appear functionally relevant given known structures of this protein from the green anole, chicken, and human. Altogether, our investigation fills a major gap in understanding of amniote MHC diversity and evolution and provides an important foundation for future squamate-specific or vertebrate-wide investigations of the MHC.
Identification of potential candidate vaccines against Mycobacterium ulcerans based on the major facilitator superfamily transporter protein
Authors: Ishwarlall Tamara Z. , Adeleke Victoria T. , Maharaj Leah , Okpeku Moses , Adeniyi Adebayo A. , Adeleke Matthew A.
Published: November 2022

Buruli ulcer is a neglected tropical disease that is characterized by non-fatal lesion development. The causative agent isMycobacterium ulcerans (M. ulcerans).There are no known vectors or transmission methods, preventing the development of control methods. There are effective diagnostic techniques and treatment routines; however, several socioeconomic factors may limit patients’ abilities to receive these treatments. The Bacillus Calmette–Guérin vaccine developed against tuberculosis has shown limited efficacy, and no conventionally designed vaccines have passed clinical trials. This study aimed to generate a multi-epitope vaccine againstM. ulceransfrom the major facilitator superfamily transporter protein using an immunoinformatics approach. TwelveM. ulceransgenome assemblies were analyzed, resulting in the identification of 11 CD8+and 7 CD4+T-cell epitopes and 2 B-cell epitopes. These conserved epitopes were computationally predicted to be antigenic, immunogenic, non-allergenic, and non-toxic. The CD4+T-cell epitopes were capable of inducing interferon-gamma and interleukin-4. They successfully bound to their respective human leukocyte antigens alleles inin silicodocking studies. The expected global population coverage of the T-cell epitopes and their restricted human leukocyte antigens alleles was 99.90%. The population coverage of endemic regions ranged from 99.99% (Papua New Guinea) to 21.81% (Liberia). Two vaccine constructs were generated using the Toll-like receptors 2 and 4 agonists, LprG and RpfE, respectively. Both constructs were antigenic, non-allergenic, non-toxic, thermostable, basic, and hydrophilic. The DNA sequences of the vaccine constructs underwent optimization and were successfullyin-silicocloned with the pET-28a(+) plasmid. The vaccine constructs were successfully docked to their respective toll-like receptors. Molecular dynamics simulations were carried out to analyze the binding interactions within the complex. The generated binding energies indicate the stability of both complexes. The constructs generated in this study display severable favorable properties, with construct one displaying a greater range of favorable properties. However, further analysis and laboratory validation are required.
Effects of gut microbiota on immune responses and immunotherapy in colorectal cancer
Authors: Hou Xinxin , Zheng Zongmei , Wei Jiao , Zhao Ling
Published: November 2022

Accumulating evidence suggests that gut microbial dysbiosis is implicated in colorectal cancer (CRC) initiation and progression through interaction with host immune system. Given the intimate relationship between the gut microbiota and the antitumor immune responses, the microbiota has proven to be effective targets in modulating immunotherapy responses of preclinical CRC models. However, the proposed putative mechanisms of how these bacteria affect immune responses and immunotherapy efficacy remains obscure. In this review, we summarize recent findings of clinical gut microbial dysbiosis in CRC patients, the reciprocal interactions between gut microbiota and the innate and/or the adaptive immune system, as well as the effect of gut microbiota on immunotherapy response in CRC. Increased understanding of the gut microbiota-immune system interactions will benefit the rational application of microbiota to the clinical promising biomarker or therapeutic strategy as a cancer immunotherapy adjuvant.
RIG-I and TLR-7/8 agonists as combination adjuvant shapes unique antibody and cellular vaccine responses to seasonal influenza vaccine
Authors: Jangra Sonia , Laghlali Gabriel , Choi Angela , Rathnasinghe Raveen , Chen Yong , Yildiz Soner , Coughlan Lynda , García-Sastre Adolfo , De Geest Bruno G. , Schotsaert Michael
Published: November 2022

Influenza vaccine effectiveness could be improved by combination with an adjuvant with the potential to enhance the host-vaccine response both quantitatively and qualitatively. The goal of this study was to explore a RIG-I agonist (SDI-nanogel) and a TLR7/8 agonist (Imidazoquinoline (IMDQ)‐PEG‐Chol) as adjuvants, when co-administered with a licensed quadrivalent inactivated influenza vaccine (QIV), and to determine the role of these adjuvants in directing helper T (Th) cell responses for their role in the immunoglobulin (Ig) class switching. Administration of QIV with the two adjuvants, individually or combined, resulted in enhanced HA-specific serum ELISA IgG titers, serum hemagglutination inhibition (HAI) titers and splenic T cell responses as examined by IFN-γ and IL-4 enzyme-linked immunosorbent spot (ELISPOT) assays, 4-weeks post-prime and post-boost vaccination in BALB/c mice. While QIV+SDI-nanogel largely induced antigen-specific IgG1 responses, QIV+IMDQ-PEG-Chol predominantly induced IgG2a antibody isotypes post-prime vaccination, suggesting efficient induction of Th2 (IL-4) and Th1 (IFN-γ) responses, respectively. Combination of the two adjuvants not only skewed the response completely towards IgG2a, but also resulted in induction of HAI titers that outperformed groups that received single adjuvant. Moreover, enhanced IgG2a titers correlate with antibody-mediated cellular cytotoxicity (ADCC) that targets both the highly conserved H1 hemagglutination (HA) stalk domain and N1 neuraminidase (NA). A booster vaccination with QIV+IMDQ-PEG-Chol resulted in a more balanced IgG1/IgG2a response in animals primed with QIV+IMDQ-PEG-Chol but increased only IgG2a titers in animals that received the combination adjuvant during prime vaccination, suggesting that class switching events in germinal centers during the prime vaccination contribute to the outcome of booster vaccination. Importantly, IMDQ-PEG-Chol, alone or in combination, always outperformed the oil-in-water control adjuvant Addavax. Vaccine-induced antibody and T cell responses correlated with protection against lethal influenza virus infection. This study details the benefit of adjuvants that target multiple innate immune receptors to shape the host vaccine response.
Spatiotemporal coastline variations in the Pearl River Estuary and the relationship with multiple human disturbances
Authors: Li Xin , Yan Haiming , Yang Ying , Xu Zhihao , Yang Huicai
Published: November 2022

