bluuebunny/crossref_metadata_2025 huggingface dataset:
Identification of a Recently Dominant Sublineage in Salmonella 4,[5],12:i:- Sequence Type 34 Isolated From Food Animals in Japan
Authors: Arai Nobuo , Sekizuka Tsuyoshi , Tamamura-Andoh Yukino , Barco Lisa , Hinenoya Atsushi , Yamasaki Shinji , Iwata Taketoshi , Watanabe-Yanai Ayako , Kuroda Makoto , Akiba Masato , Kusumoto Masahiro
Published: July 2021

Salmonella enterica subsp. enterica serovar Typhimurium sequence type 34 (ST34) and its monophasic variant (Salmonella 4,[5],12:i:-) are among the most frequently isolated clones from both humans and animals worldwide. Our previous study demonstrated that Salmonella Typhimurium/4,[5],12:i:- strains isolated in Japan could be classified into nine clades and that clade 9 consisted of ST34 strains. In Japan, ST34/clade 9 was first found in the 1990s and has become predominant among food animals in recent years. In the present study, we analyzed the whole genome-based phylogenetic relationships and temporal information of 214 Salmonella Typhimurium/4,[5],12:i:- ST34/clade 9 strains isolated from 1998 to 2017 in Japan. The 214 strains were classified into two sublineages: the newly identified clade 9–2 diverged from clade 9 in the early 2000s and has predominated in recent years. Clonally expanding subclades in clades 9–1 or 9–2 lacked Gifsy-1 or HP1 prophages, respectively, and some strains in these subclades acquired plasmids encoding antimicrobial resistance genes. Additional genome reduction around the fljB gene encoding the phase 2-H antigen was generated by an IS26-mediated deletion adjacent to the transposon in clade 9–2. Although most of the clade 9 strains were isolated from cattle in Japan, the clonally expanding subclades in clade 9–2 (i.e., all and 24% strains of subclades 9–2a and 9–2b, respectively) were isolated from swine. The spread of clade 9 in recent years among food animals in Japan was responsible for the emergence of multiple host-adapted sublineages involving the clonally expanding subclades generated by mobile genetic element-mediated microevolution.
Pharmacological Treatment in the Management of Chronic Subdural Hematoma
Authors: Wang Xing , Song Jinlei , He Qiang , You Chao
Published: July 2021

Background: Several pharmacological treatments have been used to treat patients with chronic subdural hematoma (CSDH), although little is known about the comparative effectiveness of different classes of medication. We performed a Bayesian network meta-analysis to compare and rank the efficacy and safety of five drug regimens to determine the best treatment for this group of patients.

Methods: We systematically searched PubMed, Medline, clinicaltrials.gov, the Cochrane database, and Embase to identify relevant randomized clinical trials (RCTs) comparing drug treatments in adult patients with CSDH. A network meta-analysis was conducted using a Bayesian framework. Random- and fixed-effects models were used to pool the network results, and the preferred model was selected by comparing the deviance information criteria (DIC). Efficacy outcomes included recurrence requiring surgery, changes in hematoma volume, and a good recovery. The safety outcomes were treatment-related adverse events and all-cause mortality.

Results: In this Bayesian network meta-analysis, available data were obtained from 12 eligible trials, including 2,098 patients and 5 techniques. Compared to placebo, atorvastatin (RR: 0.45, 95% CrI: 0.24–0.81) and dexamethasone (RR: 0.38, 95% CrI: 0.22–0.63) were similarly effective in reducing recurrence requiring surgery by 55% and 62%, respectively. Dexamethasone (RR: 0.46, 95% CrI: 0.23–0.91) was more effective in reducing recurrence requiring surgery than goreisan. Additionally, atorvastatin reduced the hematoma volume to a greater extent than placebo (MD: −7.44, 95% CrI: −9.49 to −5.43) or goreisan (MD: −14.09, 95% CrI: −23.35 to −4.82). Moreover, tranexamic acid (MD: −12.07, 95% CrI: −21.68 to −2.29) reduced the hematoma volume to a greater extent than goreisan. No significant differences were detected between drugs and placebo with regard to a good recovery. In terms of safety, dexamethasone (RR: 1.96, 95% CrI: 1.20–3.28) increased the risk of mortality compared to placebo.

Conclusion: These findings suggest that dexamethasone is the best treatment to reduce recurrence and atorvastatin is the best treatment to reduce hematoma volume in patients with CSDH. However, clinicians should pay close attention to the elevated risk of all-cause mortality and potential adverse events caused by dexamethasone. Future well-designed RCTs with more participants are needed to verify these findings.

Clinical Trial Registration:http://osf.io/u9hqp.
Abnormal Striatal-Cortical Networks Contribute to the Attention/Executive Function Deficits in Idiopathic REM Sleep Behavior Disorder: A Resting State Functional MRI Study
Authors: Zhang Hong-Ju , Wang Sheng-Hui , Bai Ying-Ying , Zhang Jie-Wen , Chen Shuai
Published: July 2021

Introduction

The structural and functional damages of the striatum were evident in idiopathic REM sleep behavior disorder (iRBD). With the research on iRBD deepens, cognitive impairment in iRBD is getting increasing attention. However, the mechanism of cognitive impairment in iRBD was poorly understood.

Methods

Neuropsychological assessment was carried out in 21 polysomnographies (PSGs) confirmed iRBD patients and 22 normal controls. Both regional homogeneity (ReHo) and seed-based functional connectivity (FC) rs-fMRI analyses were applied to explore the FC abnormalities and its association with cognition in iRBD patients. Positive ReHo clusters were set as seeds for further FC analysis.

