bluuebunny/crossref_metadata_2025 huggingface dataset:
Virulence of Vibrio alginolyticus Accentuates Apoptosis and Immune Rigor in the Oyster Crassostrea hongkongensis
Authors: Mao Fan , Liu Kunna , Wong Nai-Kei , Zhang Xiangyu , Yi Wenjie , Xiang Zhiming , Xiao Shu , Yu Ziniu , Zhang Yang
Published: September 2021

Vibrio species are ubiquitously distributed in marine environments, with important implications for emerging infectious diseases. However, relatively little is known about defensive strategies deployed by hosts against Vibrio pathogens of distinct virulence traits. Being an ecologically relevant host, the oyster Crassostrea hongkongensis can serve as an excellent model for elucidating mechanisms underlying host-Vibrio interactions. We generated a Vibrio alginolyticus mutant strain (V. alginolyticus△vscC) with attenuated virulence by knocking out the vscC encoding gene, a core component of type III secretion system (T3SS), which led to starkly reduced apoptotic rates in hemocyte hosts compared to the V. alginolyticusWT control. In comparative proteomics, it was revealed that distinct immune responses arose upon encounter with V. alginolyticus strains of different virulence. Quite strikingly, the peroxisomal and apoptotic pathways are activated by V. alginolyticusWT infection, whereas phagocytosis and cell adhesion were enhanced in V. alginolyticus△vscC infection. Results for functional studies further show that V. alginolyticusWT strain stimulated respiratory bursts to produce excess superoxide (O2•−) and hydrogen peroxide (H2O2) in oysters, which induced apoptosis regulated by p53 target protein (p53tp). Simultaneously, a drop in sGC content balanced off cGMP accumulation in hemocytes and repressed the occurrence of apoptosis to a certain extent during V. alginolyticus△vscC infection. We have thus provided the first direct evidence for a mechanistic link between virulence of Vibrio spp. and its immunomodulation effects on apoptosis in the oyster. Collectively, we conclude that adaptive responses in host defenses are partially determined by pathogen virulence, in order to safeguard efficiency and timeliness in bacterial clearance.
Effects of Low- and High-Level Gossypol and Sodium Butyrate Supplementation Under High-Level Gossypol Condition on Growth Performance and Intestinal Health of Hybrid Grouper (Epinephelus fuscoguttatus♀×Epinephelus lanceolatus♂)
Authors: Yin Bin , Liu Hongyu , Tan Beiping , Dong Xiaohui , Chi Shuyan , Yang Qihui , Zhang Shuang
Published: September 2021

The supplementation of gossypol in excess is noted to cause detrimental effects such as the reduction of antioxidant enzymes and disruption of lipid metabolism in animals. Studies regarding the effects of different levels of gossypol are very rare; thus, this study was conducted to evaluate the effects of low and high dietary levels of gossypol and of supplementation with 0.13 % sodium butyrate (NaB) under high gossypol conditions on the growth performance and intestinal health of hybrid grouper (Epinephelus fuscoguttatus♀×Epinephelus lanceolatus♂). Four treatments were used: Feed containing 40% fish meal was used as the control group [fishmeal (FM)], the FM diet plus 0.03% gossypol acetic acid (abbreviated as gossypol) as the low-level gossypol group (gL), FM + 0.15% gossypol was used as the high-level gossypol group (gH), and FM+0.15 % gossypol with 0.13 % NaB as the repair group (gHNaB). All diets were isonitrogenous and isolipidic. The results showed that the gL treatment significantly increased specific growth rate (SGR) and feed utilization; upregulated mRNA levels of distal intestinal transforming growth factor-β1 (tgfβ1), jam, occludin, claudin3, and zo1; and downregulated mRNA levels of il8, ifnγ, and akt. The gH treatment significantly reduced SGR and feed utilization; increased distal intestinal total nitric oxide synthase (NOS) activity and nitric oxide (NO) content; upregulated mRNA levels of distal intestinal tnfα, il1β, il6, ifnγ, caspase2, caspase9, and akt; and downregulated mRNA levels of tgfβ1, jam, and zo1. NaB supplementation significantly increased distal intestinal total NOS activity and NO content; downregulated distal intestinal tnfα, il1β, ifnγ, pi3k p85, and akt mRNA levels; and increased distal intestinal tgfβ1, jam, occludin, and zo1 mRNA levels. Above all, low- and high-level gossypol exhibited positive and negative effects on growth performance, distal intestinal anti-inflammatory capacity, and tight junctions, respectively, in hybrid groupers. NaB supplementation improved distal intestinal anti-inflammatory capacity and tight junctions in hybrid groupers to a certain extent.
A Systematic Indoor and Outdoor Study of the Effect of Particle Size and Concentration of TiO2 in Improving Solar Absorption for Solar Still Application
Authors: Samneang Heng , Kumar Laveet , Zafar Amad , Ali Muhammad Umair , Zahid Taiba , Bibi Saira , Ahmad Muhammad Shakeel , Ghafoor Usman , Selvaraj Jeyraj
Published: September 2021

