bluuebunny/crossref_metadata_2025 huggingface dataset:
Interaction between human leukocyte antigen (HLA-C) and killer cell Ig-like receptors (KIR2DL) inhibits the cytotoxicity of natural killer cells in patients with hepatoblastoma
Authors: Guo Jing-Jie , Ye Yong-Qin , Liu Yi-Di , Wu Wei-Fang , Mei Qian-Qian , Zhang Xi-Yun , Lao Jing , Wang Bin , Wang Jian-Yao
Published: November 2022

Background

Hepatoblastoma (HB) is the most common liver malignancy in childhood with poor prognosis and lack of effective therapeutic targets. Single-cell transcriptome sequencing technology has been widely used in the study of malignant tumors, which can understand the tumor microenvironment and tumor heterogeneity.

Materials and methods

Two children with HB and a healthy child were selected as the research subjects. Peripheral blood and tumor tissue were collected for single-cell transcriptome sequencing, and the sequencing data were compared and analyzed to describe the differences in the immune microenvironment between children with HB and normal children.

Results

There were significant differences in the number and gene expression levels of natural killer cells (NK cells) between children with HB and normal children. More natural killer cells were seen in children with HB compared to normal control. KIR2DL were highly expressed in children with HB.

Conclusion

Single-cell transcriptome sequencing of peripheral blood mononuclear cells (PBMC) and tumor tissue from children with HB revealed that KIR2DL was significantly up-regulated in NK cells from children with HB. HLA-C molecules on the surface of tumor cells interact with inhibitory receptor KIR2DL on the surface of NK cells, inhibiting the cytotoxicity of NK cells, resulting in immune escape of tumors. Inhibitors of related immune checkpoints to block the interaction between HLA-C and KIR2DL and enhance the cytotoxicity of NK cells, which may be a new strategy for HB treatment.
Janus kinases inhibitors for coronavirus disease-2019: A pairwise and Bayesian network meta-analysis
Authors: Niu Jianyi , Lin Zhiwei , He Zhenfeng , Yang Xiaojing , Qin Lijie , Feng Shengchuan , Guan Lili , Zhou Luqian , Chen Rongchang
Published: November 2022

Background

JAK (Janus kinases) inhibitors have been proposed as a promising treatment option for the coronavirus disease-2019 (COVID-19). However, the benefits of JAK inhibitors and the optimum thereof for COVID-19 have not been adequately defined.

Methods

Databases were searched from their inception dates to 17 June 2022. Eligible studies included randomized controlled trials and observational studies. Extracted data were analyzed by pairwise and network meta-analysis. The primary outcome was the coefficient of mortality.

Results

Twenty-eight studies of 8,206 patients were included and assessed qualitatively (modified Jadad and Newcastle–Ottawa Scale scores). A pairwise meta-analysis revealed that JAK inhibitors effectively reduced the mortality (OR = 0.54; 95% CI: 0.46–0.63; P < 0.00001; I2 = 32%) without increasing the risk of adverse events (OR = 1.02; 95% CI: 0.88–1.18; P = 0.79; I2 = 12%). In a network meta-analysis, clinical efficacy benefits were seen among different types of JAK inhibitors (baricitinib, ruxolitinib, and tofacitinib) without the observation of a declined incidence of adverse events. The assessment of rank probabilities indicated that ruxolitinib presented the greatest likelihood of benefits regarding mortality and adverse events.

Conclusion

JAK inhibitors appear to be a promising treatment for COVID-19 concerning reducing mortality, and they do not increase the risk of adverse events vs. standard of care. A network meta-analysis suggests that mortality benefits are associated with specific JAK inhibitors, and among these, ruxolitinib presents the greatest likelihood of having benefits for mortality and adverse events.

Systematic review registration

[www.crd.york.ac.uk/prospero], identifier [CRD42022343338].
In silico characterization of blaNDM-harboring plasmids in Klebsiella pneumoniae
Authors: Zeng Zhu , Lei Lei , Li Linman , Hua Shengni , Li Wenting , Zhang Limei , Lin Qiuping , Zheng Zhixiong , Yang Jing , Dou Xiaohui , Li Luan , Li Xiaobin
Published: November 2022

Klebsiella pneumoniae is a primary culprit of antibiotic-resistant nosocomial infections worldwide, and infections caused by NDM-producing strains are a major threat due to limited therapeutic options. The majority of blaNDM cases occur on plasmids; therefore, we explored the relationships between plasmids and blaNDM genes in K. pneumoniae by analyzing the variants of blaNDM, replicon types, conjugative transfer regions of 171 blaNDM-harboring plasmids from 4,451 K. pneumoniae plasmids. Of the nine identified blaNDM variants, blaNDM-1 (73.68%) and blaNDM-5 (16.37%) were the most dominant. Over half of the blaNDM-harboring plasmids of K. pneumoniae were classified into IncF plasmids. IncX3 single-replicon plasmids (46–57 kb) carried genes encoding relaxases of the MOBP family, T4CP genes of the VirD4/TraG subfamily, and VirB-like T4SS gene clusters, which were mainly geographically distributed in China. We found 10 blaNDM-harboring IncN plasmids (38.38–63.05 kb) carrying the NW-type origin of transfer (oriT) regions, genes coding for relaxases of MOBF family, genes encoding T4CPs of the TrwB/TraD subfamily, and Trw-like T4SS gene clusters, which were also mainly geographically distributed in China. Moreover, we identified 21 IncC plasmids carrying blaNDM-1 (140.1–329.2 kb), containing the A/C-type oriTs, genes encoding relaxases of MOBH family, genes encoding T4CPs belonging to TrwB/TraD subfamily, and Tra_F-like T4SS gene clusters. The blaNDM-harboring IncC plasmids were widely geographically distributed all over the world, mainly in the United States, China and Viet Nam. These findings enhance our understanding of the diversity of blaNDM-harboring plasmids in K. pneumoniae.
Detection of carbapenemase-producing Enterobacterales by means of matrix-assisted laser desorption ionization time-of-flight mass spectrometry with ertapenem susceptibility-testing disks as source of carbapenem substrate
Authors: Shaidullina Elvira R. , Romanov Andrey V. , Skleenova Elena Y. , Sheck Eugene A. , Sukhorukova Marina V. , Kozlov Roman S. , Edelstein Mikhail V.
Published: November 2022