Coastlines and estuaries as one of the most dynamic systems in the marine environment are influenced by not only natural factors but also various anthropogenic activities, but there have been limited comprehensive studies on the relationship between coastline variation and anthropogenic activities at the watershed and local scales. The Pearl River Estuary (PRE) in China has experienced remarkable coastline variation along with rapid economic development and urbanization. In this study, the coastline of the PRE was extracted using Landsat images during 1987-2017, and the impacts of multiple factors on coastline variation were explored with correlation analysis and regression analysis. Results suggested coastlines of the PRE demonstrated a clear expanding trend over recent decades, and the coastline length had increased by 74.81 km and the land area had increased by 679.25 km2 by 2017, and results also showed rapid coastline variation during 1987-2004 and relatively slow variation during 2004-2017. Artificial coastlines accounted for 80.90% of the total coastline length in 2017, while natural coastlines accounted for only 19.10%. In addition, reduction in the sand content caused by construction of reservoirs and river dredging in upstream areas played a dominant role in affecting natural coastline variation in the PRE, especially on the west coast. Moreover, the artificial coastline in the study area expanded quickly due to the influence of various human activities, among which the urbanization and land reclamation for aquaculture played a dominant role in affecting the artificial coastline variation on the east and west coasts, respectively. Results of this study have important value for understanding the individual and joint effects of various human activities on coastline variation and can provide important reference information for the sustainable management of the PRE as well as other estuaries.
Mapping of contamination problem areas in Europe’s seas using a multi-metric indicator-based assessment tool
Authors: Andersen Jesper H. , Caetano Miguel , Grouhel-Pellouin Anne , Harvey Eva Therese , Reker Johnny , Murray Ciaran J.
Published: November 2022

We report identification and mapping of areas in Europe’s seas and coastal areas impacted by contaminants, i.e., areas with concentrations above internationally agreed threshold values. The study is based on (1) a state-of-the-art data set anchored in national monitoring activities, (2) internationally agreed target values and (3) an updated version of the CHASE assessment tool (originally: the HELCOM Chemical Status Assessment Tool). The spatial cover of data enabled us to classify 1,518 spatial assessment units, with 80% of the area assessed determined to be “problem areas”. We have demonstrated that it is possible to make an integrated assessment of contaminants spanning over four marine regions, and 10 marine sub-regions (sensu the EU Marine Strategy Framework Directive), including marine and coastal waters of 30 European countries. The power of combining data of different sources and contaminant categories over larger geographical scales, is potentially and in a long-term perspective the way forward for wider use of multi-metric indicator-based assessment tools supporting informed decision-making.
Sexual dimorphism in the methane seep-dwelling Costa Rican yeti crab Kiwa puravida (Decapoda: Anomura: Kiwaidae)
Authors: Azofeifa-Solano Juan Carlos , Pereira Olívia S. , Cowell Emily Jayne , Cordes Erik E. , Levin Lisa A. , Goffredi Shana K. , Cortés Jorge
Published: November 2022

Deep-sea chemosynthesis-based ecosystems support unique biological communities, but human impacts are an increasing threat. Understanding the life-history traits of species from deep-sea chemosynthesis-based ecosystems can help to develop adequate management strategies, as these can have impacts on ecological responses to changes in the environment. Here we examined the occurrence of sexual dimorphism in the yeti crab Kiwa puravida, an endemic species from the Costa Rican Pacific margin that aggregates at active methane seeps and depends on chemosynthetic bacteria for nutrition. The two morphological features examined included the claws, suspected to be under sexual selection and used for defense, and the carpus of the second pereopod not suspected to be under sexual selection. A total of 258 specimens, 161 males, 81 females, 16 juveniles, were collected from Mound 12 at 1,000-1,040 m depth in 2017 and 2018 and analyzed. We found that males have larger and wider claws than females, while there were no differences in carpus length. These results suggest that claw weaponry is under sexual selection in K. puravida, which is probably related to the mating system of this deep-sea species. This is the first attempt to study the reproductive biology of K. puravida, and additional observations will be necessary to shed more light on this matter.
Design and modeling of a periodic single-phase sandwich panel for acoustic insulation applications
Authors: Gazzola Chiara , Caverni Stefano , Corigliano Alberto
Published: November 2022

