bluuebunny/crossref_metadata_2025 huggingface dataset:
Implantation of Bacillus pseudomycoides Chromate Transporter Increases Chromate Tolerance in Bacillus subtilis
Authors: Chromiková Zuzana , Chovanová Romana Kalianková , Tamindžija Dragana , Bártová Barbora , Radnović Dragan , Bernier-Latmani Rizlan , Barák Imrich
Published: March 2022

Chromium of anthropogenic origin contaminates the environment worldwide. The toxicity of chromium, a group I human carcinogen, is greatest when it is in a hexavalent oxidation state, Cr(VI). Cr(VI) is actively transported into the cell, triggering oxidative damage intracellularly. Due to the abundance of unspecific intracellular reductants, any microbial species is capable of bio-transformation of toxic Cr(VI) to innocuous Cr(III), however, this process is often lethal. Only some bacterial species are capable of sustaining the vegetative growth in the presence of a high concentration of Cr(VI) and thus operate as self-sustainable bioremediation agents. One of the successful microbial Cr(VI) detoxification strategies is the activation of chromate efflux pumps. This work describes transplantation of the chromate efflux pump from the potentially pathogenic but highly Cr resistant Bacillus pseudomycoides environmental strain into non-pathogenic but only transiently Cr tolerant Bacillus subtilis strain. In our study, we compared the two Bacillus spp. strains harboring evolutionarily diverged chromate efflux proteins. We have found that individual cells of the Cr-resistant B. pseudomycoides environmental strain accumulate less Cr than the cells of B. subtilis strain. Further, we found that survival of the B. subtilis strain during the Cr stress can be increased by the introduction of the chromate transporter from the Cr resistant environmental strain into its genome. Additionally, the expression of B. pseudomycoides chromate transporter ChrA in B. subtilis seems to be activated by the presence of chromate, hinting at versatility of Cr-efflux proteins. This study outlines the future direction for increasing the Cr-tolerance of non-pathogenic species and safe bioremediation using soil bacteria.
Breaking Down a Rhythm: Dissecting the Mechanisms Underlying Task-Related Neural Oscillations
Authors: Ibarra-Lecue Inés , Haegens Saskia , Harris Alexander Z.
Published: March 2022

A century worth of research has linked multiple cognitive, perceptual and behavioral states to various brain oscillations. However, the mechanistic roles and circuit underpinnings of these oscillations remain an area of active study. In this review, we argue that the advent of optogenetic and related systems neuroscience techniques has shifted the field from correlational to causal observations regarding the role of oscillations in brain function. As a result, studying brain rhythms associated with behavior can provide insight at different levels, such as decoding task-relevant information, mapping relevant circuits or determining key proteins involved in rhythmicity. We summarize recent advances in this field, highlighting the methods that are being used for this purpose, and discussing their relative strengths and limitations. We conclude with promising future approaches that will help unravel the functional role of brain rhythms in orchestrating the repertoire of complex behavior.
Safety and Efficacy of Cangrelor Among Three Antiplatelet Regimens During Stent-Assisted Endovascular Treatment of Unruptured Intracranial Aneurysm: A Single-Center Retrospective Study
Authors: Cheddad El Aouni Mourad , Magro Elsa , Abdelrady Mohamed , Nonent Michel , Gentric Jean Christophe , Ognard Julien
Published: March 2022

Introduction

Thromboembolic events represent the most frequent complications of endovascular treatment of unruptured intracranial aneurysm using stent-assisted coilling or flow diverter stents. Dual antiplatelet therapy has become the standard to prevent these but remains unstandardized. We present here a single center experience of 3 standardized antiplatelet regimens during brain aneurysm treatment, while emphasizing the use of the Cangrelor.

Method

We retrospectively reviewed data from patients treated using stent-assisted coilling or flow diverter stents from 2016 to 2021. We collected and compared safety and efficacy data within 6 months of three groups of patients corresponding to three antiplatelet standardized regimens: group T with Ticagrelor, with preprocedural preparation; group E with Eptifibatide, injected during procedure; group C with Cangrelor, injected during procedure.

Results

Data of 112 patients were analyzed and 76 belonged to group T, 21 to group E, and 15 to group C. Eleven events over the 14 recorded were adjudicated to be related to antiplatelets, their repartition did not differ between the 3 groups (p = 0.43). All symptomatic events (N = 8) were not distributed significantly differently between the 3 groups (p = 0.11) and asymptomatic events were also balanced (p = 1.00). Of these, 6 subjects had a change in the mRS score at 3–6 months. Thrombo-embolic events represented the most encountered events in the sample: 2 acute ischemic strokes were recorded in group E and 1 in group T; 1 transient ischemic stroke was noted in group E; 4 silent infarcts were found on control MRI (2 belonged to group T, 1 to group E and 1 to group C). Among 3 intracranial bleeding events, 1 was symptomatic in group C, 2 were asymptomatic in group T. On the control evaluation performed at 6 months, there was no significant difference on aneurysmal occlusion (p = 0.67).

Conclusion

This single-center retrospective study compared 3 antiplatelet regimens, finding no significant difference in the safety and efficacy in the context of endovascular treatments of unruptured aneurysm using stent or flow diverters. This study adds data for the Cangrelor use and suggests its usefulness in the field of neuro-endovascular intervention. Randomized controlled studies are warranted to confirm these results.
Association Between Preonset Anti-hypertensive Treatment and Intracerebral Hemorrhage Mortality: A Cohort Study From CHEERY
Authors: Wan Yan , Guo Hongxiu , Shen Jing , Chen Shaoli , Li Man , Xia Yuanpeng , Zhang Lei , Sun Zhou , Chen Xiaolu , Chang Jiang , Wang David , He Quanwei , Hu Bo
Published: March 2022

Introduction

Hypertension is the most prevalent risk factor for intracerebral hemorrhage (ICH). In this study, we investigated whether preonset anti-hypertensive therapy could affect the outcomes of ICH.

