bluuebunny/crossref_metadata_2025 huggingface dataset:
Robot Fully Assisted Upper-Limb Functional Movements Against Gravity to Drive Recovery in Chronic Stroke: A Pilot Study
Authors: Caimmi Marco , Giovanzana Chiara , Gasperini Giulio , Molteni Franco , Molinari Tosatti Lorenzo
Published: March 2022

Background

Stroke is becoming more and more a disease of chronically disabled patients, and new approaches are needed for better outcomes. An intervention based on robot fully assisted upper-limb functional movements is presented.

Objectives

To test the immediate and sustained effects of the intervention in reducing impairment in chronic stroke and to preliminarily verify the effects on activity.

Methodology

Nineteen patients with mild-to-severe impairment underwent 12 40-min rehabilitation sessions, 3 per week, of robot-assisted reaching and hand-to-mouth movements. The primary outcome measure was the Fugl-Meyer Assessment (FMA) at T1, immediately after treatment (n= 19), and at T2, at a 6-month follow-up (n= 10). A subgroup of 11 patients was also administered the Wolf Motor Function Test Time (WMFT TIME) and Functional Ability Scale (WMFT FAS) and Motor Activity Log (MAL) Amount Of Use (AOU), and Quality Of Movement (QOM).

Results

All patients were compliant with the treatment. There was improvement on the FMA with a mean difference with respect to the baseline of 6.2 points at T1, after intervention (n= 19, 95% CI = 4.6–7.8,p< 0.0002), and 5.9 points at T2 (n= 10, 95% CI = 3.6–8.2,p< 0.005). Significant improvements were found at T1 on the WMFT FAS (n= 11, +0.3/5 points, 95% CI = 0.2–0.4,p< 0.004), on the MAL AOU (n= 11, +0.18/5, 95% CI = 0.07–0.29,p< 0.02), and the MAL QOM (n= 11, +0.14/5, 95% CI = 0.08–0.20,p< 0.02).

Conclusions

Motor benefits were observed immediately after intervention and at a 6-month follow-up. Reduced impairment would appear to translate to increased activity. Although preliminary, the results are encouraging and lay the foundation for future studies to confirm the findings and define the optimal dose-response curve.

Clinical Trial Registration

www.ClinicalTrials.gov, identifier: NCT03208634.
Differential Cognitive Functioning and Benefit From Surgery in Patients Undergoing Coronary Artery Bypass Grafting and Carotid Endarterectomy
Authors: Relander Kristiina , Hietanen Marja , Rämö Juhani , Vento Antti , Tikkala Irene , Roine Risto O. , Lindsberg Perttu J. , Soinne Lauri
Published: March 2022

Background

Stenosing atherosclerosis in both coronary and carotid arteries can adversely affect cognition. Also their surgical treatments, coronary artery bypass grafting (CABG) and carotid endarterectomy (CEA), are associated with cognitive changes, but the mechanisms of cognitive decline or improvement may not be the same. This study was designed to compare the cognitive profile and outcome in patients undergoing surgical treatment for coronary or carotid disease.

Methods

A total of 100 CABG patients and 44 CEA patients were recruited in two previously reported studies. They were subjected to a comprehensive neuropsychological examination prior to surgery and in the acute (3–8 days) and stable (3 months) phase after operation. A group of 17 matched healthy controls were assessed with similar intervals. We used linear mixed models to compare cognitive trajectories within six functional domains between the CABG, CEA and control groups. Postoperative cognitive dysfunction (POCD) and improvement (POCI) were determined with the reliable change index method in comparison with healthy controls.

Results

Before surgery, the CEA patients performed worse than CABG patients or healthy controls in the domains of executive functioning and processing speed. The CABG patients exhibited postoperative cognitive dysfunction more often than the CEA patients in most cognitive domains in the acute phase but had regained their performance in the stable phase. The CEA patients showed more marked postoperative improvement in executive functioning than the CABG group in the acute phase, but the difference did not reach significance in the stable phase.

Conclusion

Our findings suggest that anterior cerebral dysfunction in CEA patients impairs preoperative cognition more severely than global brain dysfunction in CABG patients. However, CEA may have more beneficial effects on cognition than CABG, specifically in executive functions mainly operated by the prefrontal lobes. In addition, the results underline that POCD is a heterogeneous condition and dependent on type of revascularization surgery.
Synaptopathies in Developmental and Epileptic Encephalopathies: A Focus on Pre-synaptic Dysfunction
Authors: Spoto Giulia , Valentini Giulia , Saia Maria Concetta , Butera Ambra , Amore Greta , Salpietro Vincenzo , Nicotera Antonio Gennaro , Di Rosa Gabriella
Published: March 2022

The proper connection between the pre- and post-synaptic nervous cells depends on any element constituting the synapse: the pre- and post-synaptic membranes, the synaptic cleft, and the surrounding glial cells and extracellular matrix. An alteration of the mechanisms regulating the physiological synergy among these synaptic components is defined as “synaptopathy.” Mutations in the genes encoding for proteins involved in neuronal transmission are associated with several neuropsychiatric disorders, but only some of them are associated with Developmental and Epileptic Encephalopathies (DEEs). These conditions include a heterogeneous group of epilepsy syndromes associated with cognitive disturbances/intellectual disability, autistic features, and movement disorders. This review aims to elucidate the pathogenesis of these conditions, focusing on mechanisms affecting the neuronal pre-synaptic terminal and its role in the onset of DEEs, including potential therapeutic approaches.
Cross-Sectional Investigation of Brain Volume in Dyslexia
Authors: Ligges Carolin , Ligges Marc , Gaser Christian
Published: March 2022