MALDI-TOF mass spectrometry has become widely used in clinical microbiology and has proved highly accurate for detection of carbapenemases in Gram-negative bacteria. However, the use of carbapenem-hydrolysis assays in routine diagnostics is hampered by the need for antibiotic substances and for making their fresh solutions each time an assay is conducted. Here, we evaluated the use of commercial antibiotic susceptibility-testing disks as source of ertapenem substrate in MALDI-TOF MS-based assay for detection of carbapenemase-producing Enterobacterales (CPE). The assay was validated on 48 CPE isolates of 8 different species expressing NDM-, VIM-, KPC- and OXA-48-type carbapenemases and exhibiting various levels of resistance to carbapenems (MIC range: 0.25– > 32 mg/l), as well as on 48 carbapenemase-non-producing isolates. The assay conditions were optimized as follows: 10-μl loopful of bacterial colonies was suspended in 150 μl 0.01 M Na-PBS buffer, pH 7.4, a 10 μg ertapenem susceptibility-testing disk was immersed in the suspension and incubated 3 h at 35°C, after which supernatant was obtained by centrifugation and applied on a target plate with alpha-cyano-4-hydroxycinnamic acid matrix. Mass spectra were analyzed between 440 and 560 m/z. Carbapenemase activity was detected in all tested CPE isolates by the appearance of m/z peaks corresponding to ertapenem hydrolysis products: [Mh + H]+:494.2, [Mh + Na]+:516.2, [Mh + 2Na]+:538.2, [Mh/d + H]+:450.2, [Mh/d + Na]+:472.2, and simultaneous decrease or loss of peaks of intact antibiotic: [M + H]+:476.2, [M + Na]+:498.1, [M + 2Na]+:520.1. No hydrolysis peaks or loss of intact ertapenem peaks were observed for carbapenemase-negative strains. We therefore report the development of a sensitive, specific and cost-effective MALDI-TOF MS-based assay for detection of CPE, which makes use of antibiotic disks readily available in most laboratories.
Selective enrichment on a wide polysaccharide spectrum allowed isolation of novel metabolic and taxonomic groups of haloarchaea from hypersaline lakes
Authors: Sorokin Dimitry Y. , Elcheninov Alexander G. , Khijniak Tatiana V. , Kolganova Tatiana V. , Kublanov Ilya V.
Published: November 2022

Extremely halophilic archaea (haloarchaea) of the class Halobacteria is a dominant group of aerobic heterotrophic prokaryotic communities in salt-saturated habitats, such as salt lakes and solar salterns. Most of the pure cultures of haloarchaea were enriched, isolated, and cultivated on rich soluble substrates such as amino acids, peptides or simple sugars. So far, the evidences on the capability of haloarchaea to use different polysaccharides as growth substrates remained scarce. However, it is becoming increasingly obvious that these archaea can also actively participate in mineralization of complex biopolymers, in particular cellulose and chitin–two dominant biomass polysaccharides on the planet. Here we used an array of commercially available homo- and heteropolysaccharides to enrich hydrolytic haloarchaea from hypersaline salt lakes with neutral pH and from alkaline soda lakes. This resulted in isolation of a range of halo- and natrono-archaea, respectively, belonging to already described taxa as well as several new genus-level lineages. In some cases, the isolates enriched with different polysaccharides happened to be closely related, thus representing generalistic ecotype, while the others were narrow specialists. In general, soda lakes yielded a broader range of polysaccharide-utilizing specialists in comparison to neutral salt lakes. The results demonstrated a significant diversity of halo(natrono)archaea with a previously unrecognized potential for utilization of a broad range of natural polysaccharides in hypersaline habitats.
Alternative strategies for Chlamydia treatment: Promising non-antibiotic approaches
Authors: Hou Chen , Jin Yingqi , Wu Hua , Li Pengyi , Liu Longyun , Zheng Kang , Wang Chuan
Published: November 2022

Chlamydia is an obligate intracellular bacterium where most species are pathogenic and infectious, causing various infectious diseases and complications in humans and animals. Antibiotics are often recommended for the clinical treatment of chlamydial infections. However, extensive research has shown that antibiotics may not be sufficient to eliminate or inhibit infection entirely and have some potential risks, including antibiotic resistance. The impact of chlamydial infection and antibiotic misuse should not be underestimated in public health. This study explores the possibility of new therapeutic techniques, including a review of recent studies on preventing and suppressing chlamydial infection by non-antibiotic compounds.
Biodegradable manganese-doped hydroxyapatite antitumor adjuvant as a promising photo-therapeutic for cancer treatment
Authors: Park Sumin , Choi Jaeyeop , Doan Vu Hoang Minh , O Se Hwi
Published: November 2022