Methods

This was a retrospective cohort study. A total of 3,460 consecutive patients with acute first-ever ICH from 31 recruitment sites were enrolled into the Chinese cerebral hemorrhage: mechanism and intervention (CHERRY) study from December 1, 2018 to November 30, 2020, and 2,140 (61.8%) with hypertension history were entered into the analysis.

Results

Only 586 patients (27.4%) with hypertension history currently received anti-hypertensive therapy, and which was associated with lower systolic blood pressure (SBP) and diastolic blood pressure (DBP) on admission (SBP, p = 0.008; DBP, p = 0.017), less hematoma volume (9.8 vs. 11%, p = 0.006), and lower all-cause mortality at 3 months (15.3 vs. 19.8%, OR = 0.728, p = 0.016). In multivariable analysis, adjusting for age, gender, residence, ischemic stroke history, admission SBP and DBP, and current use of antihypertension were significantly associated with lower adjusted hazard ratios (HRs) for all-cause mortality at discharge (adjusted HR, 0.497, p = 0.012), 30 days (adjusted HR, 0.712, p = 0.015), and 90 days (adjusted HR, 0.766, p = 0.030). However, after adjusting the variable of hematoma volume, the mortality between the two groups was not significantly different.

Conclusions

Preonset anti-hypertensive therapy was associated with lower mortality of ICH, which somewhat depended on hematoma volume.
Association of Cerebrospinal Fluid Parameters and Neurofilament Light Chain With Retinal Nerve Fiber Layer Thickness in Multiple Sclerosis
Authors: Krajnc Nik , Altmann Patrick , Riedl Katharina , Mitsch Christoph , Berger Thomas , Leutmezer Fritz , Rommer Paulus , Pemp Berthold , Bsteh Gabriel
Published: March 2022

Introduction

Multiple sclerosis (MS) pathophysiology comprises both inflammatory and neurodegenerative characteristics. Cerebrospinal fluid (CSF) analysis allows for assessment of inflammation while neurofilament light chain can indicate neuroaxonal damage. Retinal thinning is a robust prognostic biomarker for neurodegeneration in MS. To date, an association between CSF parameters upon MS diagnosis and retinal thinning has not been investigated.

Aims and Objectives

We aimed to determine whether CSF parameters are associated with the evolution of retinal layer thinning in people with MS (pwMS).

Methods

For this longitudinal observational study, we investigated pwMS from the Vienna MS database (VMSD), who had undergone (1) a diagnostic lumbar puncture (LP) between 2015 and 2020, and (2) simultaneous optical coherence tomography (OCT) and/or (3) a follow-up OCT scan. Linear stepwise regression models were calculated with OCT parameters (peripapillary retinal nerve fiber layer [pRNFL] thickness at LP and at follow-up, annualized loss of pRNFL thickness [aLpRNFL]) as a dependent variable, and CSF parameters (white blood cell [WBC] count, total protein [CSFTP], CSF/serum albumin ratio [Qalb], intrathecal synthesis of immunoglobulins, neurofilament light chain [NfL] in both CSF and serum [CSFNfL/sNfL]) as independent variables adjusted for age, sex, and disease duration.

Results

We analyzed 61 pwMS (median age 30.0 years [interquartile range 25.5–35.0], 57.4% female, median disease duration 1.0 month [IQR 0–2.0] before LP, median follow-up 1.9 years [IQR 1.1–3.5]). CSFNfL and sNfL measurements were available in 26 and 31 pwMS, respectively. pRNFL thickness at LP was inversely associated with the CSF WBC count (β = −0.36; 95% CI −0.51, −0.08; p = 0.008). We did not find any association between other CSF parameters, including CSFNfL, sNfL, and aLpRNFL.

Conclusions

Increased WBC count as an indicator of acute inflammation and blood-brain-barrier breakdown seems to be associated with the amount of retinal thickness already lost at the time of LP. However, neither routine CSF parameters nor a singular NfL measurement allows the prediction of future retinal thinning.
The Involvement of Long Non-coding RNA and Messenger RNA Based Molecular Networks and Pathways in the Subacute Phase of Traumatic Brain Injury in Adult Mice
Authors: Yang Zhaoyu , Li Xuexuan , Luo Weikang , Wu Yao , Tang Tao , Wang Yang
Published: March 2022

Traumatic brain injury (TBI) is a complex injury with a multi-faceted recovery process. Long non-coding RNAs (lncRNAs) are demonstrated to be involved in central nervous system (CNS) disorders. However, the roles of lncRNAs in long-term neurological deficits post-TBI are poorly understood. The present study depicted the microarray’s lncRNA and messenger RNA (mRNA) profiles at 14 days in TBI mice hippocampi. LncRNA and mRNA microarray was used to identify differentially expressed genes. Quantitative real-time polymerase chain reaction (qRT-PCR) was employed to validate the microarray results. Bioinformatics analysis [including Gene Ontology (GO), the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway, lncRNA-mRNA co-expression network, and lncRNA-miRNA-mRNA network] were applied to explore the underlying mechanism. A total of 264 differentially expressed lncRNAs and 232 expressed mRNAs were identified (fold change > 1.5 and P-value < 0.05). Altered genes were enriched in inflammation, immune response, blood–brain barrier, glutamatergic neurological effects, and neuroactive ligand-receptor, which may be associated with TBI-induced pathophysiologic changes in the long-term neurological deficits. The lncRNAs-mRNAs co-expression network was generated for 74 lncRNA-mRNA pairs, most of which are positive correlations. The lncRNA-miRNA-mRNA interaction network included 12 lncRNAs, 59 miRNAs, and 25 mRNAs. Numerous significantly altered lncRNAs and mRNAs in mice hippocampi were enriched in inflammation and immune response. Furthermore, these dysregulated lncRNAs and mRNAs may be promising therapeutic targets to overcome obstacles in long-term recovery following TBI.
Unity Assumption in Audiovisual Emotion Perception
Authors: Sou Ka Lon , Say Ashley , Xu Hong
Published: March 2022