Results

Idiopathic REM sleep behavior disorder patients presented cognitive deficits in attention/working memory, executive function, immediate memory, and visuo-spatial ability. ReHo analysis revealed abnormal spontaneous brain activities in the striatum (right caudate, left pallidum and bilateral putamen) in iRBD. FC analysis showed decreased striatum-related FCs in the frontal, temporal, occipital lobes, thalamus, anterior cingulate gyrus, as well as decreased intrinsic FCs between bilateral putamen and between caudate and pallidum. Deficits in attention/working memory, executive function, and immediate memory were associated with abnormal striatal-cortical FCs including frontal, temporal, and anterior cingulate cortices.

Conclusion

Functional changes of striatum and cognitive impairment in iRBD were reconfirmed in the present study. Abnormal striatal-cortical networks, especially the striatal-frontal network, contribute to the working memory/executive function deficits in iRBDs. These findings supported the role of striatum not only in motor but also in cognition impairment in iRBD.
Effects of Microglial Activation and Polarization on Brain Injury After Stroke
Authors: Dong Rui , Huang Renxuan , Wang Jiaoqi , Liu Hongyu , Xu Zhongxin
Published: July 2021

Stroke is one of the most common causes of death worldwide. The subsequent development of neuroinflammation and brain edema dramatically increases the risks associated with stroke, leading to a substantial increase in mortality. Although considerable progress has been made in improving cerebral perfusion in the acute phase of stroke, effective treatment options for the subacute and chronic phases associated with cerebral infarction are limited. Microglia, the innate immune cells of the central nervous system (CNS), can be activated and polarized to take on different phenotypes in response to stimulations associated with stroke, including pro-inflammatory and anti-inflammatory phenotypes, which affect the prognosis of stroke. Therefore, investigation of the activation and polarizing mechanisms of microglia plays a critical role in treating stroke. The aim of this article was to investigate the significance of microglial phenotype regulation in stroke treatment by summarizing the activation, polarizing mechanisms, and general microglia characteristics.
Predicting Clinically Significant Improvement After Robot-Assisted Upper Limb Rehabilitation in Subacute and Chronic Stroke
Authors: Lee Jae Joon , Shin Joon-Ho
Published: July 2021

Prior studies examining predictors of favorable clinical outcomes after upper limb robot-assisted therapy (RT) have many shortcomings. Therefore, the aim of this study was to identify meaningful predictors and a prediction model for clinically significant motor improvement in upper limb impairment after RT for each stroke phase. This retrospective, single-center study enrolled patients with stroke who received RT using InMotion2 along with conventional therapy (CT) from January 2015 to September 2019. Demographic characteristics, clinical measures, and robotic kinematic measures were evaluated. The primary outcome measure was the Fugl-Meyer Assessment-Upper Extremity (FMA-UE) and we classified patients with improvement more than the minimal clinically important difference as responders for each stroke phase. Univariable and multivariable logistic regression analyses were performed to assess the relationship between potential predictors and RT responders and determine meaningful predictors. Subsequently, meaningful predictors were included in the final prediction model. One hundred forty-four patients were enrolled. The Hand Movement Scale and time since onset were significant predictors of clinically significant improvement in upper limb impairment (P = 0.045 and 0.043, respectively), as represented by the FMA-UE score after RT along with CT, in patients with subacute stroke. These variables were also meaningful predictors with borderline statistical significance in patients with chronic stroke (P = 0.076 and 0.066, respectively). Better hand movement and a shorter time since onset can be used as realistic predictors of clinically significant motor improvement in upper limb impairment after RT with InMotion2 alongside CT in patients with subacute and chronic stroke. This information may help healthcare professionals discern optimal patients for RT and accurately inform patients and caregivers about outcomes of RT.
Predictors of Early and Late Infarct Growth in DEFUSE 3
Authors: Tate William J. , Polding Laura C. , Christensen Søren , Mlynash Michael , Kemp Stephanie , Heit Jeremy J. , Marks Michael P. , Albers Gregory W. , Lansberg Maarten G.
Published: July 2021

Introduction: The goal of this study is to explore the impact of reperfusion and collateral status on infarct growth in the early and late time windows.

Materials and Methods: Seventy patients from the DEFUSE 3 trial (Endovascular Therapy Following Imaging Evaluation for Ischemic Stroke) with baseline, 24-h, and late follow-up scans were evaluated. Scans were taken with DWI or CTP at time of enrollment (Baseline), with DWI or CT 24-h after enrollment (24-h), and with DWI or CT 5 days after enrollment (Late). Early infarct growth (between baseline and 24-h scans) and late infarct growth (between 24-h and late scans) was assessed for each patient. The impact of collateral and reperfusion status on infarct growth was assessed in univariate and multivariate regression.

Results: The median early infarct growth was 30.3 ml (IQR 16.4–74.5) and the median late infarct growth was 6.7 ml (IQR −3.5–21.6) in the overall sample. Patients with poor collaterals showed greater early infarct growth (Median 58.5 ml; IQR 18.6–125.6) compared to patients with good collaterals (Median 28.4 ml; IQR 15.8–49.3, unadjusted p = 0.04, adjusted p = 0.06) but showed no difference in late infarct growth. In contrast, patients who reperfused showed no reduction in early infarct growth but showed reduced late infarct growth (Median 1.9 ml; IQR −6.1–8.5) compared to patients without reperfusion (Median 11.2 ml; IQR −1.1–27.2, unadjusted p < 0.01, adjusted p = 0.04).