Sandwich and composite panels are widely adopted in acoustic applications due to their sound insulation properties that overcome mass-law-based partitions in medium–high frequency regions. A key aspect in the design procedure of acoustic panels is the control of the resonance-dominated region of the sound transmission loss (STL) curve. Within that frequency range, such systems usually show acoustic weakness and poor insulation performances with respect to standard single-layer solutions. In the present contribution, we want to highlight an innovative approach to the sandwich partition concept. A novel single-phase sandwich panel is realized by adopting a periodic repetition of a properly designed unit cell. The resulting internal truss structure is self-sustained, and its mechanical stiffness can be tuned to maximize the STL in the resonance-dominated region. A set of parametric analyses is reported to show how the topology of the unit cell affects the noise reduction properties of the panel. Experimental validation is performed on a nylon 3D-printed prototype. The proposed panel is then integrated with some locally resonant elements that can be adopted to further improve the low-frequency STL of the solution. Industrial and production considerations are also taken into account during the design process to make the solution industrially valid with a circular economy focus.
Case report: Isoflurane therapy in a case of status asthmaticus requiring extracorporeal membrane oxygenation
Authors: Gill Brendan , Bartock Jason L. , Damuth Emily , Puri Nitin , Green Adam
Published: November 2022

Volatile anesthetics have been described as a rescue therapy for patients with refractory status asthmaticus (SA), and the use of isoflurane for this indication has been reported since the 1980s. Much of the literature reports good outcomes when inhaled isoflurane is used as a rescue therapy for patients for refractory SA. Venovenous (VV) extracorporeal membrane oxygenation (ECMO) is a mode of mechanical circulatory support that is usually employed as a potentially lifesaving intervention in patients who have high risk of mortality, primarily for underlying pulmonary pathology. VV ECMO is usually only considered in cases where patients gas exchange cannot be satisfactorily maintained by conventional therapy and mechanical ventilation strategies. We report the novel use of isoflurane delivered systemically as treatment for severe refractory SA in a patient on VV ECMO. A 51-year-old male with a history of asthma was transferred from another institution for management of severe SA. He was intubated at the referring hospital after failing non-invasive ventilation. Initial arterial blood gas (ABG) showed pH 7.21, partial pressure of carbon dioxide (PCO2) >95 mmHg, and partial pressure of oxygen (PaO2) 60 mmHg. VV ECMO was initiated on hospital day (HD) 1 due to refractory respiratory acidosis. After ECMO initiation, acid-base status improved, however, severe bronchospasm persisted and intrinsic positive end expiratory pressure (PEEP) was measured at 18 cm H2O. Systemic paralysis was employed, respiratory rate (RR) was reduced to 4 breaths per minute. This degree of bronchospasm did not allow for ECMO weaning. On HD 5, the patient received systemic isoflurane via the ECMO circuit for 20 h. The following morning, intrinsic PEEP was 4 cm H2O, and wheezing improved. He was decannulated from VV ECMO on HD 10 and extubated on HD 17. Inhaled isoflurane therapy in patients on VV ECMO for refractory SA has shown good results, but requires delivery of the medication via anesthesia ventilators. Our case highlights an effective alternative, systemic delivery of anesthetic via the ECMO circuit, as it is often difficult and dangerous to transport these patients to the operating room (OR) or have an intensive care unit (ICU) room adjusted to accommodate an anesthesia ventilator.
Disparities in the unmet mental health needs between LGBTQ+ and non-LGBTQ+ populations during COVID-19 in the United States from 21 July 2021 to 9 May 2022
Authors: Chen Shanquan , Wang Yuqi , She Rui , Qin Pei , Ming Wai-Kit
Published: November 2022

Background

Evidence highlighted the likelihood of unmet mental health needs (UMHNs) among LGBTQ+ than non-LGBTQ+ populations during COVID-19. However, there lacks evidence to accurately answer to what extent the gap was in UMHN between LGBTQ+ and non-LGBTQ+ populations. We aim to evaluate the difference in UMHN between LGBTQ+ and non-LGBTQ+ during COVID-19.

Methods

Cross-sectional data from Household Pulse Survey between 21 July 2021 and 9 May 2022 were analyzed. LGBTQ+ was defined based on self-reported sex at birth, gender, and sexual orientation identity. UMHN was assessed by a self-reported question. Multivariable logistic regressions generated adjusted odds ratios (AODs) of UMHN, both on overall and subgroups, controlling for a variety of socio-demographic and economic-affordability confounders.