We experience various sensory stimuli every day. How does this integration occur? What are the inherent mechanisms in this integration? The “unity assumption” proposes a perceiver’s belief of unity in individual unisensory information to modulate the degree of multisensory integration. However, this has yet to be verified or quantified in the context of semantic emotion integration. In the present study, we investigate the ability of subjects to judge the intensities and degrees of similarity in faces and voices of two emotions (angry and happy). We found more similar stimulus intensities to be associated with stronger likelihoods of the face and voice being integrated. More interestingly, multisensory integration in emotion perception was observed to follow a Gaussian distribution as a function of the emotion intensity difference between the face and voice—the optimal cut-off at about 2.50 points difference on a 7-point Likert scale. This provides a quantitative estimation of the multisensory integration function in audio-visual semantic emotion perception with regards to stimulus intensity. Moreover, to investigate the variation of multisensory integration across the population, we examined the effects of personality and autistic traits of participants. Here, we found no correlation of autistic traits with unisensory processing in a nonclinical population. Our findings shed light on the current understanding of multisensory integration mechanisms.
TrkB Truncated Isoform Receptors as Transducers and Determinants of BDNF Functions
Authors: Tessarollo Lino , Yanpallewar Sudhirkumar
Published: March 2022

Brain-derived neurotrophic factor (BDNF) belongs to the neurotrophin family of secreted growth factors and binds with high affinity to the TrkB tyrosine kinase receptors. BDNF is a critical player in the development of the central (CNS) and peripheral (PNS) nervous system of vertebrates and its strong pro-survival function on neurons has attracted great interest as a potential therapeutic target for the management of neurodegenerative disorders such as Amyotrophic Lateral Sclerosis (ALS), Huntington, Parkinson’s and Alzheimer’s disease. The TrkB gene, in addition to the full-length receptor, encodes a number of isoforms, including some lacking the catalytic tyrosine kinase domain. Importantly, one of these truncated isoforms, namely TrkB.T1, is the most widely expressed TrkB receptor in the adult suggesting an important role in the regulation of BDNF signaling. Although some progress has been made, the mechanism of TrkB.T1 function is still largely unknown. Here we critically review the current knowledge on TrkB.T1 distribution and functions that may be helpful to our understanding of how it regulates and participates in BDNF signaling in normal physiological and pathological conditions.
Autophagy-Mediated Synaptic Refinement and Auditory Neural Pruning Contribute to Ribbon Synaptic Maturity in the Developing Cochlea
Authors: Guo Rui , Xu Yice , Xiong Wei , Wei Wei , Qi Yue , Du Zhengde , Gong Shusheng , Tao Zezhang , Liu Ke
Published: March 2022

In rodents, massive initial synapses are formed in the auditory peripheral nervous system at the early postnatal stage, and one of the major phenomena is that the number of afferent synapses in the cochlea is significantly reduced in the duration of development. This raises the hypothesis that the number of cochlear ribbon synapses are dramatically changed with hearing development and maturation. In this study, several tracers identifying activities of autophagy were applied to estimate the level of autophagy activity in the process of ribbon synapse development in mice; further, changes in the synaptic number and spiral ganglion nerve (SGN) fibers were quantitatively measured. We found robust expression of LC3B and lysosomal-associated membrane protein 1 as well as LysoTracker in or near inner hair cells and cochlear ribbon synapses in the early stage of postnatal development. Moreover, we found a significant loss in the intensity of SGN fibers at ribbon synaptic development and hearing onset. Thus, this study demonstrates that ribbon synaptic refinement and SGN fibers pruning are closely associated with the morphological and functional maturation of ribbon synapses and that synaptic refinement and SGN fiber pruning are regulated by the robust activities of autophagy in the earlier stages of auditory development.
Milk Fat Globule Membrane Alleviates Short Bowel Syndrome-Associated Liver Injury in Rats Through Inhibiting Autophagy and NLRP3 Inflammasome Activation
Authors: Yu Zhicai , Huang Shanshan , Li Ying , Niu Yang , Chen Honghao , Wu Jiang
Published: March 2022

Background

The milk fat globule membrane (MFGM), a tri-layer membrane structure surrounding the milk fat globule, has been shown to have immune-modulating properties. This study aimed to investigate the effects of MFGM supplementation in a rat model of short bowel syndrome (SBS) associated liver disease and its possible mechanisms.

Materials and Methods

Twenty one male Sprague-Dawley rats were randomly divided into three groups: Sham, SBS (underwent massive small bowel resection), and SBS+MFGM (SBS rats supplemented with 1.5 g/kg/d MFGM). Liver pathology, myeloperoxidase (MPO) staining, serum levels of aspartate aminotransferase (AST)/alanine aminotransferase (ALT), endotoxin concentration, protein expression of autophagy and nucleotide binding oligomerization domain, leucine-rich repeat and pyrin domain-containing protein 3 (NLRP3) pathway in the liver tissue were measured.