The efficiency of a cancer therapy agent depends on its ability to eliminate tumors without endangering neighboring healthy tissues. In this present study, a novel multifunctional property enriched nanostructured system was synthesized on manganese-doped hydroxyapatite (Mn-HAp) conjugated with counter folic acid (FA) IR-783 fluorescence dye. The tailored synthesis of nano rod-shaped Mn-HAp nanoparticles with high surface area allows to conjugate FA/IR-783 dye which enhanced retention time during in vivo circulation. The drug-free Photothermal Photodynamic therapy mediated cancer treatment permits the prevention of collateral damages to non-cancerous cells. The safe HAp biomaterial matrix allows a large number of molecules on its surface due to its active different charge moieties (Ca2+/PO43-) without any recurrence toxicity. The doped Mn allows releasing of Mn2+ ions which triggered the production of toxic hydroxyl radicals (•OH) via Fenton or Fenton-like reactions to decompose H2O2 in the tumor sites. Herein, IR-783 and FA were selected for targeted fluorescence imaging-guided photothermal therapy. 6The PTT performance of synthesized nanostructured system shows enhanced potential with ∼60°C temperature elevation with 0.75 W∙cm−2 power irradiated within 7 min of treatment. PDT activity was also observed initially with Methylene Blue (MB) as a targeted material which shows a drastic degradation of MB and further in vitro studies with MDA-MB-231 breast cancer cell line show cytotoxicity due to the generated reactive oxygen species (ROS) effect. FA/IR-783 conjugated Mn-HAp nanoparticles (2.0 mol% Mn-HAp/FA-IR-783) show significant tumor-specific targeting and treatment efficiency while intravenously injected in (tail vain) BALB/c nude mice model without any recurrence. The synthesized nanostructured system had ample scope to be a promising Photo-Therapeutic agent for cancer treatment.
VEEG monitoring and electrographic seizures in 232 pediatric patients in ICU at a tertiary hospital in China
Authors: Sang Tian , Wang Ying , Wu Ye , Guan Qiao , Yang ZhiXian
Published: November 2022

Objectives

To investigate neonatal electroencephalography (EEG) background activity and electrographic seizures in patients in the pediatric intensive care unit (PICU) who underwent bedside video-electroencephalography (vEEG) monitoring.

Methods

A total of 232 pediatric patients admitted or transferred to PICU that underwent vEEG monitoring were retrospectively enrolled in this study, and electrographic status epilepticus was observed after vEEG monitoring.

Results

The median age was 1.56 years [95% confidence interval (CI) = 1.12–2.44]. Electrographic seizures occurred in 88 patients (37.9%), out of which 36 cases (40.9%) had electrographic status epilepticus. Prior epileptic encephalopathy diagnosis [odds ratio (OR) = 6.57, 95% CI = 1.91–22.59, p = 0.003], interictal epileptiform discharges (OR = 46.82, 95%CI = 5.31–412.86, p = 0.0005), slow disorganized EEG background (OR = 11.92, 95%CI = 1.31–108.71, p = 0.028), and burst-suppression EEG background (OR = 23.64, 95%CI = 1.71–327.57, p = 0.018) were the risk factors for electrographic seizures' occurrence. Of the 232 patients, the condition of 179 (77.2%) patients improved and they were discharged, 34 cases (14.7%) were withdrawn, and 18 cases (7.8%) died. The in-hospital death rate was 47.6% (10 in 21 cases) in patients with attenuated/featureless, compared to 0/23 with normal EEG background.

Conclusions

Electrographic status epilepticus occurs in more than one-third of patients with electrographic seizures. vEEG is an efficient method to determine electrographic seizures in children. Abnormal EEG background activity is associated with both electrographic seizures' occurrence and unfavorable in-hospital outcomes.
Multi-omics analysis reveals GABAergic dysfunction after traumatic brainstem injury in rats
Authors: Su Qin , Chen Qianling , Li Zhigang , Zhao Jian , Li Lingyue , Xu Luyao , Yang Bin , Liu Chao
Published: November 2022

Background

Traumatic brainstem injury (TBSI) is one of the forms of brain injury and has a very high mortality rate. Understanding the molecular mechanism of injury can provide additional information for clinical treatment.

Materials and methods

In this study, we detected transcriptome, proteomics, and metabolome expression changes in the brainstem of TBSI rats, and comprehensively analyzed the underlying mechanisms of TBSI.

Results

After TBSI, there was significant diffuse axonal injury (DAI) in the brainstem of rats. A total of 579 genes, 70 proteins, and 183 metabolites showed significant changes in brainstem tissue. Through molecular function and pathway analysis, the differentially expressed genes, proteins, and metabolites of TBSI were mainly attributed to neural signal regulation, inflammation, neuroprotection, and immune system. In addition, a comprehensive analysis of transcripts, proteins, and metabolites showed that the genes, proteins, and metabolic pathways regulated in the brainstem after TBSI were involved in neuroactive ligand-receptor interaction. A variety of GCPR-regulated pathways were affected, especially GAGA’s corresponding receptors GABAA, GABAB, GABAC, and transporter GAT that were inhibited to varying degrees.

Conclusion

This study provides insights into the development of a rapid diagnostic kit and making treatment strategies for TBSI.
The visual basis of reading and reading difficulties
Authors: Stein John
Published: November 2022