Discussion: In the DEFUSE 3 population, poor collaterals predict early infarct growth and absence of reperfusion predicts late infarct growth. These results highlight the need for timely reperfusion therapy, particularly in patients with poor collaterals and indicate that the 24-h timepoint is too early to assess the full impact of reperfusion therapy on infarct growth.

Clinical Trial Registration:http://www.clinicaltrials.gov, Unique identifier [NCT02586415].
Flow Diversion for Reconstruction of Intradural Vertebral Artery Dissecting Aneurysms Causing Subarachnoid Hemorrhage—A Retrospective Study From Four Neurovascular Centers
Authors: Maybaum Jens , Henkes Hans , Aguilar-Pérez Marta , Hellstern Victoria , Gihr Georg Alexander , Härtig Wolfgang , Reisberg André , Mucha Dirk , Schüngel Marie-Sophie , Brill Richard , Quäschling Ulf , Hoffmann Karl-Titus , Schob Stefan
Published: July 2021

Objective: Dissecting aneurysms (DAs) of the vertebrobasilar territory manifesting with subarachnoid hemorrhage (SAH) are associated with significant morbi-mortality, especially in the case of re-hemorrhage. Sufficient reconstruction of the affected vessel is paramount, in particular, if a dominant vertebral artery (VA) is impacted. Reconstructive options include stent-assisted coiling and flow diversion (FD). The latter is technically less challenging and does not require catheterization of the fragile aneurysm. Our study aims to report a multicentric experience with FD for reconstruction of DA in acute SAH.

Materials and Methods: This retrospective study investigated 31 patients (age: 30–78 years, mean 55.5 years) who had suffered from SAH due to a DA of the dominant VA. The patients were treated between 2010 and 2020 in one of the following German neurovascular centers: University Hospital Leipzig, Katharinenhospital Stuttgart, BG Hospital Bergmannstrost Halle/Saale, and Heinrich-Braun-Klinikum Zwickau. Clinical history, imaging, implanted devices, and outcomes were reviewed for the study.

Results: Reconstruction with flow-diverting stents was performed in all cases. The p64 was implanted in 14 patients; one of them required an additional balloon-expandable stent to reconstruct severe stenosis in the target segment. One case demanded additional liquid embolization after procedural rupture, and in one case, p64 was combined with a PED. Further 13 patients were treated exclusively with the PED. The p48MW-HPC was used in two patients, one in combination with two additional Silk Vista Baby (SVB). Moreover, one patient was treated with a single SVB, one with a SILK+. Six patients died [Glasgow Outcome Scale (GOS) 1]. Causes of death were periprocedural re-hemorrhage, thrombotic occlusion of the main pulmonary artery, and delayed parenchymal hemorrhage. The remaining three patients died in the acute–subacute phase related to the severity of the initial hemorrhage and associated comorbidities. One patient became apallic (GOS 2), whereas two patients had severe disability (GOS 3) and four had moderate disability (GOS 4). Eighteen patients showed a complete recovery (GOS 5).

Conclusion: Reconstruction of VA-DA in acute SAH with flow-diverting stents is a promising approach. However, the severity of the condition is reflected by high overall morbi-mortality, even despite technically successful endovascular treatment.
Short-Term Audiovisual Spatial Training Enhances Electrophysiological Correlates of Auditory Selective Spatial Attention
Authors: Hanenberg Christina , Schlüter Michael-Christian , Getzmann Stephan , Lewald Jörg
Published: July 2021

Audiovisual cross-modal training has been proposed as a tool to improve human spatial hearing. Here, we investigated training-induced modulations of event-related potential (ERP) components that have been associated with processes of auditory selective spatial attention when a speaker of interest has to be localized in a multiple speaker (“cocktail-party”) scenario. Forty-five healthy participants were tested, including younger (19–29 years;n= 21) and older (66–76 years;n= 24) age groups. Three conditions of short-term training (duration 15 min) were compared, requiring localization of non-speech targets under “cocktail-party” conditions with either (1) synchronous presentation of co-localized auditory-target and visual stimuli (audiovisual-congruency training) or (2) immediate visual feedback on correct or incorrect localization responses (visual-feedback training), or (3) presentation of spatially incongruent auditory-target and visual stimuli presented at random positions with synchronous onset (control condition). Prior to and after training, participants were tested in an auditory spatial attention task (15 min), requiring localization of a predefined spoken word out of three distractor words, which were presented with synchronous stimulus onset from different positions. Peaks of ERP components were analyzed with a specific focus on the N2, which is known to be a correlate of auditory selective spatial attention. N2 amplitudes were significantly larger after audiovisual-congruency training compared with the remaining training conditions for younger, but not older, participants. Also, at the time of the N2, distributed source analysis revealed an enhancement of neural activity induced by audiovisual-congruency training in dorsolateral prefrontal cortex (Brodmann area 9) for the younger group. These findings suggest that cross-modal processes induced by audiovisual-congruency training under “cocktail-party” conditions at a short time scale resulted in an enhancement of correlates of auditory selective spatial attention.
CDKN2A Determines Mesothelioma Cell Fate to EZH2 Inhibition
Authors: Pinton Giulia , Wang Zhuo , Balzano Cecilia , Missaglia Sara , Tavian Daniela , Boldorini Renzo , Fennell Dean A. , Griffin Martin , Moro Laura
Published: July 2021