Findings

81267 LGBTQ+ and 722638 non-LGBTQ+ were studied. The difference in UMHN between LGBTQ+ and non-LGBTQ+ (as reference) varied from 4.9% (95% CI 1.2–8.7%) in Hawaii to 16.0% (95% CI 12.2–19.7%) in Utah. In multivariable models, compared with non-LGBTQ+ populations, LGBTQ+ had a higher likelihood to report UMHN (AOR = 2.27, 95% CI 2.18–2.39), with the highest likelihood identified in transgender (AOR = 3.63, 95% CI 2.97–4.39); compared with LGBTQ+ aged 65+, LGBTQ+ aged 18–25 had a higher likelihood to report UMHN (AOR = 1.34, 95% CI 1.03–1.75); compared with White LGBTQ+ populations, Black and Hispanic LGBTQ+ had a lower likelihood to report UMHN (AOR = 0.72, 95% CI 0.63–0.82; AOR = 0.85, 95% CI 0.75–0.97, respectively).

Interpretation

During the COVID-19, LGBTQ+ had a substantial additional risk of UMHN than non-LGBTQ+. Disparities among age groups, subtypes of LGBTQ+, and geographic variance were also identified.
Size of the protein-protein energy funnel in crowded environment
Authors: Jenkins Nathan W. , Kundrotas Petras J. , Vakser Ilya A.
Published: November 2022

Association of proteins to a significant extent is determined by their geometric complementarity. Large-scale recognition factors, which directly relate to the funnel-like intermolecular energy landscape, provide important insights into the basic rules of protein recognition. Previously, we showed that simple energy functions and coarse-grained models reveal major characteristics of the energy landscape. As new computational approaches increasingly address structural modeling of a whole cell at the molecular level, it becomes important to account for the crowded environment inside the cell. The crowded environment drastically changes protein recognition properties, and thus significantly alters the underlying energy landscape. In this study, we addressed the effect of crowding on the protein binding funnel, focusing on the size of the funnel. As crowders occupy the funnel volume, they make it less accessible to the ligands. Thus, the funnel size, which can be defined by ligand occupancy, is generally reduced with the increase of the crowders concentration. This study quantifies this reduction for different concentration of crowders and correlates this dependence with the structural details of the interacting proteins. The results provide a better understanding of the rules of protein association in the crowded environment.
Novel variants provide differential stabilisation of human equilibrative nucleoside transporter 1 states
Authors: Boakes Jessica C. , Harborne Steven. P. D. , Ngo Jessie T. S. , Pliotas Christos , Goldman Adrian
Published: November 2022

Human equilibrative nucleoside transporters represent a major pharmaceutical target for cardiac, cancer and viral therapies. Understanding the molecular basis for transport is crucial for the development of improved therapeutics through structure-based drug design. ENTs have been proposed to utilise an alternating access mechanism of action, similar to that of the major facilitator superfamily. However, ENTs lack functionally-essential features of that superfamily, suggesting that they may use a different transport mechanism. Understanding the molecular basis of their transport requires insight into diverse conformational states. Differences between intermediate states may be discrete and mediated by subtle gating interactions, such as salt bridges. We identified four variants of human equilibrative nucleoside transporter isoform 1 (hENT1) at the large intracellular loop (ICL6) and transmembrane helix 7 (TM7) that stabilise the apo-state (∆Tm 0.7–1.5°C). Furthermore, we showed that variants K263A (ICL6) and I282V (TM7) specifically stabilise the inhibitor-bound state of hENT1 (∆∆Tm 5.0 ± 1.7°C and 3.0 ± 1.8°C), supporting the role of ICL6 in hENT1 gating. Finally, we showed that, in comparison with wild type, variant T336A is destabilised by nitrobenzylthioinosine (∆∆Tm -4.7 ± 1.1°C) and binds it seven times worse. This residue may help determine inhibitor and substrate sensitivity. Residue K263 is not present in the solved structures, highlighting the need for further structural data that include the loop regions.
The therapeutic effect of capsaicin on oropharyngeal dysphagia: A systematic review and meta-analysis
Authors: Yang Cong-wen , Chen Ru-dong , Feng Meng-ting , Zhang Meng-zhen , Liu Wei , Liu Xu-chang , Wang Da-chuan
Published: November 2022

Objectives

Capsaicin is a specific agonist of TRPV1 (multimodal sensory receptor), which improves oropharyngeal dysphagia by increasing sensory input from the oropharynx and hypopharynx and by increasing repetitive stimulation of the cerebral cortex. The aim of this systematic review was to evaluate the therapeutic effect of capsaicin on swallowing disorders in stroke patients and the elderly.

Method

We searched Medline, Embase, PubMed, and Cochrane Library databases. We used the Mesh terms search database to screen all clinical trials that complied with the inclusion criteria. Studies were subjected to literature screening, quality assessment, and data extraction to remove studies that did not meet the inclusion criteria. After literature screening, quality assessment, and data extraction, a systematic review and meta-analysis of the included study were performed.

Results

This systematic review and meta-analysis were prospectively registered on PROSPERO under registration number CRD42022313958. Five high-quality randomized controlled trials were ultimately included. The results of our meta-analysis showed a more significant reduction in swallowing function score change in the capsaicin group compared to the control group [SMD = −1.30, 95% CI: (−2.35, −0.25), P = 0.01] and on the Water swallowing test the improvement was significantly higher in the capsaicin group [RR = 2.46, 95% CI: (1.73, 3.50), P < 0.0001].

Conclusions

Although the results of our meta-analysis showed that capsaicin improved swallowing function, most studies had an unclear bias and included few studies. More studies are needed to support this in the future.