Most of our knowledge about the neural networks mediating reading has derived from studies of developmental dyslexia (DD). For much of the 20th C. this was diagnosed on the basis of finding a discrepancy between children’s unexpectedly low reading and spelling scores compared with their normal or high oral and non-verbal reasoning ability. This discrepancy criterion has now been replaced by the claim that the main feature of dyslexia is a phonological deficit, and it is now argued that we should test for this to identify dyslexia. However, grasping the phonological principle is essential for all learning to read; so every poor reader will show a phonological deficit. The phonological theory does not explain why dyslexic people, in particular, fail; so this phonological criterion makes it impossible to distinguish DD from any of the many other causes of reading failure. Currently therefore, there is no agreement about precisely how we should identify it. Yet, if we understood the specific neural pathways that underlie failure to acquire phonological skills specifically in people with dyslexia, we should be able to develop reliable means of identifying it. An important, though not the only, cause in people with dyslexia is impaired development of the brain’s rapid visual temporal processing systems; these are required for sequencing the order of the letters in a word accurately. Such temporal, “transient,” processing is carried out primarily by a distinct set of “magnocellular” (M-) neurones in the visual system; and the development of these has been found to be impaired in many people with dyslexia. Likewise, auditory sequencing of the sounds in a word is mediated by the auditory temporal processing system whose development is impaired in many dyslexics. Together these two deficits can therefore explain their problems with acquiring the phonological principle. Assessing poor readers’ visual and auditory temporal processing skills should enable dyslexia to be reliably distinguished from other causes of reading failure and this will suggest principled ways of helping these children to learn to read, such as sensory training, yellow or blue filters or omega 3 fatty acid supplements. This will enable us to diagnose DD with confidence, and thus to develop educational plans targeted to exploit each individual child’s strengths and compensate for his weaknesses.
Maternal melatonin treatment rescues endocrine, inflammatory, and transcriptional deregulation in the adult rat female offspring from gestational chronodisruption
Authors: Mendez Natalia , Halabi Diego , Salazar-Petres Esteban Roberto , Vergara Karina , Corvalan Fernando , Richter Hans G. , Bastidas Carla , Bascur Pía , Ehrenfeld Pamela , Seron-Ferre Maria , Torres-Farfan Claudia
Published: November 2022

Introduction

Gestational chronodisruption impact maternal circadian rhythms, inhibiting the nocturnal increase of melatonin, a critical hormone that contributes to maternal changes adaptation, entrains circadian rhythms, and prepares the fetus for birth and successful health in adulthood. In rats, we know that gestational chronodisruption by maternal chronic photoperiod shifting (CPS) impaired maternal melatonin levels and resulted in long-term metabolic and cardiovascular effects in adult male offspring. Here, we investigated the consequences of CPS on mother and adult female offspring and explored the effects of melatonin maternal supplementation. Also, we tested whether maternal melatonin administration during gestational chronodisruption rescues maternal circadian rhythms, pregnancy outcomes, and transcriptional functions in adult female offspring.

Methods

Female rats raised and maintained in photoperiod 12:12 light: dark were mated and separated into three groups: (a) Control photoperiod 12:12 (LD); (b) CPS photoperiod; and (c) CPS+Mel mothers supplemented with melatonin in the drinking water throughout gestation. In the mother, we evaluated maternal circadian rhythms by telemetry and pregnancy outcomes, in the long-term, we study adult female offspring by evaluating endocrine and inflammatory markers and the mRNA expression of functional genes involved in adrenal, cardiac, and renal function.

Results

In the mothers, CPS disrupted circadian rhythms of locomotor activity, body temperature, and heart rate and increased gestational length by almost 12-h and birth weight by 12%, all of which were rescued by maternal melatonin administration. In the female offspring, we found blunted day/night differences in circulating levels of melatonin and corticosterone, abnormal patterns of pro-inflammatory cytokines Interleukin-1a (IL1a), Interleukin-6 (IL6), and Interleukin-10 (IL10); and differential expression in 18 out of 24 adrenal, cardiac, and renal mRNAs evaluated.

Conclusion

Maternal melatonin contributed to maintaining the maternal circadian rhythms in mothers exposed to CPS, and the re-establishing the expression of 60% of the altered mRNAs to control levels in the female offspring. Although we did not analyze the effects on kidney, adrenal, and heart physiology, our results reinforce the idea that altered maternal circadian rhythms, resulting from exposure to light at night, should be a mechanism involved in the programming of Non-Communicable Diseases.
Directional prefrontal-thalamic information flow is selectively required during spatial working memory retrieval
Authors: Wang Jia , Zhang Shengnan , Liu Tiaotiao , Zheng Xuyuan , Tian Xin , Bai Wenwen
Published: November 2022

Introduction

Spatial working memory is a kind of short-term memory that allows temporarily storing and manipulating spatial information. Evidence suggests that spatial working memory is processed through three distinctive phases: Encoding, maintenance, and retrieval. Though the medial prefrontal cortex (mPFC) and mediodorsal thalamus (MD) are involved in memory retrieval, how the functional interactions and information transfer between mPFC and MD remains largely unclear.

Methods

We recorded local field potentials (LFPs) from mPFC and MD while mice performed a spatial working memory task in T-maze. The temporal dynamics of functional interactions and bidirectional information flow between mPFC and MD was quantitatively assessed by using directed transfer function.

Results

Our results showed a significantly elevated information flow from mPFC to MD, varied in time and frequency (theta in particular), accompanying successful memory retrieval.

Discussion

Elevated theta information flow, a feature that was absent on error trials, indicates an important role of the directional information transfer from mPFC to MD for memory retrieval.
Development and evaluation of an 18F-labeled nanobody to target SARS-CoV-2's spike protein
Authors: Lopes van den Broek Sara , García-Vázquez Rocío , Andersen Ida Vang , Valenzuela-Nieto Guillermo , Shalgunov Vladimir , Battisti Umberto M. , Schwefel David , Modhiran Naphak , Kramer Vasko , Cheuquemilla Yorka , Jara Ronald , Salinas-Varas Constanza , Amarilla Alberto A. , Watterson Daniel , Rojas-Fernandez Alejandro , Herth Matthias M.
Published: November 2022