Malignant pleural mesothelioma is an aggressive cancer, heterogeneous in its presentation and behaviour. Despite an increasing knowledge about molecular markers and their diagnostic and prognostic value, they are not used as much as they might be for treatment allocation. It has been recently reported that mesothelioma cells that lack BAP1 (BRCA1 Associated Protein) are sensitive to inhibition of the EZH2 (Enhancer of Zeste Homolog 2) histone methyltransferase. Since we observed strong H3K27me3 (histone H3 lysine 27 trimetylation) immunoreactivity in BAP1 wild-type mesothelioma biopsies, we decided to characterize in vitro the response/resistance of BAP1 wild-type mesothelioma cells to the EZH2 selective inhibitor, EPZ-6438. Here we demonstrate that BAP1 wild-type mesothelioma cells were rendered sensitive to EPZ-6438 upon SIRT1 (Sirtuin 1) silencing/inhibition or when cultured as multicellular spheroids, in which SIRT1 expression was lower compared to cells grown in monolayers. Notably, treatment of spheroids with EPZ-6438 abolished H3K27me3 and induced the expression of CDKN2A (Cyclin-Dependent Kinase Inhibitor 2A), causing cell growth arrest. EPZ-6438 treatment also resulted in a rapid and sustained induction of the genes encoding HIF2α (Hypoxia Inducible Factor 2α), TG2 (Transglutaminase 2) and IL-6 (Interleukin 6). Loss of CDKN2 is a common event in mesothelioma. CDKN2A silencing in combination with EPZ-6438 treatment induced apoptotic death in mesothelioma spheroids. In a CDKN2A wild-type setting apoptosis was induced by combining EPZ-6438 with 1-155, a TG2 selective and irreversible inhibitor. In conclusion, our data suggests that the expression of CDKN2A predicts cell fate in response to EZH2 inhibition and could potentially stratify tumors likely to undergo apoptosis.
N6-Methyladenosine RNA Demethylase FTO Promotes Gastric Cancer Metastasis by Down-Regulating the m6A Methylation of ITGB1
Authors: Wang Duo , Qu Xiujuan , Lu Wenqing , Wang Yizhe , Jin Yue , Hou Kezuo , Yang Bowen , Li Ce , Qi Jianfei , Xiao Jiawen , Che Xiaofang , Liu Yunpeng
Published: July 2021

Abnormal RNA m6A methylation is known to lead to the occurrence and progression of multiple cancers including gastric cancer (GC). However, the integrative effects of all m6A methylation regulators on GC prognosis are unclear. Our research aimed to globally analyze the prognosis values of all 33 m6A RNA methylation regulators in GC by univariate and multivariate Cox regression analyses. Among all 33 m6A RNA methylation regulators, fat mass and obesity-associated protein (FTO), an m6A demethylase, was identified as a key prognostic risk factor on overall survival (OS) of GC patients. It was found that FTO could promote GC cell migration and invasion abilities, and we predicted that ITGB1 was a demethylated target of FTO. Knockdown (KD) of FTO significantly down-regulated ITGB1 expression at both mRNA and protein levels and augmented ITGB1 mRNA m6A modification level. Moreover, overexpression (OE) of ITGB1 could partially reverse FTO-KD-inhibited migration and invasion of GC cells. Our study found that FTO was an independent risk factor for overall survival (OS) of GC patients and FTO could promote GC metastasis by upregulating the expression of Integrin β1(ITGB1) via decreasing its m6A level. These results indicated that FTO can be a potent GC biomarker for prognosis prediction as well as a potential target in GC treatment.
Platinum-Based Chemotherapy and Immunotherapy in Early Triple-Negative Breast Cancer: A Meta-Analysis and Indirect Treatment Comparison
Authors: He Qin , Peng Yicheng , Sun Jie , Liu Jianxia
Published: July 2021

Background

Triple-negative breast cancer (TNBC) comprises 15% of invasive breast cancers. Platinum-based chemotherapy and immune checkpoint inhibitors (ICIs) have been extensively researched in recent years as promising treatments in the neoadjuvant setting. However, clinical data is lacking in direct comparisons of these two treating regimens.

Methods

We conducted an online search on PubMed, Embase, Cochrane Online Library and key oncological meetings for available randomized controlled trials (RCTs) investigating ICIs or platinum drugs versus anthracyclines and taxane-based neoadjuvant chemotherapy (AT-based NACT). Conventional meta-analyses were conducted separately, and then indirect comparisons for clinical efficacy and safety profile were performed between ICIs and platinum drugs using AT-based NACT as a common comparator.

Results

Seven random controlled trials (RCTs) with 1,647 patients were included in the meta-analysis. The indirect comparison demonstrated that ICIs plus chemotherapy significantly improved pathological complete response (pCR) rate (p = 0.00445, OR, 1.78; 95%CI, 0.70–4.53), and decreased the adverse effect (AE) related discontinuance versus platinum-based chemotherapy (P = 0.00015; OR 0.46; 95%CI, 0.26–0.82).

Conclusion

ICIs plus chemotherapy showed increased pCR rate and decreased adverse effects compared with platinum-based chemotherapy in early TNBC. However, subgroup analysis and survival data to explore the proper patients for each treatment remains scarce. Therefore, further studies with powered direct comparisons of these two treating regimens are required.
Solitary Fibrous Tumors of the Chest: An Analysis of Fifty Patients
Authors: Zhang Jingwen , Liu Jumin , Zhang Zhihao , Tian Beizong
Published: July 2021

Background

A solitary fibrous tumor of the chest (SFTC) is a subtype of solitary fibrous tumor (SFT) with a low incidence rate. The purpose of this study is to analyze the diagnosis and treatment of SFTC and the difference between benign and malignant solitary fibrous tumor of the pleura (SFTP) to improve the understanding of this rare disease.

Methods

A retrospective analysis of fifty patients with SFTC (33 cases in the pleura and 17 in the lung) was performed. Clinical and imaging characteristics, pathological features, and treatment follow-up outcomes were analyzed.