The goal of the study was to determine whether dyslexia is associated with differences in local brain volume, and whether these local brain volume differences show cross-sectional age-effects. We investigated the local volume of gray and white brain matter with voxel-based morphometry (VBM) as well as reading performance in three age groups of dyslexic and neurotypical normal reading subjects (children, teenagers and adults). Performance data demonstrate a steady improvement of reading skills in both neurotypical as well as dyslexic readers. However, the pattern of gray matter volumes tell a different story: the children are the only group with significant differences between neurotypical and dyslexic readers in local gray matter brain volume. These differences are localized in brain areas associated with the reading network (angular, middle temporal and inferior temporal gyrus as well as the cerebellum). Yet the comparison of neurotypical and normal readers over the age groups shows that the steady increase in performance in neurotypical readers is accompanied by a steady decrease of gray matter volume, whereas the brain volumes of dyslexic readers do not show this linear correlation between brain volume and performance. This is further evidence that dyslexia is a disorder with a neuroanatomical basis in the form of a lower volume of gray matter in parts of the reading network in early dyslexic readers. The present data point out that network shaping processes in gray matter volume in the reading network does take place over age in dyslexia. Yet this neural foundation does not seem to be sufficient to allow normal reading performances even in adults with dyslexia. Thus dyslexia is a disorder with lifelong consequences, which is why consistent support for affected individuals in their educational and professional careers is of great importance. Longitudinal studies are needed to verify whether this holds as a valid pattern or whether there is evidence of greater interindividual variance in the neuroanatomy of dyslexia.
Optical Coherence Tomography Angiography Biomarkers of Retinal Thickness and Microvascular Alterations in Sjogren's Syndrome
Authors: Liu Ren , Wang Yan , Li Qiuyu , Xia Qiang , Xu Tian , Han Ting , Cai Shuang , Luo Shuilin , Wu Rui , Shao Yi
Published: March 2022

Purpose

To investigate the differences of retinal thickness (RT) and superficial vascular density (SVD) between patients with Sjogren's syndrome (SS) and healthy controls (HCs) using optical coherence tomography angiography (OCTA).

Methods

Individuals with SS and healthy controls were enrolled (n = 12 per group). An en-face OCTA scan was performed on each eye. Images were segmented into 9 subregions and macular RT and SVD were measured and compared between the 2 groups.

Results

Visual acuity (VA) differed significantly between patients with SS (24 eyes) and controls (24 eyes) (p < 0.001). In patients with SS, inner RT was reduced in the inner superior region, outer RT was reduced in the outer nasal (ON) region, and full RT was reduced in the ON region compared with the control group (p < 0.05). RT was negatively correlated with serum IgG level in the outer and full retina at ON regions (p < 0.05). SVD in the inner nasal, ON, and inner temporal regions was significantly lower in patients with SS than in control subjects (p < 0.05). SVD was positively correlated with full RT in the ON region in patients with SS (p < 0.05). The areas under the receiver operating characteristic (ROC) curves for the diagnostic sensitivity of outer RT and full RT in the ON region for SS were 0.828 (95% CI: 0.709–0.947) and 0.839 (95% CI: 0.715–0.963), respectively.

Conclusions

In patients with SS, retinal thinning in the macular area—which affects vision—can also reflect the severity of dry eyes in SS and has clinical value for assisted imaging diagnosis.
Altered Neuromagnetic Activity in Persistent Postural-Perceptual Dizziness: A Multifrequency Magnetoencephalography Study
Authors: Jiang Weiwei , Sun Jintao , Xiang Jing , Sun Yulei , Tang Lu , Zhang Ke , Chen Qiqi , Wang Xiaoshan
Published: March 2022

Objective

The aim of our study was to investigate abnormal changes in brain activity in patients with persistent postural-perceptual dizziness (PPPD) using magnetoencephalography (MEG).

Methods

Magnetoencephalography recordings from 18 PPPD patients and 18 healthy controls were analyzed to determine the source of brain activity in seven frequency ranges using accumulated source imaging (ASI).

Results

Our study showed that significant changes in the patterns of localization in the temporal-parietal junction (TPJ) were observed at 1–4, 4–8, and 12–30 Hz in PPPD patients compared with healthy controls, and changes in the frontal cortex were found at 1–4, 80–250, and 250–500 Hz in PPPD patients compared with controls. The neuromagnetic activity in TPJ was observed increased significantly in 1–4 and 4–8 Hz, while the neuromagnetic activity in frontal cortex was found increased significantly in 1–4 Hz. In addition, the localized source strength in TPJ in 1–4 Hz was positively correlated with DHI score (r = 0.7085, p < 0.05), while the localized source strength in frontal cortex in 1–4 Hz was positively correlated with HAMA score (r = 0.5542, p < 0.05).