Systematic review registration

www.crd.york.ac.uk/prospero/display_record.php?RecordID=304061, identifier: 304061.
Case report: Unusual episodic myopathy in a patient with novel homozygous deletion of first coding exon of MICU1 gene
Authors: Sharova Margarita , Skoblov Mikhail , Dadali Elena , Demina Nina , Shchagina Olga , Konovalov Fedor , Ampleeva Maria , Sharkova Inna , Kutsev Sergey
Published: November 2022

We present a patient with unusual episodes of muscular weakness due to homozygous deletion of exon 2 in the MICU1 gene. Forty-three patients from 33 families were previously described with homozygous and compound heterozygous, predominantly loss of function (LoF) variants in the MICU1 gene that lead to autosomal recessive myopathy with extrapyramidal signs. Most described patients developed muscle weakness and elevated CK levels, and half of the patients had progressive extrapyramidal signs and learning disabilities. Our patient had a few severe acute episodes of muscle weakness with minimal myopathy features between episodes and a strongly elevated Creatinine Kinase (CK). Whole exome sequencing (WES) was performed and the homozygous deletion of exon 2 was suspected. To validate the diagnosis, we performed an RNA analysis of all family members. To investigate the possible impact of this deletion on the phenotype, we predicted a new Kozak sequence in exon 4 that could lead to the formation of a truncated MICU1 protein that could partly interact with MCU protein in a mitochondrial Ca2+ complex. We suspect that this unusual phenotype of the proband with MICU1-related myopathy could be explained by the presence of the truncated but partly functional protein. This work helps to define the clinical polymorphism of MICU1 deficiency better.
Hsc70-4 aggravates PolyQ-mediated neurodegeneration by modulating NF-κB mediated immune response in Drosophila
Authors: Rai Saurabh , Tapadia Madhu G.
Published: November 2022

Huntington’s disease occurs when the stretch of CAG repeats in exon 1 of the huntingtin (htt) gene crosses the permissible limit, causing the mutated protein (mHtt) to form insoluble aggregates or inclusion bodies. These aggregates are non-typically associated with various essential proteins in the cells, thus disrupting cellular homeostasis. The cells try to bring back normalcy by synthesizing evolutionary conserved cellular chaperones, and Hsp70 is one of the families of heat shock proteins that has a significant part in this, which comprises of heat-inducible and cognate forms. Here, we demonstrate that the heat shock cognate (Hsc70) isoform, Hsc70-4/HSPA8, has a distinct role in polyglutamate (PolyQ)-mediated pathogenicity, and its expression is enhanced in the polyQ conditions in Drosophila. Downregulation of hsc70-4 rescues PolyQ pathogenicity with a notable improvement in the ommatidia arrangement and near-normal restoration of optic neurons leading to improvement in phototaxis response. Reduced hsc70-4 also attenuates the augmented immune response by decreasing the expression of NF-κB and the antimicrobial peptides, along with that JNK overactivation is also restored. These lead to the rescue of the photoreceptor cells, indicating a decrease in the caspase activity, thus reverting the PolyQ pathogenicity. At the molecular level, we show the interaction between Hsc70-4, Polyglutamine aggregates, and NF-κB, which may be responsible for the dysregulation of signaling molecules in polyQ conditions. Thus, the present data provides a functional link between Hsc70-4 and NF-κB under polyQ conditions.
Enterococcus faecium GEFA01 alleviates hypercholesterolemia by promoting reverse cholesterol transportation via modulating the gut microbiota-SCFA axis
Authors: Xu Wenfeng , Zou Kaixiang , Zhan Ying , Cai Yunjie , Zhang Zhihong , Tao Xueying , Qiu Liang , Wei Hua
Published: November 2022

This study aimed to identify cholesterol-lowering commensal strains from healthy lean individuals and to evaluate the cholesterol-lowering capacity of Enterococcus faecium GEFA01 in mice fed a high-cholesterol and high-fat diet. E. faecium GEFA01 was isolated from the feces of a healthy lean individual in a selective basal salt medium supplemented with cholesterol. E. faecium GEFA01 exhibited a cholesterol removal rate (CRR) of 46.13% by coprecipitation, assimilation, and degradation of cholesterol. Moreover, E. faecium GEFA01 significantly decreased the body weight of mice and the levels of serum total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), hepatic TC, triglycerides (TG), and LDL-C, and increased serum high-density lipoprotein cholesterol (HDL-C) levels in mice fed a high-cholesterol diet compared with the HCD group. We also observed that E. faecium GEFA01 significantly downregulated the gene expression of HMG-CoA reductase (Hmgcr), Srebp-1c, Fxr, Shp, and Fgf 15, upregulated the gene expression of low-density lipoprotein receptor (Ldlr), Abcg5/8, Abca1, cholesterol 7 alpha-hydroxylase (Cyp7a1), and Lxr in the liver of mice in relative to the HCD group, markedly increased the relative abundance of Lactobacillus, Akkermansia, Bifidobacterium, and Roseburia, and decreased the abundance of Helicobacter in the feces. Collectively, we confirmed that E. faecium GEFA01 exhibited cholesterol-lowering effects in mice fed a high-cholesterol diet, which was achieved through assimilation, coprecipitation, and degradation of cholesterol, and through modulation of the gut microbiota short-chain fatty acid (SCFA) axis that promoted reverse cholesterol transport and bile acid excretion. Our study demonstrated that E. faecium GEFA01 may be used as a probiotic candidate to lower cholesterol levels in the future.
KIDMED 2.0, An update of the KIDMED questionnaire: Evaluation of the psychometric properties in youth
Authors: López-Gajardo Miguel A. , Leo Francisco M. , Sánchez-Miguel Pedro Antonio , López-Gajardo Dori , Soulas Candelaria , Tapia-Serrano Miguel A.
Published: November 2022