COVID-19, caused by the SARS-CoV-2 virus, has become a global pandemic that is still present after more than two years. COVID-19 is mainly known as a respiratory disease that can cause long-term consequences referred to as long COVID. Molecular imaging of SARS-CoV-2 in COVID-19 patients would be a powerful tool for studying the pathological mechanisms and viral load in different organs, providing insights into the disease and the origin of long-term consequences and assessing the effectiveness of potential COVID-19 treatments. Current diagnostic methods used in the clinic do not allow direct imaging of SARS-CoV-2. In this work, a nanobody (NB) – a small, engineered protein derived from alpacas – and an Fc-fused NB which selectively target the SARS-CoV-2 Spike protein were developed as imaging agents for positron emission tomography (PET). We used the tetrazine ligation to 18F-label the NB under mild conditions once the NBs were successfully modified with trans-cyclooctenes (TCOs). We confirmed binding to the Spike protein by SDS-PAGE. Dynamic PET scans in rats showed excretion through the liver for both constructs. Future work will evaluate in vivo binding to the Spike protein with our radioligands.
Muscle mass loss is associated with physical dysfunction in patients with early rheumatoid arthritis
Authors: Pan Jie , Zou Yao-Wei , Zhu Ying-Ying , Lin Jian-Zi , Wu Tao , Yang Ze-Hong , Zhang Xue-Pei , Zhang Qian , Zheng Hu-Wei , He Xiao-Ling , Cheng Wan-Mei , Ma Jian-Da , Dai Lie
Published: November 2022

Background

Muscle mass loss is common in long-standing rheumatoid arthritis (RA). The aim was to explore the prevalence and effects of RA disease characteristics in patients with early RA.

Methods

This cross-sectional study was carried out based on a Chinese RA cohort and control subjects. The body composition (BC) was assessed using bioelectric impedance analysis. Myopenia was defined by an appendicular skeletal muscle mass index of ≤ 7.0 kg/m2 in men and ≤ 5.7 kg/m2 in women. Physical dysfunction was defined as a health assessment questionnaire disability index > 1. Propensity score matching was performed to balance age and gender differences among patients with early RA (disease duration ≤ 12 months) and established RA, and controls (with 1:3:3 matching).

Results

In total, 2017 controls and 1,008 patients with RA were recruited for this study. Among the patients with RA, there were 190 (18.8%) patients with early RA, with a median disease duration of 7 (4, 11) months. The matched patients with early RA (n = 160) showed a higher prevalence of myopenia than the matched controls (41.3 vs. 15.8%, P < 0.0167), but no difference was found in the matched patients with established RA (41.3 vs. 50.4%, P > 0.0167). Compared with the patients with established RA, the patients with early RA exhibited higher disease activity scores [disease activity score in 28 joints with four variables including C-reactive protein (DAS28-CRP): median 4.76 vs. 3.93, P < 0.001] and a higher prevalence of physical dysfunction (26.3 vs. 19.4%, P = 0.035). In the patients with early RA, patients with myopenia showed a higher prevalence of physical dysfunction than those without myopenia (41.3 vs. 15.5%, P < 0.001), among which walking and common daily activities were the most involved subdimensions. Multivariate logistic regression analysis showed that DAS28-CRP was positively associated with myopenia [adjusted odds ratio (AOR) 1.558, 95% CI (1.138–2.132)], and myopenia [AOR 2.983, 95% CI (1.192–7.465)] was independently associated with physical dysfunction in the patients with early RA.

Conclusion

Our data indicate the importance of early detection of muscle involvement in the early stage of RA and imply the significance of early aggressive control of disease activity for the prevention of myopenia and physical dysfunction in patients with early RA. Our study provides a new perspective on RA management.
A comparative study of vacuum tumbling and immersion marination on quality, microstructure, and protein changes of Xueshan chicken
Authors: Ge Qingfeng , Guo Shuyang , Chen Sheng , Wu Yuehao , Jia Zhaoyang , Kang Zhuangli , Xiong Guoyuan , Yu Hai , Wu Mangang , Liu Rui
Published: November 2022

Marination is a common technology in meat processing with advantages of enhancing tenderness, water retention, and overall quality. This study was conducted to investigate the effect of vacuum tumbling and immersion marination on meat quality, microstructure, water mobility, protein changes, and denaturation of Xueshan chicken. Results showed that vacuum tumbling significantly increased the marinating rate of chicken, tenderness, meat texture, and water retention. Meanwhile, vacuum tumbling decreased total sulfhydryl content alongside an increased protein surface hydrophobicity and free sulfhydryl content, indicating that vacuum tumbling elevated the degree of protein denaturation. Further, the peak area corresponding to the relaxation time T22 after vacuum tumbling was significantly higher than that of immersion marination, suggesting that the stability of the immobilized water of chicken was reduced by vacuum tumbling. Compared to immersion marination, vacuum tumbling improved myofibril fragmentation index (MFI) presenting fewer myofibrillar protein bands in sodium dodecyl sulfate polyacrylamide gel electrophoresis (SDS-PAGE) gel and more damaged muscular cells. Overall, vacuum tumbling could improve the marination absorptivity, protein degradation, and denaturation, resulting in changes in myofibril structure and meat quality of Xueshan chicken.
Proteomic profiling of cell line-derived extracellular vesicles to identify candidate circulatory markers for detection of gallbladder cancer
Authors: Priya Ratna , Jain Vaishali , Akhtar Javed , Saklani Neeraj , Sakhuja Puja , Agarwal Anil Kumar , Polisetty Ravindra Varma , Sirdeshmukh Ravi , Kar Sudeshna , Gautam Poonam
Published: November 2022