Results

The common symptoms of the 50 patients included a cough, expectoration, chest tightness, fever, and chest pain. Space occupying lesions were found via plain computed tomography (CT) and enhanced CT was used for enhancement of the tumors. It was also found that 18 cases had necrosis, and 5 cases had calcification. The histopathology results showed that frequent nuclear division, obvious morphological variation, necrosis, and the high expression of Ki-67 cells are markers of malignant SFTC. There were significant differences in age, chest tightness, necrotic foci in CT, and expression of Ki-67 between the benign and malignant SFTP cases. All the patients who received treatment were given an excellent prognosis.

Conclusion

A combination of enhanced CT, histopathology, and immunohistochemistry can be used for the accurate diagnosis of SFTC. Advanced age, chest tightness, necrotic foci in CT, and a high Ki-67 index were more likely to be malignant SFTP. Operation and radiofrequency ablation can provide favorable outcomes for both benign and malignant SFTC.
Crosstalk Between DNA Methylation and Gene Mutations in Colorectal Cancer
Authors: Dobre Maria , Salvi Alessandro , Pelisenco Iulia Andreea , Vasilescu Florina , De Petro Giuseppina , Herlea Vlad , Milanesi Elena
Published: July 2021

Colorectal cancer (CRC) is often characterized by mutations and aberrant DNA methylation within the promoters of tumor suppressor genes and proto-oncogenes. The most frequent somatic mutations occur within KRAS and BRAF genes. Mutations of the KRAS gene have been detected in approximately 40% of patients, while mutations in BRAF have been detected less frequently at a rate of 10%. In this study, the DNA methylation levels of 22 candidate genes were evaluated in three types of tissue: mucosal tumoral tissue from 18 CRC patients, normal adjacent tissues from 10 CRC patients who underwent surgical resection, and tissue from a control group of six individuals with normal colonoscopies. A differential methylation profile of nine genes (RUNX3, SFRP1, WIF1, PCDH10, DKK2, DKK3, TMEFF2, OPCML, and SFRP2) presenting high methylation levels in tumoral compared to normal tissues was identified. KRAS mutations (codons 12 or 13) were detected in eight CRC cases, and BRAF mutations (codon 600) in four cases. One of the CRC patients presented concomitant mutations in KRAS codon 12 and BRAF, whereas seven patients did not present these mutations (WT). When comparing the methylation profile according to mutation status, we found that six genes (SFRP2, DKK2, PCDH10, TMEFF2, SFRP1, HS3ST2) showed a methylation level higher in BRAF positive cases than BRAF negative cases. The molecular sub-classification of CRC according to mutations and epigenetic modifications may help to identify epigenetic biomarkers useful in designing personalized strategies to improve patient outcomes.
Investigation of Neural Microenvironment in Prostate Cancer in Context of Neural Density, Perineural Invasion, and Neuroendocrine Profile of Tumors
Authors: Sigorski Dawid , Gulczyński Jacek , Sejda Aleksandra , Rogowski Wojciech , Iżycka-Świeszewska Ewa
Published: July 2021

Background

Cancer stroma contains the neural compartment with specific components and action. Neural microenvironment processing includes among others axonogenesis, perineural invasion (PNI), neurosignaling, and tumor cell neural/neuroendocrine differentiation. Growing data suggest that tumor-neural crosstalk plays an important function in prostate cancer (PCa) biology. However, the mechanisms involved in PNI and axonogenesis, as well as their patho-clinical correlations in this tumor are unclear.

Methods

The present study was carried out on FFPE samples of 73 PCa and 15 benign prostate (BP) cases. Immunohistochemistry with neural markers PGP9.5, TH, and NFP was performed on constructed TMAs and selected tissue sections. The analyzed parameters of tumor innervation included small nerve density (ND) measured on pan-neural marker (PGP9.5) and TH s4tained slides, as well assessment of PNI presence and morphology. The qualitative and topographic aspects were studied. In addition, the expression of neuroendocrine marker chromogranin and NPY was assessed with dedicated indexes. The correlations of the above parameters with basic patho-clinical data such as patients’ age, tumor stage, grade, angioinvasion, and ERG status were examined.

Results

The study showed that innervation parameters differed between cancer and BP. The neural network in PCa revealed heterogeneity, and ND PGP9.5 in tumor was significantly lower than in its periphery. The density of sympathetic TH-positive fibers and its proportion to all fibers was lower in cancer than in the periphery and BP samples. Perineural invasion was confirmed in 76% of cases, usually multifocally, occurring more commonly in tumors with a higher grade. NPY expression in PCa cells was common with its intensity often rising towards PNI. ERG+ tumors showed higher ND, more frequent PNI, and a higher stage. Moreover, chromogranin-positive cells were more pronounced in PCa with higher NPY expression.

Conclusions

The analysis showed an irregular axonal network in prostate cancer with higher neural density (panneural and adrenergic) in the surroundings and the invasive front. ND and PNI interrelated with NPY expression, neuroendocrine differentiation, and ERG status. The above findings support new evidence for the presence of autocrine and paracrine interactions in prostate cancer neural microenvironment.
Comprehensive Diagnostic Nomogram for Predicting Clinically Relevant Postoperative Pancreatic Fistula After Pancreatoduodenectomy
Authors: Li Bo , Pu Ning , Chen Qiangda , Mei Yong , Wang Dansong , Jin Dayong , Wu Wenchuan , Zhang Lei , Lou Wenhui
Published: July 2021

Background

Clinically relevant postoperative pancreatic fistula (CR-POPF) remains a severe and challenging complication of pancreaticoduodenectomy (PD). This study aimed to establish a novel postoperative nomogram-based diagnostic model for the early detection of CR-POPF in patients subjected to PD.