Conclusion

Our results demonstrated that alterations in the TPJ and frontal cortex may play a critical role in the pathophysiological mechanism of PPPD. The neuromagnetic activity in TPJ may be related to dizziness symptom of PPPD patients, while the neuromagnetic activity in frontal lobe may be related to emotional symptoms of PPPD patients. In addition, frequency-dependent changes in neuromagnetic activity, especially neuromagnetic activity in low frequency bands, were involved in the pathophysiology of PPPD.
The Synaptic Extracellular Matrix: Long-Lived, Stable, and Still Remarkably Dynamic
Authors: Dankovich Tal M. , Rizzoli Silvio O.
Published: March 2022

In the adult brain, synapses are tightly enwrapped by lattices of the extracellular matrix that consist of extremely long-lived molecules. These lattices are deemed to stabilize synapses, restrict the reorganization of their transmission machinery, and prevent them from undergoing structural or morphological changes. At the same time, they are expected to retain some degree of flexibility to permit occasional events of synaptic plasticity. The recent understanding that structural changes to synapses are significantly more frequent than previously assumed (occurring even on a timescale of minutes) has called for a mechanism that allows continual and energy-efficient remodeling of the extracellular matrix (ECM) at synapses. Here, we review recent evidence for such a process based on the constitutive recycling of synaptic ECM molecules. We discuss the key characteristics of this mechanism, focusing on its roles in mediating synaptic transmission and plasticity, and speculate on additional potential functions in neuronal signaling.
Neural Circuits Underlying Social Fear in Rodents: An Integrative Computational Model
Authors: Alfieri Valerio , Mattera Andrea , Baldassarre Gianluca
Published: March 2022

Social avoidance in rodents arises from a complex interplay between the prefrontal cortex and subcortical structures, such as the ventromedial hypothalamus and the dorsal periaqueductal gray matter. Experimental studies are revealing the contribution of these areas, but an integrative view and model of how they interact to produce adaptive behavior are still lacking. Here, we present a computational model of social avoidance, proposing a set of integrated hypotheses on the possible macro organization of the brain system underlying this phenomenon. The model is validated by accounting for several different empirical findings and produces predictions to be tested in future experiments.
F-18 Fluoro-2-Deoxyglucose Positron Emission Tomography (PET)/Computed Tomography (CT) Imaging in Melanoma: Normal Variants, Pitfalls, and Artifacts
Authors: Momodu Jaleelat I. , Vangu Mboyo Di Tamba
Published: March 2022

Multimodality imaging has revolutionized diagnostic imaging for several oncologic pathologies including melanoma. Although F-18 fluoro-2-deoxyglucose positron emission tomography/ computed tomography [18F]FDG PET/CT has a high sensitivity in stage III and IV melanoma, several normal variants, and imaging pitfalls may result in falsely increased or reduced tracer uptake that may negatively impact diagnostic accuracy. In addition to normal physiologic tracer uptake, differences in the biological and molecular characteristics of different types of melanoma are also responsible for pitfalls. For instance, [18F]FDG PET/CT has a low sensitivity for detecting brain metastases due to normal physiologic [18F]FDG uptake in brain tissue while hepatic metastases from cutaneous melanoma are more [18F]FDG-avid than hepatic metastases from uveal melanoma. With the introduction of immunotherapies for melanoma, treatment response assessment using [18F]FDG PET/CT has a reduced specificity. This is due to hypermetabolic immune-related adverse effects such as hepatitis, dermatitis, and colitis resulting in false-positive uptake. In addition, immune therapy-induced initial increase in tumor uptake followed by disease response (pseudo-progression) is a cause of false-positive scan interpretation. Specific technical artifacts impact disease detection in [18F]FDG PET/CT melanoma imaging. The identification of small metastatic lymph nodes and lung nodules may be limited by the resolution of the PET/CT camera (partial volume effect). Computed tomography (CT) attenuation correction results in less apparent skin and subcutaneous lesions. Pictorial illustrations will be central to this paper for the description of these normal variants, imaging artifacts, and pitfalls. It is critical for the imaging specialist to have a clear understanding of these potential limitations of 18F-FDG PET/CT imaging in individuals who are referred with melanoma.
Best Practices for Probiotic Research in Athletic and Physically Active Populations: Guidance for Future Randomized Controlled Trials
Authors: Mohr Alex E. , Pugh Jamie , O'Sullivan Orla , Black Katherine , Townsend Jeremy R. , Pyne David B. , Wardenaar Floris C. , West Nicholas P. , Whisner Corrie M. , McFarland Lynne V.
Published: March 2022

Probiotic supplementation, traditionally used for the prevention or treatment of a variety of disease indications, is now recognized in a variety of population groups including athletes and those physically active for improving general health and performance. However, experimental and clinical trials with probiotics commonly suffer from design flaws and different outcome measures, making comparison and synthesis of conclusions difficult. Here we review current randomized controlled trials (RCTs) using probiotics for performance improvement, prevention of common illnesses, or general health, in a specific target population (athletes and those physically active). Future RCTs should address the key elements of (1) properly defining and characterizing a probiotic intervention, (2) study design factors, (3) study population characteristics, and (4) outcome measures, that will allow valid conclusions to be drawn. Careful evaluation and implementation of these elements should yield improved trials, which will better facilitate the generation of evidence-based probiotic supplementation recommendations for athletes and physically active individuals.
Tumor Mutational Burden Associated With Response to Hyperthermic Intraperitoneal Chemotherapy
Authors: Zeng Lisi , Huang Xubo , Tian Yun , Huang Jinxia , Liu Huiyan , Wen Juncai , Liu Kaihua , Shao Yang , Luo Jiali , Tang Hongsheng , Liao Quanxing , Lei Ziying , Cui Weiwen , Xia Qianghua , Guan Tianpei , Li Jin , Cui Shuzhong
Published: March 2022

Background

Gastric cancer (GC) is one of the most common cancer types, especially in Asian countries. Hyperthermic intraperitoneal chemotherapy (HIPEC) has been shown to improve the progression-free survival among gastric cancer patients with peritoneal metastases; however, not all patients demonstrate response to HIPEC.