Gallbladder cancer (GBC) is the sixth most common gastrointestinal tract cancer with a very low overall survival and poor prognosis. Profiling of cancer-derived extracellular vesicles (EVs) is an emerging strategy for identification of candidate biomarkers for the detection and prognosis of the disease. The aim of the study was to analyse the protein content from GBC cell line- derived EVs with emphasis on proteins which could be used as candidate biomarkers for the detection of GBC. NOZ and OCUG-1 cell lines were cultured and EVs were isolated from conditioned media. LC-MS/MS analysis of total EV proteins led to the identification of a total of 268 proteins in both the cell lines. Of these, 110 proteins were identified with ≥2 unique peptides with ≥2 PSMs in at least two experimental and technical replicate runs. STRING (Search Tool for the Retrieval of Interacting Genes/Proteins) database was used to perform bioinformatics analysis of 110 proteins which showed ‘cell adhesion molecule binding’, ‘integrin binding’, ‘cadherin binding’ among the top molecular functions and ‘focal adhesion’ to be among the top pathways associated with the EV proteins. A total of 42 proteins including haptoglobin (HP), pyruvate kinase (PKM), annexin A2 (ANXA2), thrombospondin 1 (THBS1), were reported to be differentially abundant in GBC tissue. Of these, 16 proteins were reported to be differentially abundant in plasma and plasma-derived EVs. We infer these proteins to be highly important to be considered as potential circulatory biomarkers for the detection of GBC. To check the validity of this hypothesis, one of the proteins, haptoglobin (HP) as a representative case, was analysed in plasma by quantitative Enzyme- linked immunosorbent assay (ELISA) and we observed its increased levels in GBC in comparison to controls (p value= 0.0063). Receiver operating characteristic (ROC) curve analysis for GBC vs controls showed an Area under the ROC Curve (AUC) of 0.8264 for HP with 22% sensitivity against 100% specificity. We propose that HP along with other candidate proteins may be further explored for their clinical application.
The importance of fusion protein activity in Ewing sarcoma and the cell intrinsic and extrinsic factors that regulate it: A review
Authors: Apfelbaum April A. , Wrenn Emma D. , Lawlor Elizabeth R.
Published: November 2022

Accumulating evidence shows that despite clonal origins tumors eventually become complex communities comprised of phenotypically distinct cell subpopulations. This heterogeneity arises from both tumor cell intrinsic programs and signals from spatially and temporally dynamic microenvironments. While pediatric cancers usually lack the mutational burden of adult cancers, they still exhibit high levels of cellular heterogeneity that are largely mediated by epigenetic mechanisms. Ewing sarcomas are aggressive bone and soft tissue malignancies with peak incidence in adolescence and the prognosis for patients with relapsed and metastatic disease is dismal. Ewing sarcomas are driven by a single pathognomonic fusion between a FET protein and an ETS family transcription factor, the most common of which is EWS::FLI1. Despite sharing a single driver mutation, Ewing sarcoma cells demonstrate a high degree of transcriptional heterogeneity both between and within tumors. Recent studies have identified differential fusion protein activity as a key source of this heterogeneity which leads to profoundly different cellular phenotypes. Paradoxically, increased invasive and metastatic potential is associated with lower EWS::FLI1 activity. Here, we review what is currently understood about EWS::FLI1 activity, the cell autonomous and tumor microenvironmental factors that regulate it, and the downstream consequences of these activity states on tumor progression. We specifically highlight how transcription factor regulation, signaling pathway modulation, and the extracellular matrix intersect to create a complex network of tumor cell phenotypes. We propose that elucidation of the mechanisms by which these essential elements interact will enable the development of novel therapeutic approaches that are designed to target this complexity and ultimately improve patient outcomes.
PSMD2 promotes the progression of bladder cancer and is correlated with immune infiltration
Authors: Wang Song , Wang He , Zhu Shaoxing , Wang Zongping
Published: November 2022

Introduction

PSMD2 plays an oncogenic role in multiple human malignancies, while it is still unclear that the potential roles and underlying mechanisms of PSMD2 in BCa.

Methods

The RNA-seq from TCGA and GTEx database was utilized to preliminarily analyze the expression of PSMD2 in BCa tissues, qRT-PCR was adopted to verify the PSMD2 expression in BCa cell lines. Cox regression analyses were applied to assess the prognostic values of PSMD2 in BCa. GSEA analysis was used to explore the underlying mechanisms of PSMD2. In vitro assays such as wound healing and colony formation assays were applied to determine the carcinogenesis of PSMD2 in BCa. xCell and ssGSEA algorithms were applied to analyze the associations of PSMD2 with TIME.

Results

The results revealed that in comparison with normal bladder tissues and cell line, PSMD2 was found to be significantly elevated in BCa tissues and cell lines. Elevated expression of PSMD2 can independently predict unfavorable OS for BCa patients. The PSMD2 expression and other clinicopathologic factors were combined to develop a nomogram, which can help to predict OS for BCa patients. GSEA analyses revealed that PSMD2 is correlated with the cell cycle, antigen processing and presentation, JAK-STAT signaling pathway, Toll like receptor signaling pathway, P53 and MAPK signaling pathway. Knockdown of PSMD2 could remarkably inhibit the wound healing and colony formation efficiency of BCa cells. xCell analysis revealed that overexpressed PSMD2 is positively related to the Th2 cells infiltrates and expression levels of immune escape markers, and negatively associated with the infiltrating levels of NK T cell and CD8+ T cell.

Discussion

In conclusion, overexpressed PSMD2 is tightly linked to the immune infiltrates and promotes the progression of BCa.
Feasibility, safety, and efficacy of circumferential spine stereotactic body radiotherapy
Authors: Dibs Khaled , Palmer Joshua D. , Prasad Rahul N. , Olausson Alexander , Bourekas Eric C. , Boulter Daniel , Ayan Ahmet S. , Cochran Eric , Marras William S. , Mageswaran Prasath , Thomas Evan , Grecula John , Guiou Michael , Soghrati Soheil , Tili Esmerina , Raval Raju R. , Mendel Ehud , Scharschmidt Thomas , Elder James B. , Lonser Russell , Chakravarti Arnab , Blakaj Dukagjin M.
Published: November 2022

Background

With advances in systemic therapy translating to improved survival in metastatic malignancies, spine metastases have become an increasingly common source of morbidity. Achieving durable local control (LC) for patients with circumferential epidural disease can be particularly challenging. Circumferential stereotactic body radiotherapy (SBRT) may offer improved LC for circumferential vertebral and/or epidural metastatic spinal disease, but prospective (and retrospective) data are extremely limited. We sought to evaluate the feasibility, toxicity, and cancer control outcomes with this novel approach to circumferential spinal disease.