Results

Both SBS and SBS + MFGM groups had higher serum levels of ALT and liver endotoxin levels than the Sham group (P < 0.05), with no difference detected between each other. Compared with the SBS group, the SBS+MFGM group showed lower liver pathology scores of steatosis and inflammation, less MPO positive cells and reduced expressions of NLRP3, apoptosis-associated speck-like protein containing a CARD (ASC), Caspase-1, interleukin (IL)-1β(P < 0.05) in the liver. Additionally, the expression of Beclin-1 and microtubule-associated protein1 light chain 3(LC3) B, the fluorescence intensity of NLRP3 and LC3B in the SBS + MFGM group were lower than the SBS group (P < 0.05). The LC3B expression was positively correlated with the NLRP3 level.

Conclusion

Enteral supplementation of MFGM help to alleviate liver injury in SBS rats, which might be related to inhibition of aberrant activation of autophagy and NLRP3 inflammasome pathways.
Novel Zinc-Related Differentially Methylated Regions in Leukocytes of Women With and Without Obesity
Authors: Noronha Natália Yumi , Barato Mariana , Sae-Lee Chanachai , Pinhel Marcela Augusta de Souza , Watanabe Lígia Moriguchi , Pereira Vanessa Aparecida Batista , Rodrigues Guilherme da Silva , Morais Déborah Araújo , de Sousa Wellington Tavares , Souza Vanessa Cristina de Oliveira , Plaça Jessica Rodrigues , Salgado Wilson , Barbosa Fernando , Plösch Torsten , Nonino Carla Barbosa
Published: March 2022

Introduction

Nutriepigenetic markers are predictive responses associated with changes in “surrounding” environmental conditions of humans, which may influence metabolic diseases. Although rich in calories, Western diets could be linked with the deficiency of micronutrients, resulting in the downstream of epigenetic and metabolic effects and consequently in obesity. Zinc (Zn) is an essential nutrient associated with distinct biological roles in human health. Despite the importance of Zn in metabolic processes, little is known about the relationship between Zn and epigenetic. Thus, the present study aimed to identify the epigenetic variables associated with Zn daily ingestion (ZnDI) and serum Zinc (ZnS) levels in women with and without obesity.

Materials and Methods

This is a case-control, non-randomized, single-center study conducted with 21 women allocated into two groups: control group (CG), composed of 11 women without obesity, and study group (SG), composed of 10 women with obesity. Anthropometric measurements, ZnDI, and ZnS levels were evaluated. Also, leukocyte DNA was extracted for DNA methylation analysis using 450 k Illumina BeadChips. The epigenetic clock was calculated by Horvath method. The chip analysis methylation pipeline (ChAMP) package selected the differentially methylated regions (DMRs).

Results

The SG had lower ZnS levels than the CG. Moreover, in SG, the ZnS levels were negatively associated with the epigenetic age acceleration. The DMR analysis revealed 37 DMRs associated with ZnDI and ZnS levels. The DMR of PM20D1 gene was commonly associated with ZnDI and ZnS levels and was hypomethylated in the SG.

Conclusion

Our findings provide new information on Zn's modulation of DNA methylation patterns and bring new perspectives for understanding the nutriepigenetic mechanisms in obesity.
Intake of Soy, Soy Isoflavones and Soy Protein and Risk of Cancer Incidence and Mortality
Authors: Fan Yahui , Wang Mingxu , Li Zhaofang , Jiang Hong , Shi Jia , Shi Xin , Liu Sijiao , Zhao Jinping , Kong Liyun , Zhang Wei , Ma Le
Published: March 2022

Background and Aims

Associations between soy intake and risk of cancer have been evaluated in prospective observational studies with inconsistent results. Whether the potential anticancer effects offered by soy were attributed to soy isoflavones and soy protein still needs to be elucidated. This study aimed to comprehensively quantify the association of soy, soy isoflavones and soy protein intake with risk of cancer incidence and cancer mortality by conducting a meta-analysis of all available studies.

Methods

PubMed, Embase, Web of Science, and Cochrane Library databases were searched up to 16 September 2021. Prospective cohort studies that examined the effect of soy, soy isoflavones and soy protein on cancer incidence and cancer mortality were identified. Random-effects models were used to pool the multivariable-adjusted relative risks (RRs) and corresponding 95% confidence intervals (CIs). The potential dose-response relations were explored by using generalized least-squares trend estimation.

Results

Eighty one prospective cohort studies were included in the meta-analysis. A higher intake of soy was significantly associated with a 10% reduced risk of cancer incidence (RR, 0.90; 95% CI, 0.83–0.96). Each additional 25 g/d soy intake decreased the risk of cancer incidence by 4%. Intake of soy isoflavones was inversely associated with risk of cancer incidence (RR, 0.94; 95% CI, 0.89–0.99), whereas no significant association was observed for soy protein. The risk of cancer incidence was reduced by 4% with each 10 mg/d increment of soy isoflavones intake. Similar inverse associations were also found for soy in relation to site-specific cancers, particularly lung cancer (RR, 0.67; 95%CI, 0.52–0.86) and prostate cancer (RR, 0.88; 95%CI, 0.78–0.99). However, high intake of soy, soy isoflavones and soy protein were not associated with cancer mortality.