Solar light absorber surface is probably one of the most important components in solar still that dictates the distillate yield. In this work, a systematic study is conducted to investigate the effect of particle size and concentration of titanium oxide (TiO2) in black paint in increasing the solar still absorber surface temperature. The various available particle sizes, i.e., 20, 150, and 400 nm, are mixed in black paint with varying concentrations and are applied on the absorber plate. XRD is used for phase identification of as-received powders. UV-Vis spectroscopy is used to examine light absorption properties. Finally, extensive indoor testing (using an improvised solar simulator) and outdoor testing are conducted to optimize the concentration. An increase in surface temperature is observed with the introduction of TiO2 nanoparticles in black paint. Furthermore, the increase in particle size leads to an increase in temperature. The highest surface temperatures of 104.86°C, 105.42°C, and 106.32°C are recorded for specimens with particles sizes 20 nm (at 15 wt% concentration), 150 nm (at 10 wt% concentration), and 400 nm (at 7 wt% concentration), respectively. Furthermore, the highest temperature of 69.69°C is recorded for TiO2-400 nm specimens under outdoor conditions, which is 15.97% higher than that of the bare aluminum plate. The increase in surface temperature may be due to high UV absorption. Moreover, an increase in particle size leads to high light-scattering ability, further improving the light-harvesting ability.
The Profile of Microbiological Pathogens in Diabetic Foot Ulcers
Authors: Chai Wei , Wang Yuqing , Zheng Huancheng , Yue Song , Liu Yan , Wu Yili , Li Xuezhi
Published: September 2021

Diabetic foot, a main complication of diabetes mellitus, renders the foot susceptible to infection, and may eventually lead to non-traumatic limb amputation due to the deterioration of diabetic foot ulcers (DFUs). Characterizing the pathogen spectrum and antibiotic susceptibility is critical for the effective treatment of DFUs. In the current study, the characteristics and antibiotic susceptibility of the pathogen spectrum were analyzed. Secretions from the DFUs of 102 patients were cultured, and dominant pathogens were identified by using test cards. Antibiotic susceptibility of dominant pathogens was assayed by the Kirby–Bauer assay. We found that the dominant pathogens varied with age, duration of diabetes, blood sugar control, and the initial cause of ulcers. Moreover, the dominant pathogens were susceptible to at least one antibiotic. However, the antibacterial efficacy of several commonly used antibiotics decreased from 2016 to 2019. Our study indicates that the identification of dominant pathogens and antibiotic susceptibility testing is essential for the treatment of DFUs with effective antibiotics, while the abuse of antibiotics should be strictly restrained to reduce the generation of antibiotic-resistant strains.
Association Between Air Pollution and Lung Lobar Emphysema in COPD
Authors: Tung Nguyen Thanh , Ho Shu-Chuan , Lu Yueh-Hsun , Chen Tzu-Tao , Lee Kang-Yun , Chen Kuan-Yuan , Wu Chih-Da , Chung Kian Fan , Kuo Han-Pin , Thao Huynh Nguyen Xuan , Dung Hoang Ba , Thuy Tran Phan Chung , Wu Sheng-Ming , Kou Hsiao-Yun , Lee Yueh-Lun , Chuang Hsiao-Chi
Published: September 2021

The development of emphysema has been linked to air pollution; however, the association of air pollution with the extent of lobar emphysema remains unclear. This study examined the association of particulate matter <2.5 μm in aerodynamic diameters (PM2.5) (≤2.5 μm), nitrogen dioxide (NO2), and ozone (O3) level of exposure with the presence of emphysema in 86 patients with chronic obstructive pulmonary disease (COPD). Exposure to the air pollution estimated using the land-use regression model was associated with lung function, BODE (a body mass index, degree of obstruction, dyspnea severity, and exercise capacity index) quartiles, and emphysema measured as low-attenuation areas on high-resolution CT (HR-CT) lung scans. Using paraseptal emphysema as the reference group, we observed that a 1 ppb increase in O3 was associated with a 1.798-fold increased crude odds ratio of panlobular emphysema (p < 0.05). We observed that PM2.5 was associated with BODE quartiles, modified Medical Research Council (mMRC) dyspnea score, and exercise capacity (all p < 0.05). We found that PM2.5, NO2, and O3 were associated with an increased degree of upper lobe emphysema and lower lobe emphysema (all p < 0.05). Furthermore, we observed that an increase in PM2.5, NO2, and O3 was associated with greater increases in upper lobe emphysema than in lower lobe emphysema. In conclusion, exposure to O3 can be associated with a higher risk of panlobular emphysema than paraseptal emphysema in patients with COPD. Emphysema severity in lung lobes, especially the upper lobes, may be linked to air pollution exposure in COPD.
Effectiveness of Probiotics and Prebiotics Against Acute Liver Injury: A Meta-Analysis
Authors: Xu Sheng , Zhao Min , Wang Qinjian , Xu Zhihua , Pan Binhui , Xue Yilang , Dai Zebin , Wang Sisi , Xue Zhanxiong , Wang Fangyan , Xu Changlong
Published: September 2021

Background and Aims: Acute liver injury (ALI) is a clinical syndrome characterized by rapid loss of liver function, which may progress to life-threatening liver failure. We conducted this meta-analysis to examine the evidence on the effects of probiotics or prebiotics on ALI.

Methods and Results: Several databases, including PubMed, EMBASE, and Cochrane Library, were scrutinized from the inception through February 2021 by combining key search terms, yielding 26 eligible studies, which concluded that modulation of gut microbiota significantly decreased aspartate transaminase [standardized mean difference (SMD): −1.51, 95% confidence interval (CI): −2.03 to −1.00], alanine aminotransferase (SMD: −1.42, 95% CI: −1.85 to −0.98), and bilirubin (SMD: −0.91, 95% CI: −1.33 to −0.49). In addition, administration of probiotics or prebiotics also promoted proliferation of Bifidobacterium (SMD: 1.21, 95% CI: −0.18 to 2.60) and inhibited Enterococcus (SMD: −1.00, 95% CI: −1.39 to −0.61), contributing to lower levels of endotoxin (SMD: −2.14, 95% CI: −2.91 to −1.37). Tight junction protein ZO-1 (SMD: 1.95, 95% CI: 0.14 to 3.76) was upregulated after intervention, thereby reducing bacterial translocation to the liver [odds ratio (OR) = 0.23, 95% CI: 0.13–0.44] and mesenteric lymph node (OR = 0.14, 95% CI: 0.08 to 0.26), with decreased tumor necrosis factor-α (SMD: −2.84, 95% CI: −3.76 to −1.93) and interleukin-6 (SMD: −2.62, 95% CI: −4.14 to −1.10). Oxidative stress was also relieved by reducing malondialdehyde (SMD: −1.83, 95% CI: −2.55 to −1.10) while elevating superoxide dismutase (SMD: 1.78, 95% CI: 1.00–2.55) and glutathione (SMD: 1.83, 95% CI: 0.76–2.91).