Background and aims

As children and adolescents' eating patterns have changed over the last few years, researchers have found inconsistencies in the current questionnaires. Therefore, this research aims to (i) update the 2019 KIDMED questionnaire; and (ii) test the psychometric properties of this new questionnaire.

Method

A study with 419 children and adolescents in southwestern Spain was conducted in 2021. The new version of the KIDMED 2.0 was tested, which measures adherence to the Mediterranean diet through 16 items, of which 12 are positive, and 4 are negative. Content validation involved consultation with nutritionists, experts, and adolescents to assess whether the questionnaire was reliable and valid regarding dietary patterns associated with the Mediterranean diet. The expert assessment provided content validity indices for the clarity and representativeness of the questionnaire. Construct validity and test-retest reliability involved 419 students (Mage = 14.40 ± 2.00) from southwestern Spain. Students responded twice (one week apart) to the KIDMED developed in the previous stage and completed a 7-day dietary record.

Results

Regarding validity, results show a moderate agreement for 10 items (ranging between 0.21 and 0.47) of the KIDMED and the 7-day dietary record. Concerning Items 3, 4, 5, and 6, the agreement was slight (ranging between 0.08 and 0.17), whereas the agreement for Item 8 was low. Cohen's kappa showed that most items had moderate to substantial test-retest reliability. Also, kappa showed significant test-retest values for all items (p < 0.001).

Conclusion

The new version of the KIDMED 2.0 was shown to be a reliable and valid instrument to measure adherence to the Mediterranean diet in children and adolescents.
Case report: Capillary hemangioma in the renal hilum mimicking paraganglioma
Authors: Jiang Weixing , Liu Xiaoqi , Wen Li
Published: November 2022

Background

Capillary hemangioma is a common benign tumor in children. Its presence in the kidney is rare, and there have been only case reports in the English literature. Herein, we report a special case of capillary hemangioma located in the renal hilum, which was suspected to be a paraganglioma.

Case presentation

A 44-year-old woman had an irregular mass in the right hilar region. She had a history of hypertension for 3 years, and her 24-hour urinary norepinephrine was slightly high (41.53 µg, normal range: 16.69-40.65 µg). Abdominal MRI revealed a mass in the renal hilum measuring approximately 4.8×4.0×3.2 cm, slightly low signal intensity on T1WI, and very high signal intensity on both T2WI and DWI. The multiphase enhanced scan showed that the tumor had obvious enhancement with a central hypointense area. Therefore, paraganglioma was initially diagnosed. Phenoxybenzamine was administered over the next 2 weeks. She performed laparoscopic right hilar area tumor resection, and the kidney was preserved. Unexpectedly, the final pathology report was capillary hemangioma.

Conclusions

Capillary hemangioma in the renal hilum is extremely rare. Surgery is the first choice to reduce the risk of compression symptoms and to rule out malignancy with respect to an undefined growing retroperitoneal mass. In addition, renal-sparing surgery should be preferred.
The effect of chemotherapy in patients with stage I mucinous ovarian cancer undergoing fertility-sparing surgery
Authors: Long Xingtao , Li Rengui , Tang Ying , Yang Lingling , Zou Dongling
Published: November 2022

Objective

To determine the effect of adjuvant chemotherapy in patients with stage I mucinous ovarian cancer (MOC) undergoing fertility-preserving surgery.

Patients and methods

The clinicopathological characteristics and survival information of young women with stage I MOC from SEER databases between 2004 and 2019 were collected. The relationship between chemotherapy and the characteristics was examined by univariate and multivariate logistic regression analyses. Univariable and multivariate Cox proportional hazards survival analysis were employed for cancer-specific survival. Cox analysis was performed to build a nomogram model.