Conclusions

Higher intake of soy and soy isoflavones were inversely associated with risk of cancer incidence, which suggested that the beneficial role of soy against cancer might be primarily attributed to soy isoflavones. These findings support recommendations to include soy as part of a healthy dietary pattern for the prevention of cancer.
Neoadjuvant Programmed Cell Death Protein 1 Blockade Combined With Stereotactic Body Radiation Therapy for Stage III(N2) Non-Small Cell Lung Cancer: A Case Series
Authors: Wang Zhen , Qiang Yong , Shen Qin , Zhu Xi-Xu , Song Yong
Published: March 2022

The addition of radiotherapy in neoadjuvant chemotherapy did not improve event-free or overall survival in resectable non-small cell lung carcinoma (NSCLC). Neoadjuvant immunotherapy produced major pathologic response(MPR) rate of up to 45%. The potential synergy between radiotherapy and immunotherapy has been described in several studies. We reported outcomes of three cases of stage III/N2 NSCLC treated with neoadjuvant immunotherapy and stereotactic body radiation therapy (SBRT) in a single center. This explanatory trial included treatment-naive patients with stage III resectable NSCLC who received two doses of the programmed cell death protein 1 (PD-1) inhibitor toripalimab after 1 week of receiving SBRT for lung lesions. Thereafter, surgery was planned 4–6 weeks after the second dose. The primary endpoints were safety and feasibility, while the secondary endpoint was the pathologic response rate. Toripalimab combined with SBRT as a neoadjuvant treatment had well-tolerable side effects and did not lead to a delay in surgery. Among the included patients, one achieved pathologic complete response (PCR), one achieved MPR, and one with 20% residual tumor did not achieve MPR. There were few side effects of toripalimab combined with SBRT as a neoadjuvant treatment, and the treatment did not cause a delay in surgery. This study preliminarily explored the outcomes of a new neoadjuvant treatment.
PLA2G6 Silencing Suppresses Melanoma Progression and Affects Ferroptosis Revealed by Quantitative Proteomics
Authors: Wang Yifei , Song Hao , Miao Qiuju , Wang Yan , Qi Jinliang , Xu Xiulian , Sun Jianfang
Published: March 2022

Although phospholipase A2 group VI (PLA2G6) is involved in oncogenesis in several human tumors, its expression and role in cutaneous malignant melanoma (CMM) pathogenesis remains unclear. Here, by using the Oncomine and CCLE online database, immunohistochemistry, RT-qPCR, and western blotting analysis, we revealed that PLA2G6 was markedly up-regulated in CMM tissues compared to nevus tissues, as well as remarkably increased in vitro in SK-MEL-28 and M14 melanoma cell lines compared to human melanocytes. In vivo, PLA2G6 was also elevated in nine melanoma tissues compared to adjacent tissues. To investigate the malignant behaviors of PLA2G6 in CMM, SK-MEL-28 and M14 cell lines with PLA2G6 stable knockdown by RNAi strategy were constructed. Through CCK8 and colony formation assays in vitro and xenograft tumor experiment in vivo, we found that knockdown of PLA2G6 dramatically inhibited cell proliferation. The results of scratch-wound and transwell assays suggested that the migration and invasion of melanoma cells were prominently suppressed after silencing PLA2G6. In addition, flow cytometry showed that the knockdown of PLA2G6 promoted the apoptosis rate of melanoma cells. To further explore the potential molecular mechanism, we used liquid chromatography coupled to tandem mass spectrometry (LC-MS/MS) proteomic and bioinformatics analysis. The GO and KEGG analysis suggested that the underlying mechanism of PLA2G6 in CMM might be associated with the ferroptosis pathway, and ferroptosis-related proteins were validated to be differentially expressed in PLA2G6 knockdown SK-MEL-28 and M14 cells. Together, these results suggested that PLA2G6 knockdown significantly inhibited cell proliferation, metastasis, and promoted apoptosis in melanoma. Our findings on the biological function of PLA2G6 and the underlying association between PLA2G6 and ferroptosis in melanoma may contribute to developing a potential therapeutic strategy for melanoma.
Tumor Burden Score Stratifies Prognosis of Patients With Intrahepatic Cholangiocarcinoma After Hepatic Resection: A Retrospective, Multi-Institutional Study
Authors: Li Hui , Liu Rongqiang , Qiu Haizhou , Huang Yang , Liu Wenbin , Li Jiaxin , Wu Hong , Wang Genshu , Li Dewei
Published: March 2022

Background

The prognostic significance of tumor burden score (TBS) on patients who underwent curative-intent resection of intrahepatic cholangiocarcinoma (ICC) has not been evaluated. The present study aimed to investigate the impact of TBS and its synergistic effect with CA19-9 (combination of TBS and CA19-9, CTC grade) on long-term outcomes.

Methods

Patients who underwent radical resection of ICC between 2009 and 2017 were retrospectively identified from a multi-center database. The overall survival (OS) and recurrence-free survival (RFS) were examined in relation to TBS, serum preoperative CA19-9, and CTC grade.

Results

A total of 650 patients were included in our study (509 in the derivation cohort and 141 in the validation cohort). Kaplan–Meier curves showed that both TBS and CA19-9 levels were strong predictors of survival outcomes. Patients with elevated TBS grade or elevated CA19-9 were associated with worse OS and RFS (both p < 0.001). As expected, CTC grade also performed well in predicting long-term outcomes. Patients with low TBS/low CA19-9 (CTC grade 1) were associated with the best OS as well as RFS, while high TBS/high CA19-9 (CTC grade 3) correlated to the worst outcomes. In the validation cohort, TBS grade, preoperative CA19-9, and CTC grade also stratified prognosis among patients (p < 0.001 for each).