Conclusion: Our findings suggest that probiotics and prebiotics could be a promising therapeutic strategy in ALI and possess a potential for clinical applications.

Systematic Review Registration:https://www.crd.york.ac.uk/PROSPERO/display_record.php?RecordID=255888, CRD42021255888.
The Active Compounds and Therapeutic Target of Tripterygium wilfordii Hook. f. in Attenuating Proteinuria in Diabetic Nephropathy: A Review
Authors: Liu Peng , Zhang Jing , Wang Yun , Shen Zhengri , Wang Chen , Chen Dan-Qian , Qiu Xinping
Published: September 2021

Tripterygium wilfordii Hook. f. (TWHF) is a traditional Chinese herbal medicine and widely used to treat diabetic kidney disease in China. Emerging evidences have revealed its ability to attenuate diabetic nephropathy (DN). Tripterygium wilfordii polyglycosides (TWPs), triptolide (TP), and celastrol are predominantly active compounds isolated from TWHF. The effects and molecular mechanisms of TWHF and its active compounds have been investigated in recent years. Currently, it is becoming clearer that the effects of TWHF and its active compounds involve in anti-inflammation, anti-oxidative stress, anti-fibrosis, regulating autophagy, apoptosis, and protecting podocytes effect. This review presents an overview of the current findings related to the effects and mechanisms of TWHF and its active compounds in therapies of DN, thus providing a systematic understanding of the mechanisms and therapeutic targets by which TWHF and its active compounds affect cells and tissues in vitro and in vivo.
Analysis of the Involvement of the Isoleucine Biosynthesis Pathway in Photoheterotrophic Metabolism of Rhodospirillum rubrum
Authors: Bayon-Vicente Guillaume , Marchand Elie , Ducrotois Jeson , Dufrasne François E. , Hallez Regis , Wattiez Ruddy , Leroy Baptiste
Published: September 2021

Purple non-sulfur bacteria (PNSB) are recognized as a highly versatile group of bacteria that assimilate a broad range of carbon sources. Growing heterotrophically, PNSB such as Rhodospirillum rubrum (Rs. rubrum) generate reduced equivalents that are used for biomass production. However, under photoheterotrophic conditions, more reduced electron carriers than required to produce biomass are generated. The excess of reduced equivalents still needs to be oxidized for the metabolism to optimally operate. These metabolic reactions are known as electron sinks. Most PNSB rely on the CO2-fixing Calvin cycle and H2 production to oxidize these reduced equivalents. In addition to these well-described electron sinks, the involvement of some pathways, such as polyhydroxyalkanoate (PHA) biosynthesis, in redox poise is still controversial and requires further studies. Among them, isoleucine biosynthesis has been recently highlighted as one of these potential pathways. Here, we explore the role of isoleucine biosynthesis in Rs. rubrum. Our results demonstrate that the isoleucine content is higher under illuminated conditions and that submitting Rs. rubrum to light stress further increases this phenomenon. Moreover, we explore the production of (p)ppGpp in Rs. rubrum and its potential link with light stress. We further demonstrate that a fully functional isoleucine biosynthesis pathway could be an important feature for the onset of Rs. rubrum growth under photoheterotrophic conditions even in the presence of an exogenous isoleucine source. Altogether, our data suggest that isoleucine biosynthesis could play a key role in redox homeostasis.
Characterization of the SPI-1 Type III Secretion System in Pseudomonas fluorescens 2P24
Authors: Wang Jing , Luo Yuan , Gu Yilin , Wei Hai-Lei
Published: September 2021

Pseudomonas fluorescens 2P24 is a plant growth-promoting rhizobacterium (PGPR) isolated from wheat take-all decline soil. Genomic analysis of strain 2P24 revealed the presence of a complete SPI-1 type III secretion system (T3SS) gene cluster on the chromosome with an organization and orientation similar to the SPI-1 T3SS gene clusters of Salmonella enterica and P. kilonensis F113. Phylogenetic analysis revealed that the SPI-1 T3SS gene cluster of strain 2P24 might be obtained from Salmonella and Shigella by horizontal gene transfer. Two transcriptional regulator homologs of HilA and InvF were found from the SPI-1 T3SS gene cluster of strain 2P24. HilA regulated the expression of the structural genes positively, such as invG, sipB, sipD, prgI, and prgK. Prediction of transcriptional binding sites and RNA-seq analysis revealed 14 genes were up-regulated by InvF in strain 2P24. Exploring potential roles of SPI-1 T3SS revealed that it was not associated with motility. However, 2P24ΔinvF reduced resistance against Fusarium graminearum significantly. 2P24ΔhilA enhanced formation of biofilm significantly at 48 h. All three mutants 2P24ΔhilA, 2P24ΔinvF, and 2P24ΔinvE-C reduced the chemotactic responses to glucose significantly. Finally, the determination of SPI-1 mutants to trigger innate immunity in Nicotiana benthamiana showed that 2P24ΔinvE-C reduced the ability to induce the production of reactive oxygen species compared with the wild type strain 2P24.
Fluorescent Multiplex Immunohistochemistry Coupled With Other State-Of-The-Art Techniques to Systematically Characterize the Tumor Immune Microenvironment
Authors: Boisson Anaïs , Noël Grégory , Saiselet Manuel , Rodrigues-Vitória Joël , Thomas Noémie , Fontsa Mireille Langouo , Sofronii Doïna , Naveaux Céline , Duvillier Hugues , Craciun Ligia , Larsimont Denis , Awada Ahmad , Detours Vincent , Willard-Gallo Karen , Garaud Soizic
Published: September 2021