Methods

Biomarkers are needed to select patients for effective treatment of HIPEC. Here, we performed whole-exome sequencing on tumor samples from 18 gastric cancer patients who received HIPEC treatment and assessed the association between genomic mutation features and progression-free survival. Exome sequencing was further conducted on tumor samples from additional 15 gastric cancer patients as a replication study.

Results

The tumor mutational burden (TMB) was significantly higher in the group of patients with a better response to HIPEC treatment than that of the others. Kaplan–Meier survival curve showed that patients with high TMB had a significantly longer survival time than that in patients with low TMB. This discovery was validated in the replication cohort. Genes bearing mutations recurrently and selectively in patients with better response to HIPEC were found in the two cohorts.

Conclusion

We found that higher TMB is significantly associated with better response to HIPEC. Our results provide useful hints for prognostic stratification of HIPEC treatment.
The Role of Tumor Stem Cell Exosomes in Cancer Invasion and Metastasis
Authors: Liu Kun , Gao Xin , Kang Baoqiang , Liu Yunpeng , Wang Dingding , Wang Yi
Published: March 2022

Exosomes are lipid membrane bilayer-encapsulated vesicles secreted by cells into the extracellular space. They carry abundant inclusions (such as nucleic acids, proteins, and lipids) that play pivotal roles in intercellular communication. Tumor stem cells are capable of self-renewal and are crucial for survival, proliferation, drug resistance, metastasis, and recurrence of tumors. The miRNAs (microRNAs) in exosomes have various functions, such as participating in inflammatory response, cell migration, proliferation, apoptosis, autophagy, and epithelial-mesenchymal transition. Tumor stem cells secrete exosomes that act as important messengers involved in various tumor processes and several studies provide increasing evidence supporting the importance of these exosomes in tumor recurrence and metastasis. This review primarily focuses on the production and secretion of exosomes from tumors and tumor stem cells and their effects on cancer progression. Cancer stem cancer derived exosome play an important massager in the tumor microenvironment. It also emphasizes on the study of tumor stem cell exosomes in the light of cancer metastasis and recurrence aiming to provide valuable insights and novel perspectives, which could be beneficial for developing effective diagnostic and treatment strategies.
The Role of Primary Tumor Resection in Patients With Pancreatic Neuroendocrine Tumors With Liver Metastases
Authors: Mou Yu , Wang Zi-Yao , Tan Chun-Lu , Chen Yong-Hua , Liu Xu-Bao , Ke Neng-Wen
Published: March 2022

Background

Liver metastases (LMs) are common in advanced pancreatic neuroendocrine tumor (PNET) patients. Currently, the benefit of primary tumor resection (PTR) in the setting of PNET patients with liver metastases is still controversial in several guidelines.

Methods

Data were extracted from the Surveillance, Epidemiology and End Results (SEER) database to evaluate this issue. The main index of interest in our study was overall survival time.

Results

Information on 536 PNET patients with liver metastases from the SEER database was identified. A total of 214 patients (PTR group) received primary tumor resection, and more than half of them (132 patients) had synchronous LM resection. The other 322 PNET patients (non-PTR group) with liver metastases did not receive primary tumor resection. A significant survival benefit was gained from PTR when compared with non-PTR patients, both in OS (72.93 ± 2.7 vs. 36.80 ± 2.22 months) and 3- or 5-year survival rates (75.1% vs. 28.9% and 67.9% vs. 22.3%, respectively). No difference was found between PTR alone and PTR with synchronous LM resection. From univariate and multivariate analyses, younger age (<65 years) and good or moderate tumor differentiation may be more important when considering primary tumor resection. However, we found that all grades of tumor differentiation could result in a better overall survival time after primary tumor resection.

Conclusion

Our study suggested that primary tumor resection in pancreatic neuroendocrine patients with liver metastases could result in a longer survival time. Primary tumor resection with synchronous liver metastasis resection was not related to a better survival benefit. This treatment strategy may routinely be taken into consideration in these patients.
Plan Quality Assessment of Fractionated Stereotactic Radiotherapy Treatment Plans in Patients With Brain Metastases
Authors: Simon Mihály , Papp Judit , Csiki Emese , Kovács Árpád
Published: March 2022

Background and Purpose

The treatment options available in the management of brain metastases includes fractionated stereotactic radiotherapy (FSRT) and stereotactic radiosurgery (SRS) treatments. FSRT treatments have proved to be useful mainly in the treatment of larger volumes. This study aims to evaluate the FSRT treatment technique used in our department based on various plan quality indices.

Methods and Materials

24 treatment plans of 23 patients were analyzed. Volumetric modulated arc therapy (VMAT) plans were generated in line with the department protocol. The following parameters were extracted: Radiation Therapy Oncology Group conformity index (RTOG CI), Paddick conformity index (Paddick CI), gradient index (GI), quality index (Q), homogeneity index (HI), and V24.4 volume as a parallel index of V12 used at SRS plan evaluation.

Results

Plan conformity was acceptable, RTOG CI mean was 0.942; Paddick CI mean was 0.824. The mean GI value was 6.146. The mean of HI and Q indices were 1.263 and 0.94, respectively. V24.4 mean was 33.434 cm3. All plans achieved clinically acceptable organs-at-risk (OAR) constraints. PTV volumes were clustered into either 10 cm3 or 15 cm3 bins depending on the plan quality metric we used. The mean values show a balanced distribution of plan indices along the various PTV bins.