Conclusions

Both tumor morphology (tumor burden) and tumor-specific biomarker (serum CA19-9) were important when evaluating prognosis of patients with resectable ICC. Serum CA19-9 and TBS showed a synergistic effect on prognostic evaluation. CTC grade was a promising tool in stratifying prognosis of ICC patients after curative resection.
An Innovative Breast-Conserving Oncoplastic Technique for Treating Small to Medium Volume Breasts With a Tumor in the Lower Quadrant: The Folding Flap Technique
Authors: Shi Wenjie , Wang Maoli , Torres-de la Roche Luz Angela , Shi Xuefeng , Gong Zhenyu , Dong Jie , Chen Zihao , Zeng Jiajia , Jiang Yicheng , Chen Zhitong , Wu Kejin , Zhuo Rui , De Wilde Rudy Leon
Published: March 2022

Background

Here, we describe an innovative oncoplastic technique for small to medium volume breasts with a tumor in the lower quadrant and this technique could provide sufficient tissue to avoid visible defects after tumor removal and help reshape the natural shape of the breast.

Methods

A detailed procedure for the folding flap technique is described step by step. Then, the results of a retrospective analysis of patients treated using this technique, including complications and disease recurrence rate, between January 2017 and November 2021 are reported. Aesthetic outcomes were evaluated on a 5-point scale proposed by the Paris Breast Center.

Results

A total of 52 patients underwent surgery with the folding flap technique, The average operation time was 98.4 min (range, 75–120 min), and the mean bleeding volume was 56.5 mL (range, 20–100 mL). A margin-positive result was confirmed in 1 patient who underwent re-excision. Short-term postoperative complications were observed in 7 patients, including 4 with fat liquefaction, 2 with seroma, and 1 with skin redness and swelling. No flap necrosis was observed. The median follow-up time was 28.6 months (range, 9–58 months), and 2 patients experienced local recurrence. The mean aesthetic score was 4.7 points, with 36 patients scoring 5 points and 26 patients scoring 4 points, respectively.

Conclusions

The folding flap technique, as an innovative and favorable oncoplastic technique for treating small- to medium-volume breasts with a tumor in the lower quadrant, could retain sufficient tissue to fill the residual cavity after the operation while improving the aesthetic outcome of the breast.
Preventing Dementia Using Saffron, The Kampo Medicine, Kamiuntanto, and Their Combination, Kamiuntantokabankoka
Authors: Kuchta Kenny , Aritake Kosuke , Urade Yoshihiro , Tung Nguyen Huu , Yuan Chun-Su , Sasaki Yui , Shimizu Koichi , Shoyama Yukihiro
Published: March 2022

The objective of this review is to evaluate the anti-dementia activities of saffron and its combination with Kampo medicine. The Kampo formula Kamiuntanto composed of 13 crude drugs is well known for its anti-dementia activity. A significant increase in choline acetyltransferase activity and mRNA levels were observed. Polygala radix was identified as the most essential component drug in Kamiuntanto, probably due to the saponins, tenuifolin, and sinapinic acid. Ginseng was also identified as an essential Kamiuntanto component in terms of its synergistic functions with Polygala radix. Saffron, which was recommended in the Bencao Gangmu for memory and dementia, and is used as an anti-spasmodic, anti-catarrhal, and sedative herbal drug. Saffron and its major constituent, crocin were shown to enhance learning-memory, non-rapid eye movement (rem) sleep, and inhibit depression and neuronal cell death due to strong anti-oxidant and anti-inflammation activities. In addition based on the epidemiological studies such as the treatment of sleeping disorders and the clinical trials of saffron for Alzheimer patients, we demonstrated the indirect and direct anti-dementia activities of crocin and saffron.
Exploring the Pharmacological Mechanisms of Xihuang Pills Against Prostate Cancer via Integrating Network Pharmacology and Experimental Validation In Vitro and In Vivo
Authors: Wu Yongrong , You Xujun , Lin Qunfang , Xiong Wei , Guo Yinmei , Huang Zhen , Dai Xinjun , Chen Zhengjia , Mei Si , Long Yan , Tian Xuefei , Zhou Qing
Published: March 2022

Background: Drug resistance is the major cause of increasing mortality in prostate cancer (PCa). Therefore, it an urgent to develop more effective therapeutic agents for PCa treatment. Xihuang pills (XHP) have been recorded as the efficient anti-tumor formula in ancient Chinese medical literature, which has been utilized in several types of cancers nowadays. However, the effect protective role of XHP on the PCa and its underlying mechanisms are still unclear.

Methods: The active ingredients of XHP were obtained from the Traditional Chinese Medicine Systems Pharmacology Database and Analysis Platform (TCMSP) and BATMAN-TCM. The potential targets of PCa were acquired from the Gene Cards and OMIM databases. R language and Perl language program were utilized to clarify the interaction between the PCa-related targets and the potential targets of XHP. The potential targets of XHP for prostate cancer were gathered from the Gene ontology and KEGG pathway. Furthermore, cell proliferation assays were verified by PC3 and LNCaP cells. The efficacy and potential mechanism tests were confirmed by the PCa PC3 cells and mice subcutaneous transplantation. The effects of PI3K/Akt/mTOR-related proteins on proliferation, apoptosis, and cell cycle of PCa cells were measured by the Cell Counting Kit-8(CCK8), TUNEL assay, real-time quantitative reverse transcription PCR (QRT-PCR), and Western Blotting, respectively.