Our expanding knowledge of the interactions between tumor cells and their microenvironment has helped to revolutionize cancer treatments, including the more recent development of immunotherapies. Immune cells are an important component of the tumor microenvironment that influence progression and treatment responses, particularly to the new immunotherapies. Technological advances that help to decipher the complexity and diversity of the tumor immune microenvironment (TIME) are increasingly used in translational research and biomarker studies. Current techniques that facilitate TIME evaluation include flow cytometry, multiplex bead-based immunoassays, chromogenic immunohistochemistry (IHC), fluorescent multiplex IHC, immunofluorescence, and spatial transcriptomics. This article offers an overview of our representative data, discusses the application of each approach to studies of the TIME, including their advantages and challenges, and reviews the potential clinical applications. Flow cytometry and chromogenic and fluorescent multiplex IHC were used to immune profile a HER2+ breast cancer, illustrating some points. Spatial transcriptomic analysis of a luminal B breast tumor demonstrated that important additional insight can be gained from this new technique. Finally, the development of a multiplex panel to identify proliferating B cells, Tfh, and Tfr cells on the same tissue section demonstrates their co-localization in tertiary lymphoid structures.
ACE2 in the Gut: The Center of the 2019-nCoV Infected Pathology
Authors: Guo Yuexin , Wang Boya , Gao Han , Gao Lei , Hua Rongxuan , Xu Jing-Dong
Published: September 2021

The 2019-nCoV is a rapidly contagious pneumonia caused by the recently discovered coronavirus. Although generally the most noticeable symptoms are concentrated in the lungs, the disorders in the gastrointestinal tract are of great importance in the diagnosis of 2019-nCoV. The angiotensin-converting enzyme 2 (ACE2), an important regulator of many physiological functions, including blood pressure and nutrients absorption, is recently identified as a vital entry for 2019-nCoV to enter host cells. In this review, we summarize its functions both physiologically and pathologically. We also elaborate its conflicting roles from the clews of contemporary researches, which may provide significant indications for pharmacological investigations and clinical uses.
Respiratory Training and Plasticity After Cervical Spinal Cord Injury
Authors: Randelman Margo , Zholudeva Lyandysha V. , Vinit Stéphane , Lane Michael A.
Published: September 2021

While spinal cord injuries (SCIs) result in a vast array of functional deficits, many of which are life threatening, the majority of SCIs are anatomically incomplete. Spared neural pathways contribute to functional and anatomical neuroplasticity that can occur spontaneously, or can be harnessed using rehabilitative, electrophysiological, or pharmacological strategies. With a focus on respiratory networks that are affected by cervical level SCI, the present review summarizes how non-invasive respiratory treatments can be used to harness this neuroplastic potential and enhance long-term recovery. Specific attention is given to “respiratory training” strategies currently used clinically (e.g., strength training) and those being developed through pre-clinical and early clinical testing [e.g., intermittent chemical stimulation via altering inhaled oxygen (hypoxia) or carbon dioxide stimulation]. Consideration is also given to the effect of training on non-respiratory (e.g., locomotor) networks. This review highlights advances in this area of pre-clinical and translational research, with insight into future directions for enhancing plasticity and improving functional outcomes after SCI.
Comparison of Management for Central Venous Stenosis With or Without Previous Catheter Placement
Authors: Ma Wei , Zhao Zhengde , Fu Qining , Hu Liangzhu , Zhao Xia , Wang Chao , Liu Yangdong
Published: September 2021

Objective: To compare central venous stenosis/occlusion with or without previous jugular catheter placement history.

Methods: Data of patients with central vein stenosis/occlusion receiving endovascular intervention in our hospital from January 2015 to December 2018 were collected and analyzed.

Results: Twenty-nine patients with previous jugular catheter placement history (CVC group) and 33 patients (excluded two with technical failure) without such history (non-CVC group) are included in this study. Previous jugular catheter placement history raised the risk of postintervention recurrence 1.02 times (CVC group vs. non-CVC group, HR = 2.02 95%CI: 0.91–4.48). The primary patency rate at 6, 12, 18, and 24 months was 76.9, 54.2, 45.5, and 25.0% separately in the CVC group and 80.6, 70.0, 67.9, and 44.4% separately in the non-CVC group. The assisted primary patency rate at 6, 12, 18, and 24 months was 92.3, 91.7, 86.4, and 68.8% separately in the CVC group and 93.5, 90.0, 82.1, and 61.1% separately in the non-CVC group. Patients in the CVC group received a higher frequency of reintervention (0.7 times/year/patient vs. 0.3 times/year/patient). There was no significant difference in the assisted primary patency rate between the two groups. Different primary interventions (angioplasty alone, bare metal stent, stent graft) did not affect primary patency and assisted primary patency, but percutaneous transluminal stenting (PTS) with a bare metal stent had a significant lower primary patency rate between 3 and 24 months compared with PTS with a stent graft (p = 0.011).