Discussion

Our results based on the derived indices show that our FSRT approach can achieve clinically acceptable treatment plans. Furthermore, the clustering of PTV volumes show that these plan quality metrics remain acceptable for a wide spectrum of PTV volumes.
Rectal Radiation Dose and Clinical Outcomes in Prostate Cancer Patients Treated With Stereotactic Body Radiation Therapy With and Without Hydrogel
Authors: Kundu Palak , Lin Eric Y. , Yoon Stephanie M. , Parikh Neil R. , Ruan Dan , Kishan Amar U. , Lee Alan , Steinberg Michael L. , Chang Albert J.
Published: March 2022

Background

Patients with prostate cancer treated with stereotactic body radiation therapy (SBRT) may experience gastrointestinal (GI) toxicity. The hydrogel may mitigate this toxicity by reducing the rectal radiation dose. The purpose of this study is to compare rectal radiation dose and GI toxicity in patients receiving prostate SBRT with and without hydrogel.

Methods

Consecutive patients treated with SBRT between February 2017 and January 2020 with and without hydrogel were retrospectively identified. Baseline characteristics including prostate volume, rectal diameter, body mass index (BMI), age, pretreatment prostate-specific antigen (PSA), Gleason score, T-stage, and androgen deprivation therapy (ADT) usage were compared. Dosimetric outcomes (V40Gy, V36Gy, V32Gy, V38Gy, and V20Gy), rates of acute (≤90 days) and late (>90 days) GI toxicity, and PSA outcomes were evaluated for patients with and without hydrogel.

Results

A total of 92 patients were identified (51 hydrogel and 41 non-hydrogel). There were no significant differences in baseline characteristics. Rectal V38(cc) was significantly less in the hydrogel group (mean 0.44 vs. mean 1.41 cc, p = 0.0002), and the proportion of patients with V38(cc) < 2 cc was greater in the hydrogel group (92% vs. 72%, p = 0.01). Rectal dose was significantly lower for all institutional dose constraints in the hydrogel group (p < 0.001). The hydrogel group experienced significantly less acute overall GI toxicity (16% hydrogel vs. 28% non-hydrogel, p = 0.006), while the difference in late GI toxicity trended lower with hydrogel but was not statistically significant (4% hydrogel vs. 10% non-hydrogel, p = 0.219). At a median follow-up of 14.8 months, there were no biochemical recurrences in either group.

Conclusion

Hydrogel reduces rectal radiation dose in patients receiving prostate SBRT and is associated with a decreased rate of acute GI toxicity.
Characteristic of Perineural Invasion in Hilar Cholangiocarcinoma Based on Whole-Mount Histologic Large Sections of Liver
Authors: Wang Si-Yuan , Jiang Nan , Zeng Jian-Ping , Yu Shao-Qing , Xiao Ying , Jin Shuo
Published: March 2022

Background & Objective

Perineural invasion is an important biological feature of hilar cholangiocarcinoma (HCCA). We developed a whole-mount histologic large sections (WHLS) of the liver to evaluate peripheral nerve invasion (PNI) of HCCA.

Methods

Using sampling, fixation, dehydration, embedding, sectioning, hematoxylin and eosin (H&E) and immunohistochemical (IHC) staining, and scanning, the characteristics of intrahepatic and extrahepatic PNI in 20 patients with Bismuth type III and type IV HCCA were analyzed with WHLS. Correlation between the characteristics of nerve invasion and tumor size, vascular invasion (artery, portal vein), degree of differentiation, microvascular invasion (MVI), carbohydrate antigen19-9 (CA19-9), and differentiation degree of HCCA was statistically evaluated.

Results

The WHLS of the liver was successfully established, which enabled us to observe intrahepatic and extrahepatic distribution of HCCA and whether surrounding tissues including nervous, blood, and lymph vessels were infiltrated. Extrahepatic and intrahepatic PNI were identified in 20 (100%) patients and 1 (5.0%) patient, respectively. Vessel density decreased in most invaded nerves presented by CD-34, which correlated with 100% of poorly differentiated and 83% of moderately differentiated tumors (P<0.008).

Conclusion

This study established a WHLS of the liver that can be used for clinical diagnosis and research, and confirmed that extrahepatic PNI is prevalent, but intrahepatic nerve invasion is rare and does not accompany the invasion scope of bile ducts in types III and IV HCCA. In addition, moderately and poorly differentiated malignant tumors are more prone to PNI, independent of blood supply.
Immune Privilege Furnishes a Niche for Latent Infection
Authors: Forrester John V. , Mölzer Christine , Kuffova Lucia
Published: March 2022