Results

All 901 eligible patients with stage I MOC were screened from the SEER database. There were 321(35.6%) patients aged 9-30 years, 580(64.4%) aged 31-45 years, 645 (71.6%) patients with stage IA/IB, 256 (28.4%) with stage IC disease, 411(45.6%) who underwent fertility-sparing surgery, and276(30.6%) who received postoperative adjuvant chemotherapy. Multivariate logistic regression analyses showed that postoperative chemotherapy was often used in patients aged 31-45 relative to aged 9-30 (HR: 2.215, 95%CI 1.443-3.401, P < 0.001) or with grade 3 compared to grade 1 tumors (HR: 7.382, 95%CI 4.054-13.443, P < 0.001) or with stage IC compared to stage IA/IB (HR: 6.436, 95%CI 4.515-9.175, P < 0.001) or with non-fertility sparing surgery relative to fertility-sparing (HR:2.226, 95%CI 1.490-3.327, P < 0.001). Multivariate analysis for the special population with fertility preservation indicated that patients with chemotherapy (HR: 2.905, 95% CI: 0.938-6.030, P=0.068) or with grade 3 (HR: 4.750, 95% CI: 1.419-15.896, P=0.011) had a greater risk of mortality. Significant CSS differences were observed between the non-chemotherapy and chemotherapy groups in MOC when patients were stage IA/IB-grade 2 (P=0.004) (10-year CSS rates of chemotherapy=84%, non-chemotherapy = 100%), but not when they were stage IA/IB-grade 1, stage IA/IB-grade 3 or stage IC (both P>0.05). A prognostic prediction nomogram model was built for stage I MOC patient who underwent fertility-sparing and the C-index was 0.709.

Discussion

The patients aged 31-45 years, with grade 3, stage IC, and non-fertility-sparing surgery were more likely to receive adjuvant chemotherapy in the real world. For stage I MOC patient who underwent fertility-sparing surgery, the choice of chemotherapy may increase the risk of death, and it should be carefully selected in clinical practice.
Primary extragastrointestinal stromal tumors of the prostate: A case report and literature review
Authors: Yang Yuxuan , Sun Dengshun , Tang Kun
Published: November 2022

Gastrointestinal stromal tumors (GISTs) are the main stromal tumors of the digestive tract. Extragastrointestinal stromal tumors (EGISTs) typically originate outside the gastrointestinal tract; are not associated with the stomach or intestinal walls; and are mainly derived from the mesentery, peritoneum, posterior peritoneum, bladder, and scrotum. However, EGISTs from the prostate are rare. Here, we present a case of EGIST that passed off in the prostate of a 62-year-old man. The patient undergoes transrectal guided trans-perineal prostate puncture, and pathological reports suggest a GIST. Tumor cells are spindle-shaped, and no obvious neoplastic necrosis is seen in the sections. Immunohistochemical results are robustly positive for CD117, DOG-1, and CD34 expression. The patient had a good prognosis after treatment with imatinib, no recurrence and no metastases after six months of follow-up, and the prognosis was good. This article also provides a literature review and discussion of the treatment of EGISTs.
Systematic assessment and optimizing algorithm of tumor mutational burden calculation and their implications in clinical decision-making
Authors: Sun Daqiang , Xu Meilin , Pan Chaohu , Tang Hongzhen , Wang Peng , Wu Dongfang , Luo Haitao
Published: November 2022

Tumor mutation burden (TMB) has been validated as a biomarker to predict the response of immune checkpoint inhibitors (ICIs) treatment in various cancers. However, the effects of different sequencing platforms, cancer types, and calculation algorithms on TMB as well as its cut-off value for predicting immunotherapy efficacy in the East Asian population still need to be further investigated. In this study, the data of 4126 samples generated by targeted panel sequencing or whole-exome sequencing (WES) in different platforms and public sequencing data from 3680 samples that contained targeted panel sequencing, WES and whole-genome sequencing (WGS) were obtained. The impact of different sequencing platforms and methods on TMB calculation was assessed. No significant bias was found in TMB calculated by different platforms. However, TMB calculated from WGS was significantly lower than those calculated from targeted panel sequencing and WES. The distribution of TMB at different sequencing depths and tumor purity were analyzed. There was no significant difference in the distribution of TMB when the sequencing depth was greater than 500, the tumor purity estimated by hematoxylin-eosin (HE) staining was between 0.1-1.0 or estimated by next-generation sequencing (NGS) was greater than 0.4. In addition, the somatic-germline-zygosity (SGZ) algorithm was optimized to calculate TMB from tumor-only sequencing samples in the East Asian population. The correlation coefficient of TMB calculated with the optimized SGZ algorithm and paired normal-tumor sequencing is 0.951. Furthermore, the optimal cut-off value of TMB in East Asian lung cancer patients treated with ICIs was determined to be 7 mut/Mb instead of 10 mut/Mb through the ROC curve and Log-rank analysis in the training cohort and validated in the test cohort. Patients with TMB ≥ 7 mut/Mb had better outcomes than patients with TMB<7 mut/Mb. In conclusion, this study systematically analyzed the factors that influenced the TMB calculation and optimized the SGZ algorithm to calculate TMB from tumor-only sequencing samples in the East Asian population. More importantly, the cut-off value of TMB for predicting immunotherapy efficacy was determined to be 7 mut/Mb instead of 10 mut/Mb in East Asian lung cancer patients, which can help in clinical decision-making.
Could Near Infrared Spectroscopy (NIRS) be the new weapon in our fight against Necrotising Enterocolitis?
Authors: Howarth Claire , Banerjee Jayanta , Leung Terence , Aladangady Narendra
Published: November 2022