Conclusion: Central venous stenosis/occlusion with a previous jugular catheter placement history develops symptoms earlier and had a worse prognosis after endovascular intervention. More efforts are needed to carry out end-stage kidney disease life plan to reduce the harm of evitable catheter placement.
Recommendations for Infantile-Onset and Late-Onset Pompe Disease: An Iranian Consensus
Authors: Fatehi Farzad , Ashrafi Mahmoud Reza , Babaee Marzieh , Ansari Behnaz , Beiraghi Toosi Mehran , Boostani Reza , Eshraghi Peyman , Fakharian Atefeh , Hadipour Zahra , Haghi Ashtiani Bahram , Moravej Hossein , Nilipour Yalda , Sarraf Payam , Sayadpour Zanjani Keyhan , Nafissi Shahriar
Published: September 2021

Background: Pompe disease, also denoted as acid maltase or acid α-glucosidase deficiency or glycogen storage disease type II, is a rare, autosomal recessive lysosomal storage disorder. Several reports have previously described Pompe disease in Iran and considering increased awareness of related subspecialties and physicians, the disease's diagnosis is growing.

Objective: This guideline's main objective was to develop a national guideline for Pompe disease based on national and international evidence adapting with national necessities.

Methods: A group of expert clinicians with particular interests and experience in diagnosing and managing Pompe disease participated in developing this guideline. This group included adult neurologists, pediatric neurologists, pulmonologists, endocrinologists, cardiologists, pathologists, and physiatrists. After developing search terms, four authors performed an extensive literature review, including Embase, PubMed, and Google Scholar, from 1932 to current publications before the main meeting. Before the main consensus session, each panel member prepared an initial draft according to pertinent data in diagnosis and management and was presented in the panel discussion. Primary algorithms for the diagnosis and management of patients were prepared in the panel discussion. The prepared consensus was finalized after agreement and concordance between the panel members.

Conclusion: Herein, we attempted to develop a consensus based on Iran's local requirements. The authors hope that disseminating these consensuses will help healthcare professionals in Iran achieve the diagnosis, suitable treatment, and better follow-up of patients with infantile-onset Pompe disease and late-onset Pompe disease.
The Effect of Oral Nutritional Formula With Three Different Proteins on Type 2 Diabetes Mellitus in vivo
Authors: Jia Ye , Leng Yue , Cruz Aliannys Lazára Puente , Bao Chun Ling , Bao Bin , Wu Wenhui , Wang Peipei , Ma Ming
Published: September 2021

Oral nutritional (ON) products are an effective way to treat patients with type 2 diabetes mellitus (T2DM) whose gastrointestinal functions are normal. The influence of ON formula prepared with three different proteins on T2DM was studied. The hyperglycaemic mouse model using a high-fat diet (HFD) combined with an intraperitoneal injection of streptozotocin (STZ) was used to simulate T2DM. The study was done for 15 weeks using seven groups of mice: control group (CG, normal mice, and normal food), non-treated group (BG, diabetic mice, and normal food), positive control group (PG, diabetic mice, and HFD), soybean protein group (SPG, diabetic mice, and HFD), silkworm pupa protein group (SPPG, diabetic mice, and HFD), whey protein group (LPG, diabetic mice, and HFD), and whey protein combined with silkworm pupa protein group (LCSSPG, diabetic mice, and HFD). The plasma levels of total cholesterol (TC), triglycerides (TG), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) were analyzed on weeks 2, 10, 12, 14, and 15. The concentration of total protein (TP) and albumin (ALB) of the plasma was increased in SPG, SPPG, and PG comparing with BG (p < 0.05). The TC, TG, and LDL-C levels were decreased, and HDL-C level was increased in SPG, PG, SPPG, PG comparing with BG (p < 0.05). Blood glucose (BLG) levels were decreased 47, 34, 24, and 21% in SPG, LCSSPG, SPPG, and PG, respectively. While BLG was not significantly changed (p ≥ 0.05) in LG after 5 weeks of treatment. Overall, the data suggested that consumption of SP, SPP, LCSSPG Oral-formula may be beneficial for the treatment of T2DM.
A Fast Protocol for Multiparametric Characterisation of Diffusion in the Brain and Brain Tumours
Authors: Loução Ricardo , Oros-Peusquens Ana-Maria , Langen Karl-Josef , Ferreira Hugo Alexandre , Shah N. Jon
Published: September 2021

Multi-parametric tissue characterisation is demonstrated using a 4-minute protocol based on diffusion trace acquisitions. Three diffusion regimes are covered simultaneously: pseudo-perfusion, Gaussian, and non-Gaussian diffusion. The clinical utility of this method for fast multi-parametric mapping for brain tumours is explored. A cohort of 17 brain tumour patients was measured on a 3T hybrid MR-PET scanner with a standard clinical MRI protocol, to which the proposed multi-parametric diffusion protocol was subsequently added. For comparison purposes, standard perfusion and a full diffusion kurtosis protocol were acquired. Simultaneous amino-acid (18F-FET) PET enabled the identification of active tumour tissue. The metrics derived from the proposed protocol included perfusion fraction, pseudo-diffusivity, apparent diffusivity, and apparent kurtosis. These metrics were compared to the corresponding metrics from the dedicated acquisitions: cerebral blood volume and flow, mean diffusivity and mean kurtosis. Simulations were carried out to assess the influence of fitting methods and noise levels on the estimation of the parameters. The diffusion and kurtosis metrics obtained from the proposed protocol show strong to very strong correlations with those derived from the conventional protocol. However, a bias towards lower values was observed. The pseudo-perfusion parameters showed very weak to weak correlations compared to their perfusion counterparts. In conclusion, we introduce a clinically applicable protocol for measuring multiple parameters and demonstrate its relevance to pathological tissue characterisation.
Prognostic and Predicted Significance of FENDRR in Colon and Rectum Adenocarcinoma
Authors: Yang Fan , Sun Siyu , Yang Fei
Published: September 2021

Background

The role of fetal-lethal non-coding developmental regulatory RNA (FENDRR) has been explored in various cancers; however, its relationship with colon adenocarcinoma/rectum adenocarcinoma (COAD/READ) remains unclear. The objectives of this study were to identify and assess any associations between FENDRR and COAD/READ using The Cancer Genome Atlas (TCGA) database and the Genetic Data Commons (GDC) Data Portal.