The microenvironment of the CNS (eye and brain) is fertile ground for infection if the barriers are breached. The result of pathogen invasion is often devastating destruction of tissues. In the eye, inflammation is broadly classified either as “infectious” (i.e. caused by infection) or “non-infectious”. However, increasingly, forms of intraocular inflammation (IOI), which clinically appear to be “non-infectious” turn out to be initiated by infectious agents, suggesting that pathogens have been retained in latent or persistent form within ocular tissues and have reactivated to cause overt disease. A similar pathogenesis applies to latent infections in the brain. Not all CNS tissues provide an equally protective niche while different pathogens escape detection using different strategies. This review summarises how immune privilege (IP) in the CNS may be permissive for latent infection and allow the eye and the brain to act as a reservoir of pathogens which often remain undetected for the lifetime of the host but in states of immune deficiency may be activated to cause sight- and life-threatening inflammation.
Understanding of Future Prescribers About Antimicrobial Resistance and Their Preparedness Towards Antimicrobial Stewardship Activities in Pakistan: Findings and Implications
Authors: Hayat Khezar , Fatima Noor , Umer Muhammad Farooq , Khan Farman Ullah , Khan Faiz Ullah , Najeeb Zia ul Rehman , Ghaffari Muhammad Abuzar , Raza Syed Qasim , Liu Wenchen , Chen Chen , Fang Yu
Published: March 2022

Background: Insufficient antimicrobial-related training for physicians during their undergraduate education could have a negative impact on their prescribing. Unlike previous studies, this study not only explored the understanding and perception of Pakistani medical students about antibiotics and resistance, but also their preparedness towards antimicrobial stewardship programs.

Methods: An online cross-sectional study was undertaken with final-year medical students using a validated questionnaire from January 2021 to May 2021. Descriptive and inference statistics were applied for data analysis.

Results: Of 411 students, only 6.3% had undergone antimicrobial resistance (AMR) training. 16.1% of students believed that antibiotics are effective for viral ailments. More than half of the students agreed that AMR is a major healthcare problem in Pakistan (65.9%). Most students viewed poor infection control practices (66.9%), the use of too many broad-spectrum antibiotics (68.4%) for a longer duration (62.8%) with inadequate doses (67.9%) as the causes of AMR. The student’s preparation was insufficient in interpreting microbiological and pathological results (26.3%), selecting the correct antibiotics (22.1%), and awareness of the antibiotic spectrum (20.9%). The median preparedness score showed significant differences with sex (p = 0.049), age (p < 0.001), institute type (p = 0.014), and family income (p = 0.006).

Conclusion: Pakistani medical students showed adequate understanding of antibiotics, but lacked preparedness for several components of ASPs, including interpretation of microbiological results and spectrum of antibiotics. More steps need to be taken to prepare medical students for AMR and stewardship initiatives adequately.
The NLRP3 Inflammasome in Non-Alcoholic Fatty Liver Disease and Steatohepatitis: Therapeutic Targets and Treatment
Authors: Yu Lili , Hong Wei , Lu Shen , Li Yanrong , Guan Yaya , Weng Xiaogang , Feng Zhiwei
Published: March 2022

Non-alcoholic fatty liver disease (NAFLD) is among the most prevalent primary liver diseases worldwide and can develop into various conditions, ranging from simple steatosis, through non-alcoholic steatohepatitis (NASH), to fibrosis, and eventually cirrhosis and hepatocellular carcinoma. Nevertheless, there is no effective treatment for NAFLD due to the complicated etiology. Recently, activation of the NLPR3 inflammasome has been demonstrated to be a contributing factor in the development of NAFLD, particularly as a modulator of progression from initial hepatic steatosis to NASH. NLRP3 inflammasome, as a caspase-1 activation platform, is critical for processing key pro-inflammatory cytokines and pyroptosis. Various stimuli involved in NAFLD can activate the NLRP3 inflammasome, depending on the diverse cellular stresses that they cause. NLRP3 inflammasome-related inhibitors and agents for NAFLD treatment have been tested and demonstrated positive effects in experimental models. Meanwhile, some drugs have been applied in clinical studies, supporting this therapeutic approach. In this review, we discuss the activation, biological functions, and treatment targeting the NLRP3 inflammasome in the context of NAFLD progression. Specifically, we focus on the different types of therapeutic agents that can inhibit the NLRP3 inflammasome and summarize their pharmacological effectiveness for NAFLD treatment.
Honokiol Inhibits HIF-1α-Mediated Glycolysis to Halt Breast Cancer Growth
Authors: Yi Xianglan , Qi Mengxin , Huang Mingxiang , Zhou Sheng , Xiong Jing
Published: March 2022

Background: Hypoxia-inducible factor-1α (HIF-1α) induces the expression of glycolysis-related genes, which plays a direct and key role in Warburg effect. In a recent study, honokiol (HNK) was identified as one of the potential agents that inhibited the HIF-1α signaling pathway. Because the HIF- 1α pathway is closely associated with glycolysis, we investigated whether HNK inhibited HIF-1α-mediated glycolysis.

Methods: The effects of HNK on HIF-1α-mediated glycolysis and other glycolysis-related genes’ expressions, cancer cells apoptosis and tumor growth were studied in various human breast cancer models in vitro and in vivo. We performed the following tests: extracellular acidification and oxygen consumption rate assays, glucose uptake, lactate, and ATP assays for testing glycolysis; WST-1 assay for investigating cell viability; colony formation assay for determining clonogenicity; flow cytometry for assessing cell apoptosis; qPCR and Western blot for determining the expression of HIF-1α, GLUT1, HK2 and PDK1. The mechanisms of which HNK functions as a direct inhibitor of HIF-1α were verified through the ubiquitination assay, the Co-IP assay, and the cycloheximide (CHX) pulse-chase assay.