Methods

Consecutive patients who underwent PD in Zhongshan Hospital, Fudan University from December 2018 to October 2020 were retrospectively enrolled. Univariate and multivariate logistic regression analyses were performed to identify independent risk factors for CR-POPF. Then, a novel predictive nomogram was established accordingly.

Results

Among the consecutive 176 patients who underwent PD, 37 (21.1%) patients developed CR-POPF. Through univariate and multivariate analyses, the drain amylase (P = 0.002), serum creatinine (P = 0.009), and serum C reactive protein (P = 0.045) at postoperative day 1 (POD1) as well as the neutrophil count (P = 0.025) and temperature (P = 0.025) at POD3 were identified as independent risk factors for CR-POPF. Based on this, a novel predictive nomogram containing these factors was constructed to predict the probability of CR-POPF after PD. The formulated nomogram showed better performance to detect CR-POPF after PD with a sensitivity of 0.784, specificity of 0.770, positive predictive value of 0.475, and negative predictive value of 0.930 when compared to other predictors. In addition, the predictive value of the nomogram was assessed by a concordance index of 0.814 (95% CI, 0.736–0.892), which was significantly higher than indicators alone. This was further validated and depicted by decision curve analysis and clinical impact curve.

Conclusion

This study established a diagnostic nomogram of postoperative objective parameters that can predict the development of CR-POPF after PD with a good discriminative ability and predictive accuracy.
Towards Tailored Gut Microbiome-Based and Dietary Interventions for Promoting the Development and Maintenance of a Healthy Brain
Authors: Larroya Ana , Pantoja Jorge , Codoñer-Franch Pilar , Cenit María Carmen
Published: July 2021

Mental health is determined by a complex interplay between the Neurological Exposome and the Human Genome. Multiple genetic and non-genetic (exposome) factors interact early in life, modulating the risk of developing the most common complex neurodevelopmental disorders (NDDs), with potential long-term consequences on health. To date, the understating of the precise etiology underpinning these neurological alterations, and their clinical management pose a challenge. The crucial role played by diet and gut microbiota in brain development and functioning would indicate that modulating the gut-brain axis may help protect against the onset and progression of mental-health disorders. Some nutritional deficiencies and gut microbiota alterations have been linked to NDDs, suggesting their potential pathogenic implications. In addition, certain dietary interventions have emerged as promising alternatives or adjuvant strategies for improving the management of particular NDDs, at least in particular subsets of subjects. The gut microbiota can be a key to mediating the effects of other exposome factors such as diet on mental health, and ongoing research in Psychiatry and Neuropediatrics is developing Precision Nutrition Models to classify subjects according to a diet response prediction based on specific individual features, including microbiome signatures. Here, we review current scientific evidence for the impact of early life environmental factors, including diet, on gut microbiota and neuro-development, emphasizing the potential long-term consequences on health; and also summarize the state of the art regarding the mechanisms underlying diet and gut microbiota influence on the brain–gut axis. Furthermore, we describe the evidence supporting the key role played by gut microbiota, diet and nutrition in neurodevelopment, as well as the effectiveness of certain dietary and microbiome-based interventions aimed at preventing or treating NDDs. Finally, we emphasize the need for further research to gain greater insight into the complex interplay between diet, gut microbiome and brain development. Such knowledge would help towards achieving tailored integrative treatments, including personalized nutrition.
The Role of High-Content Complex Dietary Fiber in Medical Nutrition Therapy for Gestational Diabetes Mellitus
Authors: Wang Hong-Kun , Cheng De-Cui , Yang Yue-Min , Wang Xia-Hong , Chen Yan , Zhang Lin , Xiu Lian , Xu Xian-Ming
Published: July 2021

Objectives: A controlled open clinical study was conducted to evaluate the role of Ricnoat, a high-content complex dietary fiber powder produced by Zhuhai Aimed Biotechnology Co. Ltd., in medical nutrition therapy (MNT) to treat gestational diabetes mellitus (GDM). The study aimed to investigate glycemic control, lipid control, weight control, and pregnancy outcomes (neonatal weight) in patients with GDM, as well as evaluate the clinical safety of Ricnoat.

Methods: A total of 120 patients with GDM who were admitted to three hospitals in Shanghai between January 2019 and January 2020 were enrolled. Ricnoat was used for intervention for patients in the experimental group. Using a χ2 test and t-test, respectively, comparisons were conducted between the measurement data and countable data of the demographics and baseline disease characteristics of the experimental group and control group.

Results: Fasting blood glucose, 2-h postprandial blood glucose, glycated hemoglobin, total cholesterol, triglycerides, low-density lipoprotein, maternal gestational weight gain, neonatal weight, serum creatinine, glutamate transaminase, and aspartate aminotransferase were lower in the experimental group than in the control group, whereas high-density lipoprotein was higher in the experimental group than in the control group. Ricnoat intervention resulted in satiety higher than the expected 80% and more common occurrence of type 4 (smooth and soft, like salami or a snake) and type 5 (a soft mass with clear edges) stools.