Methods

The records of patients with COAD/READ were collected from the GDC Data Portal. After comparing the expression level of FENDRR in COAD/READ and healthy tissues, we evaluated the association of FENDRR with clinicopathological characters and the survival rate, the impact of FENDRR on prognosis, the biological function of FENDRR, and the relative abundance of tumor-infiltrating immune cells in patients with COAD/READ. Moreover, we aimed to construct a protein-protein interaction (PPI) network for selecting genes and a ceRNA network for presenting mRNA-miRNA-lncRNA interactions.

Results

In patients with COAD/READ, FENDRR expression could differentiate tumor tissues from the adjacent healthy tissues since it was significantly lower in the former than in the latter. High FENDRR expression was correlated with poorer survival and higher tumor stage, current tumor stage, and metastasis stage, and also exhibited high scores for apoptosis, autophagy, and senescence. Immune cell infiltration analysis showed that the high expression group had significantly lower immune and stromal scores. Low FENDRR expression was correlated with poor overall survival (OS), and thus, it could serve as an independent risk factor. The prognostic models constructed in the study performed well for the prediction of OS and disease-specific survival (DFS) using FENDRR expression. Gene set enrichment analysis revealed that vascular smooth muscle contraction, melanogenesis, basal cell carcinoma, and Hedgehog signaling pathways were significantly enriched in patients with high FENDRR expression. Eight hub genes, namely, PKM, ALDOA, PFKP, ALDOC, PYGL, CTNNB1, PSMA5, and WNT5A, were selected from the PPI network, and a ceRNA network was constructed based on the differentially expressed mRNAs, miRNAs, and lncRNAs to illustrate their regulatory relationships.

Conclusion

FENDRR may serve as a potential biomarker for the diagnosis and prognosis of COAD/READ.
Cathepsins B, D, and G Are Expressed in Metastatic Head and Neck Cutaneous Squamous Cell Carcinoma
Authors: Humphries Felix , Chang-McDonald Bridget , Patel Josie , Bockett Nicholas , Paterson Erin , Davis Paul F. , Tan Swee T.
Published: September 2021

Aim

We have previously demonstrated the presence of two cancer stem cell (CSC) subpopulations within metastatic head and neck cutaneous squamous cell carcinoma (mHNcSCC) expressing components of the renin-angiotensin system (RAS), which promotes tumorigenesis. Cathepsins B, D and G are enzymes that constitute bypass loops for the RAS. This study investigated the expression and localization of cathepsins B, D, and G in relation to CSC subpopulations within mHNcSCC.

Methods

Immunohistochemical staining was performed on mHNcSCC tissue samples from 20 patients to determine the expression and localization of cathepsins B, D, and G. Immunofluorescence staining was performed on two of these mHNcSCC tissue samples by co-staining of cathepsins B and D with OCT4 and SOX2, and cathepsin G with mast cell markers tryptase and chymase. Western blotting and quantitative reverse transcription polymerase chain reaction (RT-qPCR) were performed on five mHNcSCC samples and four mHNcSCC-derived primary cell lines, to determine protein and transcript expression of these three cathepsins, respectively. Enzyme activity assays were performed on mHNcSCC tissue samples to determine whether these cathepsins were active.

Results

Immunohistochemical staining demonstrated the presence of cathepsins B, D and G in in all 20 mHNcSCC tissue samples. Immunofluorescence staining showed that cathepsins B and D were localized to the CSCs both within the tumor nests and peri-tumoral stroma (PTS) and cathepsin G was localized to the phenotypic mast cells within the PTS. Western blotting demonstrated protein expression of cathepsin B and D, and RT-qPCR demonstrated transcript expression of all three cathepsins. Enzyme activity assays showed that cathepsin B and D to be active.

Conclusion

The presence of cathepsins B and D on the CSCs and cathepsin G on the phenotypic mast cells suggest the presence of bypass loops for the RAS which may be a potential novel therapeutic target for mHNcSCC.
Robust Angle Selection in Particle Therapy
Authors: Zhou Yuan , Li Yang , Kubota Yoshiki , Sakai Makoto , Ohno Tatsuya
Published: September 2021

The popularity of particle radiotherapy has grown exponentially over recent years owing to the marked advantage of the depth–dose curve and its unique biological property. However, particle therapy is sensitive to changes in anatomical structure, and the dose distribution may deteriorate. In particle therapy, robust beam angle selection plays a crucial role in mitigating inter- and intrafractional variation, including daily patient setup uncertainties and tumor motion. With the development of a rotating gantry, angle optimization has gained increasing attention. Currently, several studies use the variation in the water equivalent thickness to quantify anatomical changes during treatment. This method seems helpful in determining better beam angles and improving the robustness of planning. Therefore, this review will discuss and summarize the robust beam angles at different tumor sites in particle radiotherapy.
Digital Quantification of Tumor PD-L1 Predicts Outcome of PD-1-Based Immune Checkpoint Therapy in Metastatic Melanoma
Authors: Placke Jan-Malte , Soun Camille , Bottek Jenny , Herbst Rudolf , Terheyden Patrick , Utikal Jochen , Pföhler Claudia , Ulrich Jens , Kreuter Alexander , Pfeiffer Christiane , Mohr Peter , Gutzmer Ralf , Meier Friedegund , Dippel Edgar , Weichenthal Michael , Zimmer Lisa , Livingstone Elisabeth , Becker Jürgen C. , Lodde Georg , Sucker Antje , Griewank Klaus , Horn Susanne , Hadaschik Eva , Roesch Alexander , Schadendorf Dirk , Engel Daniel Robert , Ugurel Selma
Published: September 2021

Background

PD-1-based immune checkpoint blockade (ICB) is a highly effective therapy in metastatic melanoma. However, 40-60% of patients are primarily resistant, with valid predictive biomarkers currently missing. This study investigated the digitally quantified tumor PD-L1 expression for ICB therapy outcome prediction.