Results: HNK increased the oxygen consumption rate while decreased the extracellular acidification rate in breast cancer cells; it further reduced glucose uptake, lactic acid production and ATP production in cancer cells. The inhibitory effect of HNK on glycolysis is HIF-1α-dependent. HNK also downregulated the expression of HIF-1α and its downstream regulators, including GLUT1, HK2 and PDK1. A mechanistic study demonstrated that HNK enhanced the self-ubiquitination of HIF-1α by recruiting two E3 ubiquitin ligases (UFL1 and BRE1B). In vitro, HNK inhibited cell proliferation and clonogenicity, as well as induced apoptosis of cancer cells. These effects were also HIF1α-dependent. In vivo, HNK inhibited tumor growth and HIF-1α-mediated glycolysis.

Conclusion: HNK has an inhibitory effect on HIF-1α-mediated glycolysis in human breast cancer. Our research revealed a new mechanism of HNK as an anti-cancer drug, thus representing a novel strategy to improve the prognosis of cancer.
Moringa oleifera Seed at the Interface of Food and Medicine: Effect of Extracts on Some Reproductive Parameters, Hepatic and Renal Histology
Authors: Attah Alfred F. , Akindele Opeyemi O. , Nnamani Petra O. , Jonah Ugochukwu J. , Sonibare Mubo A. , Moody Jones O.
Published: March 2022

The lipid-rich Seed of Moringa oleifera has been promoted as an effective water clarifier. Aside its vital nutritional application as an emerging food additive, the seed has continued to gain a wider acceptance in various global ethnomedicines for managing several communicable and lifestyle diseases, howbeit, its potential toxic effect, particularly on fertility and pregnancy outcomes has remained uninvestigated; the effect of Moringa oleifera seed (MOSE) aqueous-methanol extracts on fertility and pregnancy outcome, was investigated in vivo using female Wistar rats that were divided into 50, 100, 300 and 500 mg per kilogram body weight. Group six was given Moringa oleifera seed treated water ad-libitum (ad-libitum group). Organs harvested for histological assessment included ovary, uterus, liver and kidney. In addition to HPLC fingerprint and a preliminary peptide detection, we determined the physico-chemical characteristics and mineral content of MOSE using standard methods. Data were analyzed with significance at p ≤ 0.05. There was no significant difference in the estrus cycle, mating index, gestation survival index, gestation index, fertility index and sex ratio among all groups. Gestation length was reduced in some groups. While the male pup birth weight was comparable among the different groups, female pups birth weights were significantly reduced in 50 and 100 mg groups. Anogenital distance indices of female pups in ad libitum group were significantly increased. Pathologies were observed in liver and kidneys of dams while kidneys of pups presented a dose dependent reduction in the number of glomeruli. There were no observed pathological changes in the ovary and uterus. This study showed for the first time in rodents, that the lipid-rich MOSE is unsafe to the kidney of rodents while the lipid-free MOSE appears to be safe at doses up to 300 mg/kg body weight. Findings from this study suggested that the female pups were masculinized. In conclusion, the lipid-rich seed extracts of MOSE appear to be unsafe during pregnancy, induce hepatic and renal toxicity while the lipid-free MOSE excludes inherent toxicity as the hydrophobic part has been linked to toxicity as observed in this study due to the developmental programming effect on female offspring in rodents.
Inspiration for COVID-19 Treatment: Network Analysis and Experimental Validation of Baicalin for Cytokine Storm
Authors: You Jia , Li Huawei , Fan Peng , Yang Xi , Wei Yuanfeng , Zheng Lingnan , Li Zhaojun , Yi Cheng
Published: March 2022

Background: Cytokine storm (CS) is a systemic inflammatory syndrome and a major cause of multi-organ failure and even death in COVID-19 patients. With the increasing number of COVID-19 patients, there is an urgent need to develop effective therapeutic strategies for CS. Baicalin is an anti-inflammatory and antiviral traditional Chinese medicine. In the present study, we aimed to evaluate the therapeutic mechanism of baicalin against CS through network analysis and experimental validation, and to detect key targets of CS that may bind closely to baicalin through molecular docking.

Method: Access to potential targets of baicalin and CS in public databases. We constructed the protein-protein interaction (PPI) network of baicalin and CS by Cytoscape 9.0 software and performed network topology analysis of the potential targets. Then, the hub target was identified by molecular docking technique and validated in the CS model. Finally, GO and KEGG pathway functional enrichment analysis of common targets were confirmed using R language, and the location of overlapping targets in key pathways was queried via KEGG Mapper.

Result: A total of 86 overlapping targets of baicalin and CS were identified, among which MAPK14, IL2, FGF2, CASP3, PTGS2, PIK3CA, EGFR, and TNF were the core targets. Moreover, it was found that baicalin bound most closely to TNF through molecular docking, and demonstrated that baicalin can effectively inhibit the elevation of TNF-α in vitro and in vivo. Furthermore, bioenrichment analysis revealed that the TNF signaling pathway and IL-17 signaling pathway may be potential key pathways for baicalin to treat CS.