Conclusion: Ricnoat intervention had a significant effect on glycemic control, lipid control, weight control, and pregnancy outcomes (neonatal weight) in patients with GDM by enhancing maternal satiety and improving the stool features of pregnant women. It was also found to be safe for application during pregnancy.
Association, Correlation, and Causation Among Transport Variables of PM2.5
Authors: Zhao Zhi-Dan , Zhao Na , Ying Na
Published: July 2021

The issue of PM2.5 pollution has received significant attention in the literature as it has social, economic, and political implications. Big data sets have been collected by pollution monitoring stations (i.e., nodes) throughout the world, and this has made it possible to quantitatively characterize the dependence of PM2.5 pollution in different regions. Here we divide the dependency relationship into three types: association, correlation, and causation. This study conducted such relationships using three approaches: the random matrix theory (RMT), cross-correlation, and convergent cross-mapping (CCM). The aim of this study is to determine the above three relationships between pollution data from different nodes. A random matrix analysis revealed that pollutant time series are not completely random, but are associated. Further analysis showed that PM2.5 sequences had clear short-range correlations, yet the long-range correlations were blurred. Moreover, at the collect level, there were no clear causalities among pollutant concentrations from different geographical regions, regardless of distance and direction. These results indicate that the dependence of PM2.5 pollution between different sites is complex. Nonetheless, this comprehensive analysis based on big data provided insights into critical issues of general interest, including pollution-induced climate change, and pollution abatement.
Strength Performance Across the Oral Contraceptive Cycle of Team Sport Athletes: A Cross-Sectional Study
Authors: Reif Astrid , Wessner Barbara , Haider Patricia , Tschan Harald , Triska Christoph
Published: July 2021

Oral contraceptive pills (OCP) are very popular in female athletes not only for contraceptive effects but also due to the possibility of cycle manipulation. Moreover, it is debatable whether the manipulation of the menstrual cycle has a beneficial effect on exercise performance. Therefore, the aim of this study was to investigate potential differences in knee-extensor and flexor strength performance of first division team sport athletes between phases of the oral contraceptive cycle. Sixteen female handball players (age: 23.3 ± 3.1 years; body mass: 67.0 ± 8.52 kg; body stature: 1.68 ± 0.05 m) using a monophasic OCP participated in strength performance tests, once during OCP consumption (CONS) and once during withdrawal (WITH). Tests were performed on a dynamometer to measure knee-extensor and flexor maximal voluntary isokinetic and isometric torque. Prior to each test, body mass was assessed, and venous blood samples were collected. Wilcoxon signed-rank test and magnitude-based inferences have been conducted to analyze differences between WITH and CONS. Significance was accepted at P < 0.05. No significant differences between oral contraceptive cycle phases of knee-extensor and flexor strength parameters and body mass have been indicated (all at P > 0.05). Follicle-stimulating hormone (FSH) (P = 0.001) and luteinizing hormone (P = 0.013) were significantly higher in WITH, whereby estradiol and progesterone showed no significant difference between phases (both at P > 0.05). These results support the notion that knee-extensor and flexor isokinetic and isometric strength performance does not differ between phases of oral contraceptive cycle in well-trained team sport athletes. OCP intake is suggested to cause a stable but downregulated hormone cycle, which has no effect on knee-extensor and flexor strength when comparing oral contraceptive cycle phases. Therefore, manipulation of the female cycle using OCP in order to achieve a higher knee-extensor and flexor strength performance does not seem to be justified; however, it is currently unclear if cycle manipulation might affect other physiological systems.
Annexin A1 Tripeptide Mimetic Increases Sirtuin-3 and Augments Mitochondrial Function to Limit Ischemic Kidney Injury
Authors: Suliman Hagir , Ma Qing , Zhang Zhiquan , Ren Jiafa , Morris Benjamin T. , Crowley Steven D. , Ulloa Luis , Privratsky Jamie R.
Published: July 2021

Background:Acute kidney injury (AKI) is one of the most common organ failures following surgery. We have developed a tripeptide mimetic (ANXA1sp) of the parent annexin A1 molecule that shows promise as an organ protectant limiting cellular stress; however, its potential as a kidney protective agent remains unexplored, and its mechanism of action is poorly understood. Our hypothesis was that ANXA1sp would limit kidney injury following surgical ischemic kidney injury.

Methods:In a blinded fashion, wildtype mice were assigned to receive vehicle control or ANXA1sp one hour prior to and one hour after kidney vascular clamping. Our primary outcomes were markers of kidney injury and function as measured by serum creatinine and histologic injury scoring of kidney tissue sections. Immunofluorescence microscopy, real-time PCR, and Western blot were used to assess cell death, oxidative stress, and mitochondrial biomarkers. Anin vitromodel of oxygen-glucose deprivation in immortalized kidney tubule cells was used.

Results:ANXA1sp given prior to and after ischemic kidney injury abrogated ischemic kidney injury. ANXA1sp limited cell death bothin vivoandin vitroand abrogated oxidative stress following ischemia. ANXA1sp significantly increased the expression of markers associated with protective mitophagy and limited the expression of markers associated with detrimental mitochondrial fission. ANXA1sp upregulated the expression of the mitochondrial protectant sirtuin-3 (SIRT3) in the mitochondria of kidney tubular cells. Silencing of SIRT3 reversed ANXA1sp-mediated protection against hypoxic cell death.