Patients and Methods

Tumor tissues taken prior to PD-1-based ICB for unresectable metastatic disease were collected within the prospective multicenter Tissue Registry in Melanoma (TRIM). PD-L1 expression (clone 28-8; cut-off=5%) was determined by digital and physician quantification, and correlated with therapy outcome (best overall response, BOR; progression-free survival, PFS; overall survival, OS).

Results

Tissue samples from 156 patients were analyzed (anti-PD-1, n=115; anti-CTLA-4+anti-PD-1, n=41). Patients with PD-L1-positive tumors showed an improved response compared to patients with PD-L1-negative tumors, by digital (BOR 50.5% versus 32.2%; p=0.026) and physician (BOR 54.2% versus 36.6%; p=0.032) quantification. Tumor PD-L1 positivity was associated with a prolonged PFS and OS by either digital (PFS, 9.9 versus 4.6 months, p=0.021; OS, not reached versus 13.0 months, p=0.001) or physician (PFS, 10.6 versus 5.6 months, p=0.051; OS, not reached versus 15.6 months, p=0.011) quantification. Multivariable Cox regression revealed digital (PFS, HR=0.57, p=0.007; OS, HR=0.44, p=0.001) and physician (OS, HR=0.54, p=0.016) PD-L1 quantification as independent predictors of survival upon PD-1-based ICB. The combination of both methods identified a patient subgroup with particularly favorable therapy outcome (PFS, HR=0.53, p=0.011; OS, HR=0.47, p=0.008).

Conclusion

Pre-treatment tumor PD-L1 positivity predicted a favorable outcome of PD-1-based ICB in melanoma. Herein, digital quantification was not inferior to physician quantification, and should be further validated for clinical use.
Complex Regional Pain Syndrome. A Comprehensive Review on Neuroplastic Changes Supporting the Use of Non-invasive Neurostimulation in Clinical Settings
Authors: Zangrandi Andrea , Allen Demers Fannie , Schneider Cyril
Published: September 2021

Background: Complex regional pain syndrome (CRPS) is a rare debilitating disorder characterized by severe pain affecting one or more limbs. CRPS presents a complex multifactorial physiopathology. The peripheral and sensorimotor abnormalities reflect maladaptive changes of the central nervous system. These changes of volume, connectivity, activation, metabolism, etc., could be the keys to understand chronicization, refractoriness to conventional treatment, and developing more efficient treatments.

Objective: This review discusses the use of non-pharmacological, non-invasive neurostimulation techniques in CRPS, with regard to the CRPS physiopathology, brain changes underlying chronicization, conventional approaches to treat CRPS, current evidence, and mechanisms of action of peripheral and brain stimulation.

Conclusion: Future work is warranted to foster the evidence of the efficacy of non-invasive neurostimulation in CRPS. It seems that the approach has to be individualized owing to the integrity of the brain and corticospinal function. Non-invasive neurostimulation of the brain or of nerve/muscles/spinal roots, alone or in combination with conventional therapy, represents a fertile ground to develop more efficient approaches for pain management in CRPS.
Drug Repurposing Prediction and Validation From Clinical Big Data for the Effective Treatment of Interstitial Lung Disease
Authors: Siswanto Soni , Yamamoto Hiroki , Furuta Haruka , Kobayashi Mone , Nagashima Takuya , Kayanuma Gen , Nagayasu Kazuki , Imai Yumiko , Kaneko Shuji
Published: September 2021

Interstitial lung diseases (ILDs) are a group of respiratory disorders characterized by chronic inflammation and fibrosis of the pulmonary interstitial tissues. Although the etiology of ILD remains unclear, some drug treatments are among the primary causes of ILD. In the present study, we analyzed the FDA Adverse Event Reporting System and JMDC Inc. insurance claims to identify a coexisting drug that reduced the incidence of ILD associated with the use of an anti-arrhythmic agent, amiodarone, and found that the thrombin inhibitor dabigatran prevented the amiodarone-induced ILD in both clinical datasets. In an experimental validation of the hypothesis, long-term oral treatment of mice with amiodarone caused a gradual decrease in body weight caused by respiratory insufficiency. In the lungs of amiodarone-treated mice, infiltration of macrophages was observed in parallel with a delayed upregulation of the platelet-derived growth factor receptor α gene. In contrast, co-treatment with dabigatran significantly attenuated these amiodarone-induced changes indicative of ILD. These results suggest that dabigatran is effective in preventing drug-induced ILD. This combinatorial approach of drug repurposing based on clinical big data will pave the way for finding a new treatment with high clinical predictability and a well-defined molecular mechanism.
Study on the Hepatoprotection of Schisandra chinensis Caulis Polysaccharides in Nonalcoholic Fatty Liver Disease in Rats Based on Metabolomics
Authors: Feng Yanbo , Li Han , Chen Cong , Lin Hao , Xu Guangyu , Li He , Wang Chunmei , Chen Jianguang , Sun Jinghui
Published: September 2021