Methods

We retrospectively identified all circumferential SBRT courses delivered between 2013 and 2019 at a tertiary care institution for post-operative or intact spine metastases. Radiotherapy was delivered to 14–27.5 Gy in one to five fractions. Feasibility was assessed by determining the proportion of plans for which ≥95% planning target volume (PTV) was coverable by ≥95% prescription dose. The primary endpoint was 1-year LC. Factors associated with increased likelihood of local failure (LF) were explored. Acute and chronic toxicity were assessed. Detailed dosimetric data were collected.

Results

Fifty-eight patients receiving 64 circumferential SBRT courses were identified (median age 61, KPS ≥70, 57% men). With a median follow-up of 15 months, the 12-month local control was 85% (eight events). Five and three recurrences were in the epidural space and bone, respectively. On multivariate analysis, increased PTV and uncontrolled systemic disease were significantly associated with an increased likelihood of LF; ≥95% PTV was covered by ≥95% prescription dose in 94% of the cases. The rate of new or progressive vertebral compression fracture was 8%. There were no myelitis events or any grade 3+ acute or late toxicities.

Conclusions

For patients with circumferential disease, circumferential spine SBRT is feasible and may offer excellent LC without significant toxicity. A prospective evaluation of this approach is warranted.
Encouraging efficacy of a comprehensive therapy consisting of sintilimab, bevacizumab biosimilar IBI305, hypo-fractionated intensity-modulated radiotherapy, and oxaliplatin for a maxillary metastasis from hepatocellular carcinoma: A case report and literature review
Authors: Liang Xuexia , Liu Qiaodan , Yao Wei , Zhu Shuqin
Published: November 2022

Oro-maxillo-facial metastasis from hepatocellular carcinoma (HCC) is very rare, and reports on treating maxillary metastasis from HCC are unavailable. Anti-angiogenesis therapy combined with immunotherapy represented by programmed cell death 1 (PD-1) or its ligand (PD-L1) inhibitor has become the standard treatment of advanced HCC. However, integrating chemoradiotherapy into immunotherapy–bevacizumab combination therapy has not been reported. Here, we presented a Chinese woman with maxillary metastasis from HCC who achieved a nearly complete response (CR) to a quadruple treatment scheme consisting of a PD-1 monoclonal antibody (sintilimab), bevacizumab biosimilar IBI305, hypo-fractionated intensity-modulated radiotherapy (hfIMRT), and concurrent oxaliplatin. This comprehensive treatment is an innovative and effective therapy for advanced HCC.
HLA-BAT1 alters migration, invasion and pro-inflammatory cytokines in prostate cancer
Authors: García-Vargas Aileen M. , Roque-Reyes Yarelis M. , Arroyo-Villegas Desiree M. , Santiago-Negron Daniel , Sánchez-Vázquez María M. , Rivera-Torres Alejandro , Reyes-Meléndez Andrea C. , Cardona-Berdecía Valerie , García-Maldonado Miosotis , Víquez Olga M. , Martínez-Ferrer Magaly
Published: November 2022

Prostate cancer (PCa) accounts for more than 1 in 5 diagnoses and is the second cause of cancer-related deaths in men. Although PCa may be successfully treated, patients may undergo cancer recurrence and there is a need for new biomarkers to improve the prediction of prostate cancer recurrence and improve treatment. Our laboratory demonstrated that HLA-B-associated transcript 1 (BAT1) was differentially expressed in patients with high Gleason scores when compared to low Gleason scores. BAT1 is an anti-inflammatory gene but its role in PCa has not been identified. The objective of this study is to understand the role of BAT1 in prostate cancer. In vitro studies showed that BAT1 down-regulation increased cell migration and invasion. In contrast, BAT1 overexpression decreased cell migration and invasion. RT-PCR analysis showed differential expression of pro-inflammatory cytokines (TNF-α and IL-6) and cell adhesion and migration genes (MMP10, MMP13, and TIMPs) in BAT1 overexpressed cells when compared to BAT1 siRNA cells. Our in vivo studies demonstrated up-regulation of TNF-α, IL-6, and MMP10 in tumors developed from transfected BAT1 shRNA cells when compared to tumors developed from BAT1 cDNA cells. These findings indicate that BAT1 down-regulation modulates TNF-α and IL-6 expression which may lead to the secretion of MMP-10 and inhibition of TIMP2.
Is neoadjuvant chemoradiotherapy for pancreatic cancer beneficial: A systematic review and meta-analysis
Authors: Luo Wenhao , Wang Yawen , Tao Yinjie , Zhang Taiping
Published: November 2022