Conclusions:ANXA1sp limits kidney injury, upregulates SIRT3, and preserves mitochondrial integrity following ischemic kidney injury. ANXA1sp holds considerable promise as a perioperative kidney protectant prior to ischemia inducing surgery and kidney transplantation.
The Mitochondrial PHB Complex Determines Lipid Composition and Interacts With the Endoplasmic Reticulum to Regulate Ageing
Authors: Lourenço Artur B. , Rodríguez-Palero María Jesús , Doherty Mary K. , Cabrerizo Granados David , Hernando-Rodríguez Blanca , Salas Joaquín J. , Venegas-Calerón Mónica , Whitfield Phillip D. , Artal-Sanz Marta
Published: July 2021

Metabolic disorders are frequently associated with physiological changes that occur during ageing. The mitochondrial prohibitin complex (PHB) is an evolutionary conserved context-dependent modulator of longevity, which has been linked to alterations in lipid metabolism but which biochemical function remains elusive. In this work we aimed at elucidating the molecular mechanism by which depletion of mitochondrial PHB shortens the lifespan of wild type animals while it extends that of insulin signaling receptor (daf-2) mutants. A liquid chromatography coupled with mass spectrometry approach was used to characterize the worm lipidome of wild type and insulin deficient animals upon PHB depletion. Toward a mechanistic interpretation of the insights coming from this analysis, we used a combination of biochemical, microscopic, and lifespan analyses. We show that PHB depletion perturbed glycerophospholipids and glycerolipids pools differently in short- versus long-lived animals. Interestingly, PHB depletion in otherwise wild type animals induced the endoplasmic reticulum (ER) unfolded protein response (UPR), which was mitigated in daf-2 mutants. Moreover, depletion of DNJ-21, which functionally interacts with PHB in mitochondria, mimicked the effect of PHB deficiency on the UPRER and on the lifespan of wild type and insulin signaling deficient mutants. Our work shows that PHB differentially modulates lipid metabolism depending on the worm’s metabolic status and provides evidences for a new link between PHB and ER homeostasis in ageing regulation.
Unraveling Genetic Diversity Amongst European Hazelnut (Corylus avellana L.) Varieties in Turkey
Authors: Oztolan-Erol Nihal , Helmstetter Andrew J. , İnan Asuman , Buggs Richard J. A. , Lucas Stuart J.
Published: July 2021

European hazelnut (Corylus avellana) is a diploid (2n = 22), monecious and wind-pollinated species, extensively cultivated for its nuts. Turkey is the world-leading producer of hazelnut, supplying 70–80% of the world’s export capacity. Hazelnut is mostly grown in the Black Sea Region, and maintained largely through clonal propagation. Understanding the genetic variation between hazelnut varieties, and defining variety-specific and disease resistance-associated alleles, would facilitate hazelnut breeding in Turkey. Widely grown varieties ‘Karafındık’ (2), ‘Sarıfındık’ (5), and ‘Yomra’ (2) were collected from Akçakoca in the west, while ‘Tombul’ (8), ‘Çakıldak’ (3), ‘Mincane’ (2), ‘Allahverdi’ (2), ‘Sivri’ (4), and ‘Palaz’ (5) were collected from Ordu and Giresun provinces in the east (numbers in parentheses indicate sample sizes for each variety). Powdery mildew resistant and susceptible hazelnut genotypes were collected from the field gene bank and heavily infected orchards in Giresun. Every individual was subjected to double digest restriction enzyme-associated DNA sequencing (ddRAD-seq) and a RADtag library was created. RADtags were aligned to the ‘Tombul’ reference genome, and Stacks software used to identify polymorphisms. 101 private and six common alleles from nine hazelnut varieties, four private from resistants and only one from susceptible were identified for diagnosis of either a certain hazelnut variety or powdery mildew resistance. Phylogenetic analysis and population structure calculations indicated that ‘Mincane’, ‘Sarıfındık’, ‘Tombul’, ‘Çakıldak’, and ‘Palaz’ were genetically close to each other; however, individuals within every varietal group were found in different sub-populations. Our findings indicated that years of clonal propagation of some preferred varieties across the Black Sea Region has resulted in admixed sub-populations and great genetic diversity within each variety. This impedes the development of a true breeding variety. For example, ‘Tombul’ is the most favored Turkish variety because of its high quality nuts, but an elite ‘Tombul’ line does not yet exist. This situation continues due to the lack of a breed protection program for commercially valuable hazelnut varieties. This study provides molecular markers suitable for establishing such a program.
Structural Modeling and in planta Complementation Studies Link Mutated Residues of the Medicago truncatula Nitrate Transporter NPF1.7 to Functionality in Root Nodules
Authors: Yu Yao-Chuan , Dickstein Rebecca , Longo Antonella
Published: July 2021

Symbiotic nitrogen fixation is a complex and regulated process that takes place in root nodules of legumes and allows legumes to grow in soils that lack nitrogen. Nitrogen is mostly acquired from the soil as nitrate and its level in the soil affects nodulation and nitrogen fixation. The mechanism(s) by which legumes modulate nitrate uptake to regulate nodule symbiosis remain unclear. In Medicago truncatula, the MtNPF1.7 transporter has been shown to control nodulation, symbiosis, and root architecture. MtNPF1.7 belongs to the nitrate/peptide transporter family and is a symporter with nitrate transport driven by proton(s). In this study we combined in silico structural predictions with in planta complementation of the severely defective mtnip-1 mutant plants to understand the role of a series of distinct amino acids in the transporter’s function. Our results support hypotheses about the functional importance of the ExxE(R/K) motif including an essential role for the first glutamic acid of the motif in proton(s) and possibly substrate transport. Results reveal that Motif A, a motif conserved among major facilitator transport (MFS) proteins, is essential for function. We hypothesize that it participates in intradomain packing of transmembrane helices and stabilizing one conformation during transport. Our results also question the existence of a putative TMH4-TMH10 salt bridge. These results are discussed in the context of potential nutrient transport functions for MtNPF1.7. Our findings add to the knowledge of the mechanism of alternative conformational changes as well as symport transport in NPFs and enhance our knowledge of the mechanisms for nitrate signaling.