The aim of this study was to investigate the hepatoprotection of Schisandra chinensis Caulis polysaccharides (SCPs) in the nonalcoholic fatty liver disease (NAFLD) induced by high-fat diet (HFD) in rats. A total of 30 Wistar rats were randomly divided into the control group (CON), model group (MOD), and Schisandra chinensis caulis polysaccharide (SCP) group. Except for those in the CON group, the other rats were fed with high-fat diet for 4 weeks to establish an NAFLD model. From the 5th week, rats in the SCP group were given SCP solution (100 mg kg−1) by gavage for 6 weeks, and those in the CON and MOD groups were given an equal volume of distilled water in the same way. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C) levels in serum, the malondialdehyde (MDA) level, glutathione peroxidase (GSH-Px), and superoxide dismutase (SOD) activities in the liver tissue were detected. The small molecular metabolites in the blood of rats were determined by the metabolomics method of ultra-high-performance liquid chromatography-quadrupole/electrostatic field orbitrap high-resolution mass spectrometry (UHPLC-Q-Orbitrap-MS/MS) combined with multivariate analysis. The enrichment analysis and pathway analysis of the different metabolites were carried out. The therapeutic mechanism of SCP in NAFLD rats was verified by western blot. The results showed that the levels of AST, ALT, TG, TC, and LDL-C in the serum of rats in the SCP group were significantly lower, and the levels of HDL-C were significantly higher than those in the MOD group. The screening and analysis of the metabolic pathways showed that SCP could alleviate the development of NAFLD by regulating the expression of UDP-glucose pyrophosphorylase (UGP2), UDP-glucose 6-dehydrogenase (UGDH), acetyl CoA carboxylase (ACC), and fatty acid synthase (FAS) in the liver of NAFLD rats. This study may provide a theoretical basis for the development and utilization of SCP.
Therapeutic Potential of the Cyclin-Dependent Kinase Inhibitor Flavopiridol on c-Myc Overexpressing Esophageal Cancer
Authors: Hassan Md Sazzad , Cwidak Nicholas , Johnson Chloe , Däster Silvio , Eppenberger-Castori Serenella , Awasthi Niranjan , Li Jun , Schwarz Margaret A. , von Holzen Urs
Published: September 2021

Tumors with elevated c-Myc expression often exhibit a highly aggressive phenotype, and c-Myc amplification has been shown to be frequent in esophageal cancer. Emerging data suggests that synthetic lethal interactions between c-Myc pathway activation and small molecules inhibition involved in cell cycle signaling can be therapeutically exploited to preferentially kill tumor cells. We therefore investigated whether exploiting elevated c-Myc expression is effective in treating esophageal cancer with the CDK inhibitor flavopiridol. We found frequent overexpression of c-Myc in human esophageal cancer cell lines and tissues. c-Myc overexpression correlated with accelerated esophageal cancer subcutaneous xenograft tumor growth. Esophageal cancer cells with elevated c-Myc expression were found preferentially more sensitive to induction of apoptosis by the CDK inhibition flavopiridol compared to esophageal cancer cells with lower c-Myc expression. In addition, we observed that flavopiridol alone or in combination with the chemotherapeutic agent nanoparticle albumin-bound paclitaxel (NPT) or in combinations with the targeted agent BMS-754807 significantly inhibited esophageal cancer cell proliferation and subcutaneous xenograft tumor growth while significantly enhancing overall mice survival. These results indicate that aggressive esophageal cancer cells with elevated c-Myc expression are sensitive to the CDK inhibitor flavopiridol, and that flavopiridol alone or in combination can be a potential therapy for c-Myc overexpressing esophageal cancer.
Comparative Efficacy of Jaungo, A Traditional Herbal Ointment, and the Water-in-Oil Type Non-Steroidal Moisturizer for Radiation-Induced Dermatitis in Patients With Breast Cancer: A Study Protocol for a Prospective, Randomized, Single-Blinded, Pilot Study
Authors: Kim Eun Hye , Yoon Jee-Hyun , Park Su Bin , Lee Jee Young , Chung Weon Kuu , Yoon Seong Woo
Published: September 2021

Background: Radiation-induced dermatitis (RID) is a common complication of radiation therapy (RT). Although it has a high prevalence and can even trigger the premature end of conventional cancer therapies, there is no standard management. This study aims to evaluate whether topical use of Jaungo (Shiunko), a traditional herbal ointment mainly composed of Lithospermi radix and Angelica sinensis, could reduce RID compared to the water-in-oil type non-steroidal moisturizer in patients with breast cancer.

Methods: This is a prospective, single-blinded, randomized controlled pilot trial that investigates the effect of topical application of Jaungo for the prevention of RID in postoperative breast cancer patients scheduled for RT, in comparison with the non-steroidal moisturizer, with a random distribution of 50 patients across the two groups. RT will be administered for 5–7 weeks with a biological equivalent dose (BED10) of 60 Gy or more, and the interventions will be applied 3 times a day during RT duration. Participants will be assessed a total of nine times, including eight visits during the period of RT and one visit at a 2-week follow-up period after the end of treatment. The incidence and severity of RID, quality of life, skin reaction symptoms, and maximum pain related to RID will be measured. The incidence rate of grade 2 or higher RID using the Radiation Therapy Oncology Group (RTOG) in the two groups will be statistically compared as the primary outcome. The types and frequencies of adverse events will be also collected and evaluated. All assessments will be performed by independent radiology oncologists.

Discussion: This trial is currently ongoing and is recruiting. This study will determine the preventive efficacy of Jaungo in RID with postoperative breast cancer patients and provide evidence in traditional Korean medicine clinical practice.