There is no ideal single gut tissue or inflammatory biomarker available to help to try and identify Necrotising Enterocolitis (NEC) before its clinical onset. Neonatologists are all too familiar with the devastating consequences of NEC, and despite many advances in neonatal care the mortality and morbidity associated with NEC remains significant. In this article we review Near Infrared Spectroscopy (NIRS) as a method of measuring regional gut tissue oxygenation. We discuss its current and potential future applications, including considering its effectiveness as a possible new weapon in the early identification of NEC.
Involvement of oxidative species in cyclosporine-mediated cholestasis
Authors: Nsengimana Bernard , Okpara Edozie Samuel , Hou Wanqing , Yan Chuyun , Han Shuxin
Published: November 2022

Cyclosporine is an established medication for the prevention of transplant rejection. However, adverse consequences such as nephrotoxicity, hepatotoxicity, and cholestasis have been associated with prolonged usage. In cyclosporine-induced obstructive and chronic cholestasis, for example, the overproduction of oxidative stress is significantly increased. Additionally, cyclosporine exerts adverse effects on liver function and redox balance responses in treated rats, as evidenced by its increasing levels of aspartate aminotransferase (AST), alanine aminotransferase (ALT), and bilirubin while also decreasing the levels of glutathione and NADPH. Cyclosporine binds to cyclophilin to produce its therapeutic effects, and the resulting complex inhibits calcineurin, causing calcium to accumulate in the mitochondria. Accumulating calcium with concomitant mitochondrial abnormalities induces oxidative stress, perturbation in ATP balance, and failure of calcium pumps. Also, cyclosporine-induced phagocyte oxidative stress generation via the interaction of phagocytes with Toll-like receptor-4 has been studied. The adverse effect of cyclosporine may be amplified by the release of mitochondrial DNA, mediated by oxidative stress-induced mitochondrial damage. Given the uncertainty surrounding the mechanism of cyclosporine-induced oxidative stress in cholestasis, we aim to illuminate the involvement of oxidative stress in cyclosporine-mediated cholestasis and also explore possible strategic interventions that may be applied in the future.
Salvianolic acid A regulates pyroptosis of endothelial cells via directly targeting PKM2 and ameliorates diabetic atherosclerosis
Authors: Zhu Ji , Chen Hang , Le Yifei , Guo Jianan , Liu Zhijun , Dou Xiaobing , Lu Dezhao
Published: November 2022

Rescuing endothelial cells from pyroptotic cell death emerges as a potential therapeutic strategy to combat diabetic atherosclerosis. Salvianolic acid A (SAA) is a major water-soluble phenolic acid in the Salvia miltiorrhiza Bunge, which has been used in traditional Chinese medicine (TCM) and health food products for a long time. This study investigated whether SAA-regulated pyruvate kinase M2 (PKM2) functions to protect endothelial cells. In streptozotocin (STZ)-induced diabetic ApoE−/− mice subjected to a Western diet, SAA attenuated atherosclerotic plaque formation and inhibited pathological changes in the aorta. In addition, SAA significantly prevented NLRP3 inflammasome activation and pyroptosis of endothelial cells in the diabetic atherosclerotic aortic sinus or those exposed to high glucose. Mechanistically, PKM2 was verified to be the main target of SAA. We further revealed that SAA directly interacts with PKM2 at its activator pocket, inhibits phosphorylation of Y105, and hinders the nuclear translocation of PKM2. Also, SAA consistently decreased high glucose-induced overproduction of lactate and partially lactate-dependent phosphorylation of PKR (a regulator of the NLRP3 inflammasome). Further assay on Phenylalanine (PKM2 activity inhibitor) proved that SAA exhibits the function in high glucose-induced pyroptosis of endothelial cells dependently on PKM2 regulation. Furthermore, an assay on c16 (inhibitor of PKR activity) with co-phenylalanine demonstrated that the regulation of the phosphorylated PKR partially drives PKM2-dependent SAA modulation of cell pyroptosis. Therefore, this article reports on the novel function of SAA in the pyroptosis of endothelial cells and diabetic atherosclerosis, which provides important insights into immunometabolism reprogramming that is important for diabetic cardiovascular disease complications therapy.
Schisantherin A inhibits cell proliferation by regulating glucose metabolism pathway in hepatocellular carcinoma
Authors: Feng Fan , Pan Lianhong , Wu Jiaqin , Liu Mingying , He Long , Yang Li , Zhou Wei
Published: November 2022

Schisantherin A (STA) is a traditional Chinese medicine extracted from the plant Schisandra chinensis, which has a wide range of anti-inflammatory, antioxidant, and other pharmacological effects. This study investigates the anti-hepatocellular carcinoma effects of STA and the underlying mechanisms. STA significantly inhibits the proliferation and migration of Hep3B and HCCLM3 cells in vitro in a concentration-dependent manner. RNA-sequencing showed that 77 genes are upregulated and 136 genes are downregulated in STA-treated cells compared with untreated cells. KEGG pathway analysis showed significant enrichment in galactose metabolism as well as in fructose and mannose metabolism. Further gas chromatography-mass spectrometric analysis (GC-MS) confirmed this, indicating that STA significantly inhibits the glucose metabolism pathway of Hep3B cells. Tumor xenograft in nude mice showed that STA has a significant inhibitory effect on tumor growth in vivo. In conclusion, our results indicate that STA can inhibit cell proliferation by regulating glucose metabolism, with subsequent anti-tumor effects, and has the potential to be a candidate drug for the treatment of liver cancer.