Conclusion: Based on this study, baicalin was identified as a potential drug for the alleviation of CS, and the possible key targets and pathways of baicalin for the treatment of CS were elucidated to reveal the main pharmacological mechanisms.
Insight Into the Mechanism of Exercise Preconditioning in Ischemic Stroke
Authors: Zhu Yuanhan , Sun Yulin , Hu Jichao , Pan Zhuoer
Published: March 2022

Exercise preconditioning has attracted extensive attention to induce endogenous neuroprotection and has become the hotspot in neurotherapy. The training exercise is given multiple times before cerebral ischemia, effectively inducing ischemic tolerance and alleviating secondary brain damage post-stroke. Compared with other preconditioning methods, the main advantages of exercise include easy clinical operation and being readily accepted by patients. However, the specific mechanism behind exercise preconditioning to ameliorate brain injury is complex. It involves multi-pathway and multi-target regulation, including regulation of inflammatory response, oxidative stress, apoptosis inhibition, and neurogenesis promotion. The current review summarizes the recent studies on the mechanism of neuroprotection induced by exercise, providing the theoretical basis of applying exercise therapy to prevent and treat ischemic stroke. In addition, we highlight the various limitations and future challenges of translational medicine from fundamental study to clinical application.
Imaging Regional Lung Structure and Function in Small Animals Using Synchrotron Radiation Phase-Contrast and K-Edge Subtraction Computed Tomography
Authors: Bayat Sam , Fardin Luca , Cercos-Pita José Luis , Perchiazzi Gaetano , Bravin Alberto
Published: March 2022

Synchrotron radiation offers unique properties of coherence, utilized in phase-contrast imaging, and high flux as well as a wide energy spectrum which allow the selection of very narrow energy bands of radiation, used in K-edge subtraction imaging (KES) imaging. These properties extend X-ray computed tomography (CT) capabilities to quantitatively assess lung morphology, and to map regional lung ventilation, perfusion, inflammation, aerosol particle distribution and biomechanical properties, with microscopic spatial resolution. Four-dimensional imaging, allows the investigation of the dynamics of regional lung functional parameters simultaneously with structural deformation of the lung as a function of time. These techniques have proven to be very useful for revealing the regional differences in both lung structure and function which is crucial for better understanding of disease mechanisms as well as for evaluating treatment in small animal models of lung diseases. Here, synchrotron radiation imaging methods are described and examples of their application to the study of disease mechanisms in preclinical animal models are presented.
Binding Affinity Characterization of Four Antennae-Enriched Odorant-Binding Proteins From Harmonia axyridis (Coleoptera: Coccinellidae)
Authors: Qu Cheng , Yang Zhao-kai , Wang Su , Zhao Hai-peng , Li Feng-qi , Yang Xin-ling , Luo Chen
Published: March 2022

Harmonia axyridisis an important natural enemy that consumes many agricultural and forestry pests. It relies on a sensitive olfactory system to find prey and mates. Odorant-binding proteins (OBPs) as the first-step of recognizing volatiles, transport odors through sensillum lymph to odorant receptors (ORs). However, little is known about the molecular mechanisms ofH. axyridisolfaction. In this study, fourH. axyridisantenna specific OBP genes,HaxyOBP3,5,12, and15, were bacterially expressed and the binding features of the four recombinant proteins to 40 substances were investigated using fluorescence competitive binding assays. Three-dimensional structure modeling and molecular docking analysis predicted the binding sites between HaxyOBPs and candidate volatiles. Developmental expression analyses showed that the four HaxyOBP genes displayed a variety of expression patterns at different development stages. The expression levels ofHaxyOBP3andHaxyOBP15were higher in the adult stage than in the other developmental stages, andHaxyOBP15was significantly transcriptionally enriched in adult stage. Ligand-binding analysis demonstrated that HaxyOBP3 and HaxyOBP12 only combined with two compounds, β-ionone and p-anisaldehyde. HaxyOBP5 protein displayed binding affinities with methyl salicylate, β-ionone, and p-anisaldehyde (Ki = 18.15, 11.71, and 13.45 μM). HaxyOBP15 protein had a broad binding profile with (E)-β-farnesene, β-ionone, α-ionone, geranyl acetate, nonyl aldehyde, dihydro-β-ionone, and linalyl acetate (Ki = 4.33–31.01 μM), and hydrophobic interactions played a key role in the binding of HaxyOBP15 to these substances according to molecular docking. Taken together, HaxyOBP15 exhibited a broader ligand-binding spectrum and a higher expression in adult stage than HaxyOBP3, 5, and 12, indicating HaxyOBP15 may play a greater role in binding volatiles than other three HaxyOBPs. The results will increase our understanding of the molecular mechanism ofH. axyridisolfaction and may also result in new management strategies (attractants/repellents) that increase the biological control efficacy ofH. axyridis.
“Let Us All Enjoy the Fish”: Alternative Pathways and Contingent Histories of Collective Action and Governance Among Maritime Societies of the Western Peninsular Coast of Florida, USA, 100–1600 CE
Authors: Pluckhahn Thomas J. , Jackson Kendal , Rogers Jaime A.
Published: March 2022

Ethnographers have ably documented the great extent and diversity of social institutions that contemporary fishers and shellfishers employ to collectively manage common property resources. However, the collective action regimes developed among ancient maritime societies remain understudied by archaeologists. We summarize research into the development and form of collective action among the maritime societies of the western peninsular coast of Florida, USA, drawing on our own recent work in the Tampa Bay area and previous work elsewhere in the region, especially the Calusa area to the south. Archaeological evidence suggests that collective action became more important in Tampa Bay in the first centuries CE, probably owing to a marine transgression that resulted in more productive estuaries. Groups here staked claims to productive estuarine locations through the founding of villages, the building of mounds, and the construction of relatively simple marine enclosures. Historically, these changes resulted in societies of relatively small scale and limited authoritarian government. In contrast, collective action developed later in the Calusa area, may have begun in relation to resource scarcity than plenty, and may been founded in kinship rather than in public ritual. Collective action in the Calusa area resulted in projects of greater scale and complexity, providing a foundation for more hierarchical and authoritarian social formations.