To examine the potential benefits and adverse events of neoadjuvant Chemoradiotherapy (CRT) versus upfront surgery in pancreatic cancer (PC) patients. Extensive librarian-led literature searches were conducted on PubMed, Web-of-Science, Scopus, Google Scholar, the Cochrane Central Library and Embase. The primary outcomes were resectability, adverse events, pathological and survival outcomes. Five studies, including 437 participants, were analyzed. Upfront surgery had a significantly higher resectability among PC patients than neoadjuvant CRT group (Odds ratio = -0.11, 95% CI = -0.19–0.02, P = 0.01). The neoadjuvant CRT group had a comparatively higher Ro resection rate (OR = 3.38, 95% CI = 2.03–5.62, P < 0.01), fewer severe adverse events(OR = 0.56, 95% CI = 0.34–0.92, P = 0.02), lower positive LN rate(OR = 0.18, 95% CI = 0.11-0.31, P < 0.01) and higher 2-year OS(OR = 1.60, 95% CI = 1.02-2.52, P = 0.04) among PC patients than control group. There was no significant difference between neoadjuvant CRT and upfront surgery among PC patients on postoperative complications(OR = 1.49, 95% CI = 0.86-2.57, P = 0.16), metastasis rate(OR = 1.32, 95% CI = 0.42-4.18, P = 0.64) and 1-year OS(OR = 1.30, 95% CI = 0.85-1.98, P = 0.22). This systematic review confirmed the status of neoadjuvant CRT in the PC treatment. The neoadjuvant CRT could increase the R0 resection rate, which was important to the survival and life quality of patients. The specific choice of various neoadjuvant CRT therapy needs to be further studied. Individualized neoadjuvant therapy should be suitable for each patient, and patients with PC are best managed by a multidisciplinary team.
A multicenter, open-label study for efficacy and safety evaluation of anagrelide in patients with treatment-naïve, high-risk essential thrombocythemia as a primary treatment
Authors: Byun Ja Min , Kim Ho Young , Nam Seung-Hyun , Shin Ho-Jin , Song Seulki , Park Jinny , Han Sang Hoon , Park Yong , Yuh Young Jin , Mun Yeung-Chul , Do Young Rok , Sohn Sang Kyun , Bae Sung Hwa , Shin Dong-Yeop , Yoon Sung-Soo
Published: November 2022

As the discussion of first-line anagrelide treatment is ongoing, we aimed to prospectively examine the efficacy and safety of anagrelide in cytoreduction therapy-naïve high risk essential thrombocythemia (ET) patients in Korea. Seventy patients from 12 centers were treated with anagrelide monotherapy for up to 8 weeks, followed up until 24 months. At week 8, 50.0% of the patients were able to achieve platelet < 600 x 109/L, and by 12 months, 55/70 (78.6%) patients stayed on anagrelide, and 40.0% patients showed platelet normalization. 14 patients required additional hydroxyurea (HU) for cytoreduction. The median daily dose of needed HU was 500mg (range 250mg – 1500mg). The efficacy was independent of the somatic mutation status. There were 4 thromboembolic events and 7 bleeding events during the follow-up period. The most common adverse events associated with anagrelide use were headache, followed by palpitation/chest discomfort, edema and generalized weakness/fatigue. 7 patients wished to discontinue anagrelide treatment due to adverse events (3 due to headache; 2 due to edema; 1 due to palpitation and 1 due to skin eruption). All in all, first-line anagrelide treatment showed a favorable response with tolerable safety profiles regardless of somatic mutation status.
Task-dependent plasticity in distributed neural circuits after transcranial direct current stimulation of the human motor cortex: A proof-of-concept study
Authors: Hodkinson Duncan J. , Jackson Stephen R. , Jung JeYoung
Published: November 2022

The ability of non-invasive brain stimulation to induce neuroplasticity and cause long-lasting functional changes is of considerable interest for the reversal of chronic pain and disability. Stimulation of the primary motor cortex (M1) has provided some of the most encouraging after-effects for therapeutic purposes, but little is known about its underlying mechanisms. In this study we combined transcranial Direct Current Stimulation (tDCS) and fMRI to measure changes in task-specific activity and interregional functional connectivity between M1 and the whole brain. Using a randomized counterbalanced sham-controlled design, we applied anodal and cathodal tDCS stimulation over the left M1. In agreement with previous studies, we demonstrate that tDCS applied to the target region induces task-specific facilitation of local brain activity after anodal tDCS, with the stimulation effects having a negative relationship to the resting motor threshold. Beyond the local effects, tDCS also induced changes in multiple downstream regions distinct from the motor system that may be important for therapeutic efficacy, including the operculo-insular and cingulate cortex. These results offer opportunities to improve outcomes of tDCS for the individual patient based on the degree of presumed neuroplasticity. Further research is still warranted to address the optimal stimulation targets and parameters for those with disease-specific symptoms of chronic pain.
Safety, pharmacokinetics, and pharmacodynamics of SHR7280, an oral gonadotropin-releasing hormone antagonist in healthy premenopausal women
Authors: Xu Yi , Hu Wei , Li Jian , Jiang Xin , Shi Ping , Shen Kai , Shen Yu , Ma Lingyu , Cao Yu
Published: November 2022

Background: Treatment with gonadotropin-releasing hormone (GnRH) antagonists is a powerful strategy to suppress gonadotropin activity in women with sex hormone-dependent disorders. Herein, we provide the safety, pharmacokinetics (PK), and pharmacodynamics (PD) profiles of SHR7280, an oral non-peptide GnRH antagonist in healthy premenopausal women.

Methods: In this randomized, double-blinded, placebo-controlled, dose-ascending, phase 1 trial, healthy premenopausal women were randomized to receive SHR7280 or placebo orally. Four doses of SHR7280 (200, 300, 400, and 500 mg BID) were planned. Safety, PK, and PD parameters were evaluated.

Results: SHR7280 presented tolerable toxicity and most adverse events were mild in severity. SHR7280 showed rapid onset of action (median Tmax ranged from 1.0 to 1.2 h for each dose), and plasma exposure was dose-dependent. PD results showed that SHR7280 300 mg BID and above suppressed estrogen concentration within the estradiol (E2) treatment window for endometriosis (20–50 pg/ml), inhibited the emergence of the peak of luteinizing hormone (LH) and the concentration of follicle stimulating hormone (FSH), and maintained the concentration of progesterone (P) in an anovulatory state (2 nmol/L).

Conclusion: SHR7280 showed favorable safety, PK, and PD profiles in the dose range of 200–500 mg BID in healthy premenopausal women. This study supports the continued clinical development of SHR7280 as a GnRH antagonist for sex hormone-dependent disorders in women.

Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT04554043, Identifier NCT04554043