Results: The active components of four traditional Chinese medicines in XHP were searched on the TCMSP and Batman TCM database. The biological active components of XHP were obtained as OB ≥30% and DL ≥0.18. The analysis of gene ontology and KEGG pathway identified the PI3K/Akt/mTOR signaling pathway as the XHP-associated pathway. Collectively, the results of in vitro and in vivo experiments showed that XHP had the effect of inhibiting on the proliferation of PC3 and LNCaP cells. XHP promoted the apoptosis and restrained the cell cycle and invasion of the PC3 cells and subcutaneous transplantation. Meanwhile, the suppression of XHP on the level of expression of PI3K, Akt, and mTOR-pathway-related pathway proteins has been identified in a dose-dependent manner.

Conclusion: PI3K/Akt/mTOR pathway-related pathway proteins were confirmed as the potential XHP-associated targets for PCa. XHP can suppress the proliferation of prostate cancer via inhibitions of the PI3K/Akt/mTOR pathway.
Comparative Efficacy of Different Drugs for Lower Urinary Tract Symptoms due to Benign Prostatic Hyperplasia: A Bayesian Network Meta-Analysis
Authors: Fan Zhinan , Shi Hongjin , Zhang Jinsong , Wang Haifeng , Wang Jiansong
Published: March 2022

Background: Lower urinary tract symptoms (LUTS) caused by benign prostatic hyperplasia (BPH) are common in middle-aged and elderly men. The current drugs for treating this disease include α1-adrenoceptor antagonists (ABs), muscarinic receptor antagonists (MRAs), phosphodiesterase five inhibitors (PDE5-Is), and β3-adrenoceptor agonists (B3As). However, direct comparative studies analyzing different therapies are limited; therefore, we conducted a network meta-analysis (NMA) to evaluate the efficacy of different drug regimens for treating BPH/LUTS.

Methods: The PubMed, EMbase, Web of Science, and Cochrane Library databases were searched to collect randomized controlled trials (RCTs) of different drug treatments for BPH/LUTS from January 2000 to April 2021. The NMA was performed using R 4.1 software.

Results: Fifty-five RCTs were included among a total of 1639 trials. ① ABs + PDE5-Is, ABs + B3As, ABs + MRAs, ABs, and PDE5-IS were superior to the placebo in improving the total International Prostate Symptom Score (IPSS), IPSS-Voiding, and IPSS-storage. ② For increasing the maximum flow rate (Qmax), ABs + PDE5-Is, ABs + MRAs, and ABs were more effective than the placebo. ③ Regarding reducing post-void residual urine (PVR), none of the six treatment plans had significant effects.

Conclusion: Combination therapy showed greater efficacy than monotherapy, and ABs + PDE5-Is was the most successful treatment for improving the overall IPSS score. ABs are a primary therapeutic measure to increase Qmax, and ABs + PDE5-I may be a more suitable choice for enhancing Qmax. The combination of MRA and AB+ MRA may lead to an increase in PVR.

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Identification of WT161 as a Potent Agent for the Treatment of Colitis by Targeting the Nucleotide-Binding Domain-Like Receptor Family Pyrin Domain Containing 3 Inflammasome
Authors: Long Xiuyan , Yu Xiaoyu , Gong Pan , Wang Xiaoyan , Tian Li
Published: March 2022

Inflammatory bowel diseases (IBD), including Crohn’s disease and ulcerative colitis (UC), are chronic and recurrent intestinal inflammatory disorders. Numerous studies have revealed that the nucleotide-binding domain-like receptor family pyrin domain containing 3 (NLRP3) inflammasome plays a pivotal role in the pathogenesis of IBD, and inhibition of the NLRP3 inflammasome alleviates colitis in experimental animals. Our previous study showed that C646, an inhibitor of histone acetyltransferase p300, has a protective role in dextran sulfate sodium (DSS)-induced colitis by targeting the NLRP3 inflammasome, making us further study the inhibitors of histone deacetylases (HDACs) in the treatment of colitis. In this study, we have shown that WT161, an inhibitor of HDAC6, exerts a protective role in a colitis model, blocks NLRP3 inflammasome activation, disrupts ASC speck formation, and decreases the expression of NLRP3. This study uncovers a new inhibitor of the NLRP3 inflammasome and suggests its potential application in the treatment of active IBD.
Special Thai Oolong Tea: Chemical Profile and In Vitro Antidiabetic Activities
Authors: Rujanapun Narawadee , Jaidee Wuttichai , Duangyod Thidarat , Phuneerub Pravaree , Paojumroom Napassawan , Maneerat Tharakorn , Pringpuangkeo Chuchawal , Ramli Salfarina , Charoensup Rawiwan
Published: March 2022

Special Thai oolong tea is oolong tea (Camellia sinensis (L.) Kuntze) steamed with selected Thai botanical drugs. Oolong tea steamed with ginger (Zingiber officinale), lemongrass (Cymbopogon citratus), and celery (Anathallis graveolens L.) is called eternity tea (EN), whereas peaceful rest (PR) tea is made of oolong tea leaves steamed with Indian gooseberry (Phyllanthus emblica), Turkey berry (Solanum torvum), and wild betel leaf bush leaves (Piper sarmentosum). Oolong tea is known for its numerous biological activities including antidiabetic properties. However, the effect of the additional botanical drugs on the biological activities of special oolong teas has not yet been explored. From the results, the PR extract exhibited the best activity in the in vitro assays relevant to antidiabetic properties such as chemical antioxidant, anti-inflammation, anti-adipogenesis, enzyme inhibition, and glucose uptake and consumption. The UHPLC-QTOF-MS/MS profiles of PR and EN extracts indicated chemical profiles different from oolong tea. For instance, gingerdiol and gingerol were detected in EN, whereas piperettine I was detected in PR. Therefore, it was inferred that among the three tea extracts, the additional compounds in PR contributed to good activities compared to oolong and EN. It is also important to highlight that the PR extract inhibited glucose uptake and consumption by adipocytes and skeletal muscles at concentrations of 500 and 100 μg/ml, respectively, as well as metformin activity (p < 0.05). Findings from this study support the antidiabetic potential of PR tea.
Effects of Antihypertensive Drugs on Thyroid Function in Type 2 Diabetes Patients With Euthyroidism
Authors: Yang Lijuan , Sun Xiuqin , Zhao Yi , Tao Hong
Published: March 2022

Objective: There is little literature about whether antihypertensive drugs would affect thyroid function in patients with euthyroid type 2 diabetes, which was significant in maintaining a proper balance of thyroid function. A retrospective cohort study was conducted to evaluate the influence of antihypertensive drugs on thyroid function in patients with type 2 diabetes with euthyroidism.

Design and Methods: The study involved dividing 698 patients with antihypertensive monotherapy into five groups according to the antihypertensive drugs they were treated with. Antihypertensive drugs included in this study were β-blockers, angiotensin-converting enzyme inhibitors (ACEI), angiotensin receptor blockers (ARB), and calcium channel blockers (CCB). The clinical data and thyroid function level between or within groups were compared. Multiple logistic regression analysis was conducted to evaluate the association of antihypertensive drugs with thyroid function level.

Results: Selective β1- adrenergic receptor blockers treatment was related to thyroid-stimulating hormone (TSH), increasing in patients with diabetes and euthyroidism as shown by multiple logistic regression analysis. The association existed after adjustment for confounding factors. No significant influence on thyroid function was found among other antihypertensive drugs.

Conclusion: These data show the TSH-lifting effect of selective β1-adrenergic receptor blockers in patients with type 2 diabetes with euthyroidism.
Statin Therapy for Hyperlipidemic Patients With Chronic Kidney Disease and End-Stage Renal Disease: A Retrospective Cohort Study Based on 925,418 Adults in Taiwan
Authors: Sung Fung-Chang , Jong Ying-Chin , Muo Chih-Hsin , Hsu Chih-Cheng , Tsai Wen-Chen , Hsu Yueh-Han
Published: March 2022

Background: For non-dialysis patients with hyperlipidemia, statins may provide clinical benefits in reducing mortality risk; however, the optimal treatment for dialysis patients with hyperlipidemia remains debatable. We evaluated the mortality risks for hyperlipidemic patients with renal disorders associated with statin therapy (ST), using the insurance claims data of Taiwan.

Methods: From hyperlipidemic patients diagnosed in 2000–2011, we identified 555,153 patients receiving statin treatment for at least 90 days continuously and 1,141,901 non-statin users, and then randomly selected, from both groups, the propensity score-matched subcohorts of statin users and nonusers in a 1:1 pair by renal function: 415,453 pairs with normal renal function , 43,632 pairs with chronic kidney disease (CKD), and 3,624 pairs with end-stage renal disease (ESRD). We compared the mortalities, by the end of 2016, from all causes, cancer, heart disease, and septicemia between statin users and non-users and between hydrophilic-statin users and lipophilic-statin users. The Cox method estimated ST users to non-user hazard ratios. The time-dependent model was also conducted as sensitivity analysis.

Results: The mean ages were 58.7 ± 10.7, 64.2 ± 10.7, and 62.2 ± 10.8 years in normal renal function, CKD, and ESRD groups, respectively. Compared with non-users, statin users had reduced mortality risks from all causes for 32%–38%, from cancer for 37%–46%, from heart disease for 6%–24%, and from septicemia for 17%–21% in all three renal groups. The hydrophilic statin therapy was superior than the lipophilic statin therapy, particularly for reducing deaths from all-causes and cancer. The results under the time-dependent model were similar.

Conclusion: Statin therapy is associated with reduced all-causes and non-cardiovascular mortality in ESRD patients.
The Abcc6a Knockout Zebrafish Model as a Novel Tool for Drug Screening for Pseudoxanthoma Elasticum
Authors: Van Gils M. , Willaert A. , Coucke P. J. , Vanakker O. M.
Published: March 2022

Pseudoxanthoma elasticum (PXE) is a multisystem ectopic mineralization disorder caused by pathogenic variants in the ABCC6 gene. Though complications of the disease can be treated, PXE itself remains currently intractable. A strategy for rapid and cost-effective discovery of therapeutic drugs would be to perform chemical compound screening using zebrafish, but this approach remains to be validated for PXE. In this paper, we validate a stable CRISPR/Cas9 abcc6a knockout zebrafish model–which has spinal column hypermineralization as its primary phenotypic feature–as a model system for compound screening in ectopic mineralization. We evaluated the anti-mineralization potential of five compounds, which had (anecdotal) positive effects reported in Abcc6 knockout mice and/or PXE patients. Abcc6a knockout zebrafish larvae were treated from 3 to 10 days post-fertilization with vitamin K1, sodium thiosulfate, etidronate, alendronate or magnesium citrate and compared to matching controls. Following alizarin red S staining, alterations in notochord sheath mineralization were semiquantified and found to largely congrue with the originally reported outcomes. Our results demonstrate that the use of this abcc6a knockout zebrafish model is a validated and promising strategy for drug discovery against ectopic mineralization.